Teses / dissertações: "Animal model of infection"

1

Maglennon, G. A. "Study of papillomavirus latent infection in an animal model". Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1306763/.

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Papillomaviruses cause a wide spectrum of benign and neoplastic diseases in humans and animals. They may also cause infections that are characterised by the absence of clinical signs of disease and some of these may represent viral latency. Many viruses have a latent stage of their life cycle and papillomaviruses appear to be no different. For example, some low-risk human papillomavirus types such as HPV-11 and HPV-6 can cause infections that resemble latency. It has recently been shown that rabbit oral papillomavirus (ROPV) is an appropriate model of these virus types. Infection of the tongue mucosa with ROPV leads to the formation of benign papillomas that form and regress within a matter of weeks. In this thesis, we show that ROPV is a suitable model system for the study of latent papillomavirus infections. The regression of ROPV papillomas is followed by the persistence of viral DNA and RNA in the absence of clinical signs of disease. Persistence of ROPV DNA is generally restricted to basal epithelial cells at sites of previous infection. Low copy numbers of viral DNA in the basal layer are compatible with infection remaining in only a subset of these cells (possibly epithelial stem cells). Typically there is no amplification of viral DNA in the upper layers of the epithelium. ROPV proteins are undetectable during latency suggesting that the productive stages of the life cycle are not completed. Low levels of ROPV early transcripts are detectable and it is possible that early proteins are necessary to allow stable maintenance of viral episomes in basal epithelial cells. We attempt to demonstrate the ability of latent ROPV infection to reactivate to form clinical disease. Evidence of spontaneous reactivation was seen on one occasion, but efforts to initiate reactivation by immunosuppressing rabbits were hampered by the toxicity of the drugs used. However, our preliminary data suggest that immunosuppression of rabbits can cause reactivation of latent ROPV.

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2

Wen, Li. "Immune responses to vaginal viral infection in a mouse model". Thesis, The University of Sydney, 1998. https://hdl.handle.net/2123/27666.

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Viral infection in the female reproductive tract is a global health problem, with high morbidity and mortality worldwide. However, immune protection of the female reproductive tract against virus infection is poorly understood. The aim of the study described in this thesis was to investigate the immune responses to vaginal West Nile virus (WNV) infection in an experimental mouse model, in an attempt to characterize the immune mechanisms involved in protecting the host against viral infection in the female genital tract. WNV is a neurotropic flavivirus which can infect both humans and animals, and which belongs to a virus family causing serious disease throughout the world. The mouse model of genital tract infection with WNV is not representative of the human situation; nevertheless, such models may be an appropriate tool to identify virus antigen components which may be effective in eliciting protective immunity at the genital mucosal surface. The progesterone-dominated mouse model is mainly used in the experiments of the present study. This model impairs the vaginal epithelial barrier, increasing the susceptibility of adult mice to vaginal virus infection. Virus-infected cells were detected in the vaginal epithelium of BALB/c mice from day 2 to day 7 after infection by immunoperoxidase labelling of WNV protein. A series of immune responses were evoked following vaginal WNV infection. Specific anti-WNV IgM and IgG antibodies were detected in vaginal washing by ELISA, associated with an increasing lgM and IgG containing cell infiltration, and a significant B220+ B cell infiltration in the vaginal mucosa. A correlated accumulation of B220+ B cells in the iliac lymph nodes (ILN) was detected by flow cytometry. B cells presented a major cell population infiltrating in the vagina and proliferation in the ILN indicates that humoral immunity plays an important role against vaginal WNV infection. Locally produced IgG is the major antibody contributing to anti-WNV responses to infection in the vagina. The role of cellular immunity to protect animal against vaginal WNV infection was also examined in this study. The expression of major histocompatibility complex class II (MHC-II) molecules in the vaginal mucosa was upregulated after infection, which suggests the possibility that interferon-y (IFN-y) participates in the immune response, since MHC-11 expression is increased by IFN-Y· The infiltration of CD4 helper T cells (Th cells) and CD8 (cytotoxic lymphocytes [CTL]) in the vagina were also significant increased after infection. These responses were coincident with a significant proliferation of CD4 and CD8 T cells from day 3 after infection. These results suggest IFN-y, CD4 T cells play an important role against WNV vaginal infection. ICAM-1, VCAM-1 and CD44 adhesion molecules were involved in response to infection. Upregulation expression of ICAM-1 and CD44, and a de novo induction of VCAM-1 expression in the vagina were detected after virus infection, and these responses paralleled the infiltration of immune cells in the vagina. Such responses were significantly accelerated and of greater magnitude in intravaginal (IVAG) immune, intraperitoneal (i.p.) immune and intradermal (i.d.) immune mice after intravaginal challenge with WNV, and this immunity completely protected animals against subsequent vaginal infection. Unexpectedly, the immune responses in i.d. immune mice were much stronger than IVGA immune mice. Moreover, there was a markedly higher CD4 and CD8 T cell infiltration and VCAM-1 expression in the vaginal mucosa, a significantly higher proliferation of CD4 and CD8 T cells in ILN, and a similar B220 B cell infiltration in the vagina and proliferation in the ILN. This suggests that i.d. immunization may be a possible route to induce immunity for prevention of vaginal viral infection. The role of IL-5 in host immunity to vaginal WNV infection was investigated by using IL-5 gene knockout (GKO) mice. It was found that IL-5 GKO mice were more susceptible to WNV vaginal infection. Thus, infected cells could be detected in vagina epithelium earlier and remained for a longer duration than in normal control mice. The susceptibility of GKO mice to vaginal WNV infection correlated with delayed specific anti-WNV IgM and lgG antibodies in vaginal washings, lower numbers of IgG-containing plasma cell infiltrating the vagina, and a significantly lower B220 B cell and CD8 T cell infiltrate at certain time points compared normal control mice. However, a significant CD4 T cell infiltration and significant upregulation of expression of ICAM-1, VCAM-1 and MHC-II molecules in the vaginal mucosa at the later stage of infection, implies a compensatory mechanism may exist. The expression of IL-4 mRNA in the vaginal mucosa was enhanced after virus infection, coincident with the detection of specific anti-WNV lgG, suggesting that IL-4 contributed to specific antibody production and thus contributes to the eradication of WNV vaginal infection. In this study, it was found that BALB/c mice are more susceptible to WNV vaginal infection than C57BL/6 mice, since the mortality to WNV vaginal infection in BALB/c mice was 10-fold higher than C57BL/6, and WNV-infected cells were detected in vaginal epithelium from day 2 to day 7 after infection in BALB/c mice, while these cells could only be detected on day 5 after infection in C57BL/6 mice. The susceptibility of BALB/c mice to WNV vaginal infection correlated with a markedly lower B220 B cell and CD8 T cell infiltration in the vagina of this strain than in C57BL/6 mice. These results indicate that immune responses to vaginal WNV infection is genetically determined, varying in different mouse strains. In a pilot experiment, the oestrogen-dominated model was used to compare immunity to intravaginal WNV infection in animals with a different hormonal status. Oestrogen-dominated mice were refractory to vaginal infection, but such resistance gave no protection against secondary virus challenge in the progesterone phase. These mice presented a similar pattern of epithelial cell infection as progesterone dominated naive mice in primary infection, though the infiltration of B220 B cells and CD8 T cells in the vagina of these mice was higher than in progesterone dominated naive mice after infection, and the proliferation of total lymphocytes and CD8 T cells in ILN of these mice was also higher than in progesterone-dominated naive mice in the early course of the infection. Interestingly, the infiltration of CD4+ T cells in the vagina of virus-challenged progesterone phase immune mice was significant higher than oestrogen phase immune mice after rechallenge, and the proliferation of total lymphocytes, B220 B cells and CD8 T cells in ILN of the former was higher than latter at day 1 after challenge. These results suggest that the weaker and different profile of immunity initiated in the oestrogen phase does not produce full protection against secondary vaginal challenge. The results from this study provides basic information about immune responses to vaginal virus infection and as such may contribute to the long-term development of vaccines to prevent the sexual transmission of viruses.

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3

Shrief, Raghdaa. "Surrogate Markers of Infection Suitable for Monitoring Infectious Burden in Animal Models of Aspergillosis". Thesis, University of Manchester, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.525921.

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4

Shanmuganathan, Subathra Devi. "The woodchuck as an animal model for the study of the immune response in hepadna virus infection". Thesis, University College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.298130.

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5

CARRARO, MONICA. "Identification of infection biomarkers in a murine model of pneumonia by Streptococcus pneumoniae". Doctoral thesis, Università di Siena, 2018. http://hdl.handle.net/11365/1037742.

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Streptococcus pneumoniae infections remain a public health problem despite the availability of vaccines. In order to study alternative preventive strategies it is essential to have a reliable animal model of the infection. To date, the majority of vaccine efficacy evaluation studies still rely on direct read-outs such as the survival rate after challenge and the CFU counts in blood and in the lungs. A murine model of lung infection was developed in which animal death was not the endpoint: clinical parameters, cellular lung infiltrate and systemic immune response were evaluated in (i) infected mice, (ii) vaccinated mice, and (iii) vaccinated and challenged mice. All these parameters were used to identify biomarkers of sublethal pneumonia and protection following vaccination with the pneumococcal conjugate vaccine. Female C57BL/6 mice were infected with different doses of S. pneumoniae strain TIGR4, the dose of 1.6 x 107 CFUs was capable to induce measurable signs of the disease with a 100% survival and was therefore used for subsequent experiments. Histological examination and flow cytometry analysis of the lung tissue were performed at different time-points after bacterial inoculation. Data revealed that absolute numbers of the cell populations evaluated through flow cytometry were significantly different 7 days after the infection from those of uninfected mice, and histological evaluation of the lungs at this time-point also revealed the presence of leukocyte infiltrate. The presence of the infiltrate represented a biomarker of infection. When mice were vaccinated prior to pneumococcal challenge, they showed no weight loss and a mild infiltrate in the lungs. The absence of the infiltrate in relation with mild clinical signs and a good humoral response defined the protected phenotype. The type of immune response mounting following interaction of the immune system with S. pneumoniae was evaluated using mice splenocytes re-stimulated in vitro with inactivated TIGR4. The production of 23 cytokines was measured, revealing that splenocytes started to react to in vitro re-stimulation at 4 days after infection and peaking 7 days after infection. A predominant production of IFN-γ and IL-17 was observed in infected mice, while this profile was skewed to Th2 characteristic cytokines such as IL-4 and IL-5 when mice had received the vaccine. These features, together with cellular infiltrates observed in the lungs, can be considered biomarkers of protection that could be used to study the protection induced by a vaccine candidate using parameters other than the survival rates and the CFU counts. We identified measurable and reliable biomarkers of pneumococcal pneumonia that could be investigated in vaccine efficacy studies and could become tools to develop new immunization strategies against S. pneumoniae.

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6

Shen, Hong. "Hepatitis C infection models". Thesis, Paris 5, 2012. http://www.theses.fr/2012PA05T016.

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L'hépatite C (VHC) est l'une des causes principales de maladies du foie dans le monde, qui représentent un risque élevé d'évoluer vers la cirrhose et le carcinome hépatocellulaire. Actuellement, le traitement standard de l’infection par le VHC est l'interféron pégylé-(peg-IFN) et la ribavirine. Bien que le taux de la réponse virale soutenue (RVS) au traitement se soit améliorée au cours de ces années, cette thérapie n'est pas efficace chez tous les patients. En outre, plusieurs effets secondaires toxiques, de complications et le coût élevé limitent la compliance du patient et l'efficacité du traitement. Il n'existe pas de modèle simple d'infection par le VHC et il est nécessaire de développer des modèles in vitro et in vivo utiles pour étudier la physiopathologie de l'infection par le VHC, y compris les événements précoces de l'infection aiguë (l'entrée du virus, des mécanismes immunologiques et génétiques prédictifs) ainsi que l'évaluation de la puissance des médicaments antiviraux contre le VHC. Nous rapportons ici, nos efforts visant à développer des modèles appropriés de l'infection par le VHC. Dans un premier temps, nous avons établi un modèle de petit animal pour étudier l'infection par le VHC. Tupaia est un petit animal, apparenté aux primates et peu couteux. Dans notre travail, nous avons étudié la susceptibilité du tupaia à l'infection par VHC. Douze tupaias adultes ont été inoculés avec le VHC provenant de sérum de patient et d'ARN du VHC (génotype 1a). Trois jeunes tupaias ont été artificiellement nourris pendant un mois et ensuite inoculés par le VHC provenant de sérum du patient. L'ARN du VHC, les anticorps anti-VHC et l’évolution des quasi-espèces du VHC ont été déterminées chez l'animal avant et après l'inoculation. L'infection transitoire et intermittente s'est produite chez deux des 3 jeunes tupaias et l’infection chronique par le VHC s’est produite chez quatre tupaias sur 12 tupaias adultes. Le tupaia devrait représenter un modèle utile pour l'étude de l’infection chronique par le VHC. Dans une deuxième étape, un système de culture in vitro d'hépatocytes primaires de Tupaia a été établi, dans lequel l'infection par le VHC ne pouvait être bloquée ni par le CD81 soluble ni par des anticorps dirigés contre le CD81. Pour comprendre ces résultats, nous avons cloné, séquencé la grande boucle extracellulaire (LEL) du CD81 chez le Tupaia et analysé l'interaction de la protéine d’enveloppe E2 du VHC avec la LEL du CD81 chez le Tupaia par un test « enzyme-linked immunosorbent assay » (EIA). Nous avons constaté que chez le Tupaia, la séquence d'acides aminés du LEL de CD81 qui se lie au VHC présentait en 6 résidus d'acides aminés différents par rapport à la séquence humaine et la capacité de LEL de CD81 à se lier à la proteine d’enveloppe E2 du VHC a également diminuée. La structure différente de CD81 chez l’homme et chez le tupaia pourrait expliquer l'altération de l'interaction entre CD81 et la proteine E2 du VHC. Ce résultat démontre un rôle important de LEL du CD81 pour l'entrée du VHC. Dans une troisième étape, nous avons développé un modèle ex vivo de culture de tranches de foie humain et leur infection par le VHC. Le développement de lignées cellulaires provenant d’hepatocarcinome, permissives à la réplication du VHC, a fourni d'importants nouveaux outils virologiques pour étudier les mécanismes de l'infection par le VHC, mais ce modèle expérimental reste relativement éloigné des conditions physiologiques et pathologiques. Nous rapportons ici le développement d'un nouveau modèle ex vivo utilisant la culture de tranches de foie humain adulte, démontrant, pour la première fois, la capacité d’isolats primaires ainsi que JFH -1, H77/C3, Con1/C3 (HCVcc), de répliquer et de produire de novo des particules virales infectieuses ayant un titre viral élevé…
Hepatitis C virus (HCV) is one of the major causes of liver disease all over the world which has a high risk to progress to cirrhosis and hepatocellular carcinoma. Currently, the licensed standard treatment of HCV infection is Pegylated-interferon (peg-IFN) and ribavirin. Although the sustained viral response (SVR) rate of treatment has improved during these years, this therapy is not effective in all patients. In addition, several toxic side effects, complication and high cost limit the patient compliance and the efficacy of the treatment. There is no easy model of HCV infection and it is necessary to develop useful in vitro and in vivo models to study the pathobiology of HCV infection, including early events of acute infection (viral entry, immunological mechanisms, and genetic predictors) as well as the evaluation of the potency of the HCV antiviral drugs. We report here in our efforts in developing suitable models of HCV infection. In a first step, we preliminary established a small animal model to study HCV infection. Tupaia is a small, closed related to primate and cost-effective animal. In our work, we investigated the susceptibly of tupaia to HCV infection. Twelve adult tupaias were inoculated with native HCV from patient serum and full-length HCV RNA (Genotype 1a). Three young tupaias were artificially breeded for a month and then inoculated by native HCV from patient serum. HCV RNA, anti-HCV and HCV quasi species evolution were determined in the animal before and after inoculation. Transient and intermittent infection occurred in two among 3 young tupaias and HCV chronic infection occurred in four among 12 adult tupaias. Tupaia should represent a useful model for study HCV chronic infection. In a second step, an in vitro culture system of primary tupaia hepatocytes has been established in which HCV infection could be blocked neither by the soluble CD81 nor by antibodies against CD81. To understand these results, we cloned, sequenced the large extracellular loop (LEL) of tupaia CD81 and analyzed the interaction of HCV E2 with the tupaia CD81 LEL by enzyme-linked immunosorbent assay (EIA). We found that in the tupaia the amino acids sequence of HCV CD81 LEL presented in 6 different amino acid residues compared with human CD81 LEL sequence and the CD81 LEL ability to bind to HCV E2 was also decreased. The different structure of CD81 between human and tupaia could explain the alteration of the interaction between HCV E2 and CD81. This result demonstrated an important role of CD81 LEL for HCV entry. In a third step, we developed an ex vivo model of human liver slices culture and their infection with HCV. The development of human cultured HCV-replication-permissive hepatocarcinoma cell lines has provided important new virological tools to study the mechanisms of HCV infection; however this experimental model remains distantly related to physiological and pathological conditions. Here, we report the development of a new ex vivo model using human adult liver slices culture, demonstrating, for the first time, the ability of primary isolates to undergo de novo viral replication with the production of high titer infectious virus, as well as JFH-1, H77/C3, Con1/C3 (HCVcc). This experimental model was validated by demonstrating the HCV neutralization or HCV inhibition, in a dose-dependent manner, either by CD81 or E2 specific antibodies or convalescent serum from a recovered HCV patient, or by anti-viral drugs. This new ex vivo model represents a powerful tool for studying the viral life cycle, dynamics of virus spread in the liver and also for evaluating the efficacy of the new antiviral drugs. In the last step, we evaluated the efficacy of the new antiviral drugs with our ex vivo model of human adult liver slices. HCV NS3/4A protease is essential for viral replication and has been one of the most important target for developing specific antiviral drug

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7

Furr, Patricia Mary. "The development and value of animal models of mycoplasmal infection". Thesis, Open University, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.358598.

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8

Peterson, Christopher. "Evaluation of Therapeutics for an Enterovirus 71 Infection in an AG129 Mouse Model". DigitalCommons@USU, 2018. https://digitalcommons.usu.edu/etd/7278.

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Discovered in 1969 in California, enterovirus 71 (EV-71) is a serious cause of disease in young children. It is one of the major causative agents of hand, food, and mouth disease (HFMD), and can produce neurological complications, such as meningitis, encephalitis, and an acute flaccid paralysis. For serious cases, the fatality rate can be up to 26%, almost exclusively in young children. While the virus was initially discovered in the United States, it was soon detected in the Eastern hemisphere, causing outbreaks in Europe and Asia. The largest outbreak occurred in Taiwan in 2008, with approximately 490,000 cases and 128 fatalities. However, despite the seriousness of EV-71, there are currently no approved antiviral treatments. Physicians rely on supportive care and the off-label use of a purified antibody mixture, intravenous immunoglobulin, for treatment. Part of the difficulty in developing antivirals for EV-71 is a lack of drug testing in animal models. Animal testing is a crucial step in drug development, determining which compounds will progress to clinical trials in humans. However, viruses that cause disease in humans do not necessarily cause disease or the same type of disease in animals. As such, viruses often need to be adapted before they can cause disease in their animal hosts. Adaption isn’t always successful and can result in a virus that produces disease that is unlike that seen in humans. Furthermore, some animal models can produce disease only under a strict set of conditions, such as newborn mice. Sometimes these animal model conditions may be impractical for testing potential treatments. At the Institute for Antiviral Research (IAR), we developed an animal model for EV-71 in four-week-old AG129 mice. AG129 mice lack the alpha, beta, and gamma interferon receptors, making them immunocompromised. Being immunocompromised, these mice are more susceptible to infection, including infection from human viruses. In our model, EV-71 infection produces neurological signs, including a rear-limb paralysis (similar to the paralysis seen children with EV-71). The virus is also lethal in these animals, which provides an observable and consistent baseline for evaluating potential drugs. We assessed twenty-four potential treatments in our EV-71 model. Two compounds, STF434 and STF1019, provided 30% and 87% protection against mortality. Intravenous immunoglobulin was also examined and found to be about 50% protective against mortality, depending on the dose and time of administration. Intravenous immunoglobulin also reduced inflammatory modulators (cytokines) in the brain and spinal cord. We consider this to be highly relevant, given that inflammation is a serious component of EV-71 infection.

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9

Xi, Jin [Verfasser], e Thomas [Akademischer Betreuer] Iftner. "An Out-bred Animal Model of Cottontail Rabbit Papillomavirus Latent Infection / Jin Xi ; Betreuer: Thomas Iftner". Tübingen : Universitätsbibliothek Tübingen, 2019. http://d-nb.info/1197610812/34.

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10

Clasper, Jonathan Charles. "Secondary intramedullary nailing of the tibia in an animal model of an external fixator pin track infection". Thesis, University of Southampton, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268414.

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11

Richetto, J. "LATE PRENATAL INFECTION AND NEURODEVELOPMENTAL DISORDERS: CHARACTERIZATION OF AN IMMUNE-MEDIATED MOUSE MODEL". Doctoral thesis, Università degli Studi di Milano, 2014. http://hdl.handle.net/2434/244209.

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Compelling evidence suggests that the aetiology of multifactorial and multisymptomatic psychiatric diseases include exposures to adverse events during prenatal and early postnatal life, which may disrupt the correct maturation of neural system and lead to long-lasting changes in brain function. Prenatal insults, and in particular prenatal infection, could thus act as a “primer” for the neuropsychiatric route, even if the specificity of the illness that develops is strongly influenced by the genetic and environmental context in which the process occurs (Meyer, 2013b). A similar concept of “early-life programming of adult disease” has been put forward by the seminal work of David Barker conducted in the context of cardiovascular disease (Dover, 2009), suggesting that specific environmental factors acting during sensitive prenatal or early postnatal developmental periods can induce persistent changes in physiological, emotional and behavioural functions throughout life (Bale et al, 2010). Against this background, the aim of my PhD thesis was to investigate and further characterize an established murine model of prenatal infection that is based on maternal administration of the viral mimic polyriboinosinic-polyribocytidilic acid [Poly(I:C)], focusing on different aspects of the relationship between altered neurodevelopment and psychiatric disease. First, I will give an overview of the state of the art regarding the association between prenatal infection and different neurodevelopmental illnesses as identified by human epidemiological studies, and then I will present our preclinical results obtained in an experimental model system of prenatal immune activation.

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12

Clancy, Chad S. "Male Reproductive Infection and Sexual Transmission of Zika Virus in an Immunocompromised Mouse Model". DigitalCommons@USU, 2019. https://digitalcommons.usu.edu/etd/7478.

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Zika virus (ZIKV) is a sexually transmitted viral infection most frequently transmitted by mosquitoes. The source of infectious virions in the male reproductive tract has yet to be elucidated. The goals of the studies included developing and characterizing two mouse models for reproductive transmission studies and demonstration of sexual transmission of virus via artificial insemination. The mouse strains used in the study lacked receptors to interferon molecules, key signaling proteins of the host immune response. Inflammation severity was assessed during acute disease, 5-11 days after infection using a novel histopathology grading system. ZIKV proteins and genome were initially detected in epididymal epithelial cells in males. Inflammation was first observed in the epididymis and progressed to the testicle in both AG129 and Ifnar-/- males. Infection of Ifnar-/- mice may better recapitulate Zika virus pathology in humans due to milder histopathologic lesions, the presence of histologically normal sperm in epididymal tubules, and an ability to survive the acute phase of disease. In further studies, male Ifnar-/- mice were challenged subcutaneously with ZIKV. Artificial insemination fluid derived from experimentally infected males showed positive sexual transmission at 7 days post infection (DPI) but not 35 or 70 DPI. These studies show passage of virus from epididymal flush and seminal plasma to females via insemination during acute ZIKV disease in males and provides a model for sexual transmission of ZIKV.

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13

Parsons, Sven David Charles. "Natural animal model systems to study tuberculosis". Thesis, Stellenbosch : University of Stellenbosch, 2010. http://hdl.handle.net/10019.1/4505.

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Thesis (PhD (Molecular Biology and Human Genetics))--University of Stellenbosch, 2010.
ENGLISH ABSTRACT: The growing global epidemic of human tuberculosis (TB) results in 8 million new cases of this disease and 2 million deaths annually. Control thereof will require greater insight into the biology of the causative organism, Mycobacterium tuberculosis, and into the pathogenesis of the disease. This will benefit the design of new vaccines and diagnostic assays which may reduce the degree of both disease transmission and progression. Animal models have played a vital role in the understanding of the aetiology, pathogenesis, and treatment of TB. Much of such insight has been obtained from experimental infection models, and the development of new vaccines, for example, is dependant on these. Nonetheless, studies utilising naturally occurring TB in animals, such as those which have investigated the use of interferon-gamma release assays (IGRA) for its diagnosis, have contributed substantially to the body of knowledge in this field. However, there are few such examples, and this study sought to identify and investigate naturally occuring animal TB in South Africa as an opportunity to gain further insight into this disease. During the course of this study, the dassie bacillus, a distinctly less virulent variant of M. tuberculosis, was isolated from a rock hyrax from the Western Cape Province of South Africa. This has provided new insight into the widespread occurrence of this organism in rock hyrax populations, and has given impetus to further exploring the nature of the difference in virulence between these pathogens. Also investigated was M. tuberculosis infection in dogs in contact with human TB patients. In so doing, the first reported case of canine TB in South Africa was described, v a novel canine IGRA was developed, and a high level of M. tuberculosis infection in these animals was identified. This supports human data reflecting high levels of transmission of this pathogen during the course of human disease. Additionally, the fact that infected companion animals may progress to disease and potentially act as a source of human infection was highlighted. However, an attempt to adapt a flow cytometric assay to study cell-mediated immune responses during canine TB revealed the limitations of such studies in species in which the immune system remains poorly characterised. The use of IGRAs to diagnose TB was further explored by adapting a human assay, the QuantiFERON-TB Gold (In-Tube Method), for use in non-human primates. These studies have shown that such an adaption allows for the sensitive detection of TB in baboons (Papio ursinus) and rhesus macaques (Macaca mulatta) and may be suitable for adaption for use in other species. However, they have also evidenced the limitation of this assay to specifically detect infection by M. tuberculosis. Finally, to contextualise the occurrence of the mycobacterial infections described above, and other similar examples, these have been reviewed as an opinion piece. Together, these investigations confirm that animal models will continue to make important contributions to the study of TB. More specifically, they highlight the opportunities that naturally occuring animal TB provides for the discovery of novel insights into this disease.
AFRIKAANSE OPSOMMING: Wêreldwye tuberkulose (TB) epidemie veroorsaak agt miljoen nuwe gevalle en twee miljoen sterftes jaarliks. Ingryping by die beheer hiervan vereis begrip van die biologie van die mikroörganisme Mycobacterium tuberculosis, die oorsaak van TB, asook van die patogenese van die siekte self. Hierdie kennis kan lei tot ontwerp van nuwe entstowwe en diagnostiese toetse wat gevolglik beide die oordrag- en vordering van die siekte mag bekamp. Dieremodelle speel lankal 'n rol in ons begrip van die etiologie-, patogenese- en behandeling van TB. Insig is grotendeels verkry vanaf eksperimentele infeksiemodelle, en ontwikkeling van entstowwe, onder andere, is afhanklik van soortgelyke modelle. Desnieteenstaande, studies wat natuurlike TB voorkoms in diere ondersoek, byvoorbeeld dié wat op die ontwikkeling van interferon-gamma vrystellingstoetse (IGVT) fokus, het merkwaardige bydrae gemaak tot kennis en begrip in hierdie studieveld. Daar is slegs enkele soortgelyke voorbeelde. Om hierdie rede is die huidige studie uitgevoer waarbinne natuulike diere-TB geïdentifiseer en ondersoek is in Suid-Afrika om verdere kennis en insig te win aangaande TB. Die "dassie bacillus", bekend om beduidend minder virulent te wees as M. tuberculosis, is tydens hierdie studie geïsoleer vanuit 'n klipdassie (Procavia capensis) in die Wes-Kaapse provinsie, Suid-Afrika. Insig in die wydverspreide voorkoms van hierdie organisme in klipdassie bevolkings is gevolglik verkry en verskaf momentum om die aard van verskil in virulensie tussen dié patogene te bestudeer. vii Voorts is M. tuberculosis infeksie bestudeer in honde wat in kontak is met menslike TB pasiënte en word die eerste geval van honde TB dus in Suid-Afrika beskryf. In hierdie groep diere, is 'n hoë vlak van M. tuberculosis infeksie geïdentifiseer deur gebruik te maak van 'n nuut ontwikkelde IGVT vir die diagnose van honde TB. Gevolglik ondersteun dié studie bevindinge van menslike studies wat toon dat besondere hoë vlakke van M. tuberculosis oordrag voorkom gedurende die verloop van die siekte. Verder toon die studie dat geïnfekteerde troeteldiere 'n bron van menslike infeksie kan wees. 'n Poging om 'n vloeisitometriese toets te ontwikkel om die aard van selgefundeerde immuunreaksies te bestudeer in honde met TB toon die beperkings van dergelike studies in spesies waarin die immuunsisteem gebrekkig gekarakteriseer is. Die gebruik van IGVT'e in die diagnose van TB is verder ondersoek deur 'n menslike toets (QuantiFERON-TB Gold, In-Tube Method) aan te pas vir die gebruik van nie-menslike primaat gevalle. Hierdie studies toon gevolglik dat so 'n aanpassing toepaslik is vir hoogs sensitiewe deteksie van TB in chacma bobbejane (Papio ursinus) en rhesus ape (Macaca mulatta), en mag ook aangepas word vir gebruik in ander spesies. Tog word die beperkings van hierdie toets om infeksie wat spesifiek deur M. tuberculosis veroorsaak uitgelig. Ter afsluiting word hierdie studie in konteks geplaas deur 'n oorsig te gee van bogenoemde- en soortgelyke gevalle van dierlike infeksie deur mikobakterieë in Suid-Afrika. Hierdie studies bevestig dat dieremodelle steeds belangrike toevoegings maak tydens die bestudering van TB en lig veral die moontlikhede uit dat bestudering van natuulike TB in diere kan lei tot die ontdekking van nuwe insigte ten opsigte van die siekte self.

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Calabro, Lorenzo. "Improving in vivo models of fracture fixation associated osteomyelitis". Thesis, Queensland University of Technology, 2013. https://eprints.qut.edu.au/64112/1/Lorenzo_Calabro_Thesis.pdf.

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This project’s aim was to create new experimental models in small animals for the investigation of infections related to bone fracture fixation implants. Animal models are essential in orthopaedic trauma research and this study evaluated new implants and surgical techniques designed to improve standardisation in these experiments, and ultimately to minimise the number of animals needed in future work. This study developed and assessed procedures using plates and inter-locked nails to stabilise fractures in rabbit thigh bones. Fracture healing was examined with mechanical testing and histology. The results of this work contribute to improvements in future small animal infection experiments.

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Pearce, Emma St Clair. "Development of antibodies and characterisation of the humoral immune responses in a surrogate animal model for hepatitis C virus (HCV)". Thesis, Queen Mary, University of London, 2017. http://qmro.qmul.ac.uk/xmlui/handle/123456789/25978.

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Hepatitis C virus (HCV) infection has become a global public health concern with over 130 million people chronically infected and over 350,000 deaths every year from HCV-related liver diseases. GB virus-B (GBV-B) infection in tamarins is a surrogate model for acute HCV infection. Whilst HCV infection commonly leads to chronicity, GBV-B is naturally cleared. To better understand this natural clearance, this project aimed to study the associated humoral immune response to GBV-B. Additionally, GBV-B-specific antibodies were produced with the aim of characterising the pathology of the virus. Previously, there was no available GBV-B neutralisation assay to identify antibodies in this animal model. Therefore, a GBV-B neutralisation assay, based on a method that is known to be successful for the closely-related HCV, was developed. This method involved producing pseudotyped retroviral particles (PV) expressing the GBV-B envelope that could infect a human hepatocarcinoma cell line. GBV-B PV production was confirmed by western blotting. Future studies can now test archived tamarin sera in this assay for the presence of neutralising antibodies. Neutralising antibodies found through this model could be epitope mapped, and incorporated into HCV vaccine design strategies. To study the pathology of GBV-B infection, GBV-B-specific antibodies were also produced using two techniques in parallel- classical hybridoma technology and ribosome display. Antibodies targeting the nucleocapsid core protein of GBV-B have been previously detected in tamarins and served as the target for production of GBV-B antibodies using both aforementioned technologies. GBV-B core-specific antibodies were successfully isolated using both technologies and can now be used in downstream techniques, such as immunohistochemistry, to characterise the pathology of GBV-B infection thereby further validating the use of the animal model.

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Campbell, Regenia Beth Phillips. "Arrested and Aberrant: Effects of Amoxicillin in a Murine Model of Chlamydial Infection". Digital Commons @ East Tennessee State University, 2013. https://dc.etsu.edu/etd/2269.

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Chlamydia trachomatis is the most common sexually transmitted bacterial disease agent worldwide, and, though frequently asymptomatic, can cause extreme pathology including infertility. Chlamydial species exhibit a unique biphasic developmental cycle. Once attached to a cell surface, infectious elementary bodies (EB) are internalized within an inclusion, the membrane-bound structure in which EB transform to noninfectious, replicable reticulate bodies (RB). After multiple rounds of division, RB condense to form EB, which are released and can infect new host cells. In culture, exposure to stressors, such as beta-lactam antibiotics, induce chlamydiae to reversibly detour from normal development into a noninfectious, viable state termed persistence. Cell culture data suggest that persistent forms are resistant to azithromycin (AZM), a front-line antibiotic, and are able to alter the host transcriptome. Though persistence has been described in culture for over 50 years, whether or not it: i) occurs in vivo; and ii) influences chlamydial pathogenesis, transmission and therapy has remained unresolved. To address these questions, we developed an animal model of persistent chlamydial infection using amoxicillin (AMX) treatment. AMX exposure decreased shedding of infectious chlamydiae in C. muridarum-infected mice without affecting chlamydial viability, demonstrating the presence of persistent chlamydiae. Shedding of infectious EB resumed following AMX cessation. Shedding data and microarray analyses suggested that host immunity might limit chlamydia’s exit from persistence in our model. Thus, we hypothesized that cyclophosphamide (CTX) treatment would increase the magnitude of chlamydial shedding observed after AMX-treatment cessation. CTX treatment increased post-AMX shedding by more than 10-fold compared to AMX-only controls. To determine whether persistent chlamydiae are resistant to antibiotic eradication in vivo, we induced persistence by administering AMX and treated mice with various AZM dosing regimes. Persistently infected mice demonstrated increased treatment failure following AZM therapy compared to productively infected controls. These data suggest that persistent chlamydiae are refractory to treatment in vivo and provide an explanation for the observation that treatment fails in some patients. In addition to creating the first fully characterized, experimentally tractable, in vivo model of chlamydial persistence, these experiments provide evidence that persistent/stressed chlamydial forms may serve as a long-term reservoir of infectious organisms in vivo.

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Akiyama, Hisashi. "Construction of New Simian/Human Immunodeficiency Chimeric Viruses (SHIVs) towards a Better Animal Model for HIV-1 Infection in Humans". Kyoto University, 2004. http://hdl.handle.net/2433/147694.

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Kyoto University (京都大学)
0048
新制・課程博士
博士(人間・環境学)
甲第10935号
人博第222号
15||177(吉田南総合図書館)
新制||人||56(附属図書館)
UT51-2004-G782
京都大学大学院人間・環境学研究科人間・環境学専攻
(主査)教授速水正憲, 教授加藤真, 教授松井正文, 教授小松賢志, 助教授三浦智行
学位規則第4条第1項該当

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Fortier, Marie-Eve. "Development of animal models to study effects of maternal infection during pregnancy on offspring behavior". Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=103513.

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Maternal infections during pregnancy are thought to be an important environmental risk factor for psychiatric illnesses of neurodevelopmental origin such as schizophrenia and autism. It has been suggested that the mother's immune response may be affecting the offspring's neurodevelopment and later behavior. In this thesis, we aimed to develop animal models to study the effects of maternal immune activation (MIA) on offspring behavior. In a first experiment, pregnant rats were injected with bacterial endotoxin (lipopolysaccharide, LPS) on gestational day (E) 18 and 19. The exposed offspring displayed increased amphetamine-induced locomotion, a behavioral indicator of mesolimbic dopamine activity. In a second experiment, LPS was administered in a chronic manner by using osmotic pumps from E18 to birth. Adult offspring displayed decreased prepulse inhibition (PPI), indicating disrupted sensorimotor gating. Prior to studying the effects of MIA elicited by the viral mimic polyinosinic:polycytidylic acid (poly I:C), we characterized the immune reaction it triggered in adult male rats. We demonstrated that poly I:C injection induced a robust febrile response, decreased food intake and body weight, and increased pro-inflammatory cytokines in the circulation. In another study, we compared the disruptive effects of MIA induced by the immunogens poly I:C or LPS to that induced by local inflammation, elicited by intramuscular injection of turpentine. In the same study, we also investigated the existence of gestational windows of susceptibility to the disruptive effects of MIA on offspring PPI. MIA induced by LPS or turpentine significantly decreased offspring PPI only when administered at certain times during gestation. Poly I:C had no effect at the dose administered. Thus our results demonstrated that selection of the immune agent and gestational time of administration are both critical factors in MIA models. Finally, we investigated if gestational MIA affected offspring immune function. Our results indicated no change in pyrogenic and cytokine responses to an immune challenge in adult MIA-exposed rats. In conclusion, the work in this thesis provides evidence that gestational MIA can cause lasting alterations in offspring behavior. This lends support to the idea that the association between prenatal infection and increased schizophrenia in human epidemiological studies reflects a causal relationship.
On considère les infections maternelles durant la grossesse comme étant un facteur de risque environnemental important des maladies psychiatriques d'origine neurodéveloppementale telles la schizophrénie et l'autisme. On a attribué de telles altérations sur le développement neurologique de la progéniture à la réponse immunitaire de la mère. Dans ce projet de thèse, nous envisagions de créer un modèle animal nous permettant d'observer les effets de l'activation de l'immunitaire maternelle (AIM) sur le comportement de la progéniture. Au cours d'une première expérience, les rates étaient injectées d'une endotoxine bactérienne (lipopolysaccharide, LPS) aux jours (E) 18 et 19 de la gestation. La progéniture soumise à ce traitement exhibait une élévation dans la locomotion liée aux amphétamines, un indicateur comportemental de l'activité du système dopaminergique mésolimbique. La deuxième expérience consistait à administrer la LPS de manière chronique à l'aide de pompes osmotiques, depuis E18 jusqu'à la naissance. À l'âge adulte, la progéniture présentait une baisse de l'inhibition du réflexe de sursaut acoustique (PPI), indiquant un dérèglement du filtrage sensori-moteur. Préalablement à l'étude des effets de l'AIM provoquée par la mimique virale acide polyinosinique:polycytidylique (poly I:C), nous avons analysé la réponse immunitaire qu'elle provoquait chez le rat adulte mâle. Nous avons démontré que l'injection du poly I:C entraînait une réponse fébrile considérable, une diminution de l'appétit et du poids des animaux et une élévation du taux de cytokines pro-inflammatoires dans le sang. Au cours d'une autre étude, nous avons comparé les effets perturbateurs de l'AIM causée par les immunogènes poly I:C ou LPS, et celle causée par l'inflammation locale par injection intramusculaire de térébenthine. Dans cette même étude, nous avons analysé la présence de périodes de susceptibilité aux conséquences de l'AIM durant la gestation sur le PPI de la progéniture. L'AIM provoquée par l'injection de LPS ou de térébenthine diminuait de façon significative le PPI uniquement lorsqu'administré à des moments précis durant la gestion. Le poly I:C n'a eu aucun effet à la dose administré. Ainsi, nos résultats démontrent que l'agent immunitaire sélectionné et le moment durant la gestation où il sera utilisé sont des facteurs cruciaux dans la création de modèles d'AIM. Finalement, nous avons examiné la relation entre l'AIM durant la gestation et la fonction immunitaire de la progéniture. Nos résultats n'indiquent aucune altération de la réponse pyrogénique ou celle des cytokines suite à l'injection d'un immunogène chez les rats adultes exposés à une AIM in utero. En conclusion, les travaux effectués durant ce projet de thèse démontre que l'AIM durant la gestation peut causer des modifications permanentes sur le comportement de la progéniture. Ce constat vient supporter la notion selon laquelle le lien établi entre l'infection prénatale et le risque élevé de schizophrénie relève d'une relation causale.

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Yugo, Danielle Marie. "Pathogenesis and Cross-species Infection of Hepatitis E Virus". Diss., Virginia Tech, 2019. http://hdl.handle.net/10919/86785.

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Hepatitis E Virus (HEV), the causative agent of hepatitis E, is a zoonotic pathogen of worldwide significance. The genus Orthohepevirus A of the family Hepeviridae includes all mammalian strains of HEV and consists of 8 recognized genotypes. Genotypes 1 and 2 HEVs only infect humans and genotypes 3 and 4 infect humans and several other animal species including pigs and rabbits. An ever-expanding host range of genetically-diversified strains of HEV now include bat, fish, rat, ferret, moose, wild boar, mongoose, deer, and camel. Additionally, the ruminant species goats, sheep, and cattle have been implicated as potential reservoirs as well. My dissertation research investigates a novel animal model for HEV, examines the immune dynamics during acute infection, and evaluates the possibility of additional animal reservoirs of HEV. The first project established an immunoglobulin (Ig) heavy chain knock-out JH (-/-) gnotobiotic piglet model that mimics the course of acute HEV infection observed in humans and evaluated the pathogenesis of HEV infection in this novel animal model. The dynamics of acute HEV infection in gnotobiotic pigs were systematically determined with a genotype 3 human strain of HEV. We also investigated the potential role of immunoglobulin heavy-chain JH in HEV pathogenesis and immune dynamics during the acute stage of virus infection. This novel gnotobiotic pig model will aid in future studies into HEV pathogenicity, an aspect which has thus far been difficult to reproduce in the available animal model systems. The objective of the second project for my PhD dissertation was to determine if cattle in the United States are infected with a bovine strain of HEV. We demonstrated serological evidence of an HEV-related agent in cattle populations with a high level of IgG anti-HEV prevalence. We demonstrated that calves from a seropositive cattle herd seroconverted to IgG binding HEV during a prospective study. We also showed that the IgG anti-HEV present in cattle has an ability to neutralize genotype 3 human HEV in vitro. However, our exhaustive attempts to detect HEVrelated sequence from cattle in the United States failed, suggesting that one should be cautious in interpreting the IgG anti-HEV serological results in bovine and other species. Collectively, the work from my PhD dissertation delineated important mechanisms in HEV pathogenesis and established a novel animal model for future HEV research.
Ph. D.
Hepatitis E Virus (HEV), the causative agent of hepatitis E, is a zoonotic pathogen of worldwide significance. According to the World Health Organization, there are approximately 20 million HEV infections annually, which result in 3.3 million cases of acute hepatitis E and >44,000 HEV-related deaths. Hepatitis E is a self-limiting acute disease in general, but carries the ability to cause high mortality in pregnant women and chronic hepatitis in immunocompromised individuals. The underlying mechanisms of HEV host tropism and progression of disease to chronicity are unknown. My dissertation work investigates a novel animal model for HEV, evaluates the possibility of additional animal reservoirs of HEV, and examines the immune dynamics during acute infection. The first project established an immunoglobulin (Ig) heavy chain knock-out JH (-/-) gnotobiotic piglet model that mimics the course of acute HEV infection observed in humans. The dynamics of acute HEV infection were determined in both the knock-out and wild-type piglets with a genotype 3 strain of human HEV. We also investigated the potential role of immunoglobulin heavy-chain JH in HEV pathogenesis and virus infection. In the second project, we determined if cattle in the United States are infected with a bovine strain of HEV. We showed serological evidence of an HEV-related agent in cattle as well as calves born in a seropositive herd. Despite the detection of specific antibodies recognizing HEV in cattle, definitive evidence of virus infection could not be demonstrated. Our exhaustive attempts to detect HEV-related sequence from cattle in the United States failed, suggesting that one should be cautious in interpreting the IgG anti-HEV serological results in bovine and other species. Collectively, the work from my PhD dissertation research delineated important mechanisms in HEV pathogenesis and established a novel animal model for future HEV research.

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Sun, Yi-Qian. "Experimental Helicobacter pylori infection in an animal model : gastric microflora, morpho-functional development, mucosal barrier function, and effects of antioxidants in Mongolian gerbils /". Linköping : Univ, 2004. http://www.bibl.liu.se/liupubl/disp/disp2004/med876s.pdf.

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Haynes, Rashade Ameir Hakim II. "Studies of the early immunological and virological events following Human T Lymphotropic Virus Type 1 infection in the rabbit model". The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1243527169.

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Leeming, Gail. "Alterations in the expression of CCSP and SPLUNC1 in the respiratory tract following viral infection of murine models". Thesis, University of Liverpool, 2010. http://livrepository.liverpool.ac.uk/1494/.

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Murid herpesvirus 4 (MHV-68) has been widely studied as a model of gammaherpesvirus infection. Infection of Apodemus sylvaticus, a natural host for MHV-68, revealed that a virally-encoded chemokine binding protein (M3) influences the composition of the perivascular and peribronchiolar inflammatory infiltration and the formation of BALT in the lung during lytic infection. In addition, host genes were identified which were expressed at higher levels in the presence of MHV-68 M3 at 14 days post infection (dpi), including Clara cell secretory protein (CCSP), Short palate lung and nasal epithelium clone 1 (SPLUNC1) and Anterior gradient 3 (AGR3). The aim of this work was to further investigate the expression of these genes and their corresponding proteins in relation to respiratory viral infection. CCSP and SPLUNC1 have previously been shown to have antiinflammatory properties in models of virus, bacteria and allergen induced inflammation. AGR3 is thought to be homologous to AGR2, which is associated with the transition of Clara cells to mucous cells in the lung. Following MHV-68 infection in A. sylvaticus, levels of both CCSP and SPLUNC1 were reduced in the bronchioles at 7 dpi and increased at 14 dpi, compared to mock-infected controls. In the absence of M3, the level of CCSP was reduced compared to wild type MHV-68 infected animals at both timepoints, whereas no significant difference in the expression of SPLUNC1 in the bronchioles was present. The regulation of both of these genes has previously been associated with interferon γ (IFNγ); infection of 129 wild type and IFNγR-/- mice revealed that CCSP expression was increased and SPLUNC1 expression decreased in the presence of IFNγ. However, this effect was smaller than that due to MHV-68 infection. Expression of AGR3 in the respiratory tract was increased in response to MHV-68 infection, whereas AGR2 was decreased. To investigate whether these effects were specific to MHV-68, infection with other respiratory viruses, with different cellular tropisms in the respiratory tract were examined in BALB/c mice. Infection with Human respiratory syncytial virus, Sendai virus and several strains of Influenzavirus A led to a decrease in both CCSP and SPLUNC1 expression during acute infection, when this was associated with a significant inflammatory response in the lung. The findings of this work showed that CCSP and SPLUNC1 are constitutively expressed in the non-ciliated cells of the respiratory epithelium and support the hypothesis that they have an antiinflammatory role in the lung. Expression of both proteins is reduced in the event of acute viral infection resulting in significant inflammation. In MHV-68 infection of A. sylvaticus, increased expression of CCSP and SPLUNC1 at later timepoints suggests that these proteins are implicated in the resolution of the inflammatory response.

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Buckingham, Erin M. "Studies of gammaherpesvirus infection and host response /". Connect to abstract via ProQuest. Full text is not available online, 2007.

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SAURIN, JEAN-CHRISTOPHE. "Hepatocarcinome et infection par le virus vhb : etude de l'expression d'oncogenes dans un modele animal, la marmotte". Lyon 1, 1993. http://www.theses.fr/1993LYO1M143.

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Patrick, Lindsay Alexandra Laurentia. "Investigation of the effect of intrauterine inflammation and infection on fetal brain injury using human and animal models". Thesis, Kingston, Ont. : [s.n.], 2008. http://hdl.handle.net/1974/1055.

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Gatin, Laure. "Infections péri prothétiques et bactéries multi résistantes : un challenge médico-chirurgical". Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLV053/document.

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La survenue d’une infection péri prothétique (IPP) est la principale complication de la chirurgie prothétique articulaire, depuis son invention par Robert et Jean Judet en 1947. Comme le nombre de prothèses articulaires posées chaque année augmente de façon importante, ces infections sont de plus en plus fréquentes et l’optimisation de leur prise en charge est un enjeu important sur le plan médical et économique.Les modèles animaux d’IPP permettent de comprendre les mécanismes éthio-pathogéniques et tester de nouvelles thérapeutiques. Une analyse critique de la littérature a été effectuée en évaluant chaque modèle selon son type d’inoculation qui influence les taux et la sévérité de l’infection expérimentale obtenue.Un modèle expérimental d’IPP chez le lapin obtenu par remplacement partiel du genou et inoculation locale a été utilisé pour tester l’efficacité de nouvelles thérapeutiques au cours d’infections à deux bactéries multi résistantes qui posent des problèmes en thérapeutique humaine.Dans un 1er temps nous avons évalué l’efficacité de la ceftaroline (CPT) céphalosporine bactéricide in vivo contre le Staphylococcus aureus résistant à la méticilline (SARM) en la comparant à la vancomycine en association ou non à la rifampicine. 5.107UFC (Unités Formant Colonies) de SARM (Concentration Minimale Inhibitrice (CMI) de 0,38, 0,006, et 1 mg/l pour CPT, RIF, et VAN, respectivement) était injecté dans le genou. Les animaux infectés ont été randomisés et recevaient : aucun traitement (contrôles), CPT (60 mg/kg im), VAN (60 mg/kg im), CPT plus RIF (10 mg/kg im), ou VAN plus RIF débutant 7 jours après l'inoculation et durant 7 jours. L’efficacité des traitements a été évaluée sur la quantité de bactéries persistantes dans l’os (tibia proximal) après traitement. Ce travail a montré que la CPT et la VAN étaient efficace en monothérapie mais que seule l’association avec la rifampicine permettait de stériliser la quasi totalité des animaux. La CPT apparaît donc comme un traitement potentiellement efficace dans cette infection.Dans un 2ème temps nous avons étudié l'efficacité de la colistine (COL) dans le ciment, seule ou en combinaison avec des injections intramusculaires (im) de COL et/ou de méropénème (MRP) dans des infections à Klebsiella pneumoniae résistantes aux carbapénèmes (KPC). Un modèle proche de celui décrit pour le SARM a été utilisé. La souche KPC99YC est une souche clinique, résistante à la gentamicine (CMI 8mg/l) intermédiaire à l'imipénème (CMI 4mg/l), et sensible à la COL (CMI 0,25mg/l). L’inoculum était de 1.109UFC. Sept jours après l'infection, les prothèses étaient remplacées par espaceur sans antibiotique (contrôle), ou par espaceur imprégné de COL (3 MUI de COL/40g de ciment), ou par espaceur sans antibiotique et injections de COL (12 mg/kg im), ou l’association des deux, ou injections de COL avec espaceur en ciment imprégné de COL associé ou non à des injections de MRP (80 mg/kg im). Le traitement durait 7 jours. Tous les lapins témoins étaient infectés à J15, avec une moyenne de densité bactérienne de 6,17 [5,69, 7,04] CFU/g d'os. Contrairement à la COL locale, la COL systémique seule ou combinée avec le MRP était plus efficace que le contrôle sur le nombre de bactéries dans l'os à la fin du traitement. L’association COL locale + systémique était significativement plus efficace que le groupe témoin sur le dénombrement bactérien. D’ailleurs, c'était le seul schéma efficace sur le nombre de lapins avec un os stérile et à la limite de significativité par rapport au traitement systémique seul. Une souche résistante à la COL a été détectée dans le traitement local seul mais pas avec l’association de COL locale et systémique.Les modes d’inoculation directs sont les plus efficaces pour reproduire une IPP aigue. Les études expérimentales permettent de tester des traitements innovants en particulier pour les infections à bactéries multi résistantes
The occurrence of prosthetic joint infection (PJI) is the main complication of joint prosthetic surgery since its invention by Robert and Jean Judet in 1947. Since the number of articular prostheses placed each year increases significantly, these infections are more and more frequent and the optimization of their management is an important medical and economic stake.The animal models of PJI make it possible to understand the ethiopathogenic mechanisms and to test new therapeutics. A critical analysis of the literature was carried out by evaluating each model according to its type of inoculation which influences the rates and the severity of the experimental infection obtained.An experimental model of PJI in rabbits obtained by partial replacement of the knee and local inoculation was used to test the efficacy of new therapeutics during infections with two multi-resistant bacteria which pose problems in human therapeutics.In a first step we evaluated the efficacy of ceftaroline (CPT) cephalosporin bactericidal in vivo against methicillin-resistant Staphylococcus aureus (MRSA) by comparing it with vancomycin (VAN) in combination with or without rifampin (RIF). 5.107UFC MRSA (Minimum Inhibitory Concentration (MIC) of 0.38, 0.006, and 1 mg/l for CPT, RIF, and VAN, respectively) was injected into the knee. Infected animals were randomized to receive no treatment (control), CPT (60 mg/kg im), VAN (60 mg/kg im), CPT plus RIF (10 mg/kg im) or VAN plus RIF, 7 days after inoculation and for 7 days. The efficacy of treatments was evaluated on the amount of persistent bacteria in the bone (proximal tibia) after treatment. This work has shown that CPT and VAN were effective as monotherapy, but only the combination with RIF allowed the sterilization of almost all animals. CPT appears to be a potentially effective treatment in this infection.In a second step we studied the efficacy of colistin (COL) in cement, alone or in combination with intramuscular (im) injections of COL and/or meropenem (MRP) in carbapenem-resistant Klebsiella pneumoniae infections (KPC). A model close to that used for MRSA was used. The strain KPC99YC is a clinical strain, resistant to gentamicin (MIC 8mg/L) intermediate to imipenem (MIC 4mg/l), and sensitive to COL (MIC 0,25mg/l). The inoculum was 1,109UFC. Seven days after the infection, the prosthesis were replaced by antibiotic-free spacer (control), or by COL-impregnated spacer (3 MIU of COL/40g of cement), or by antibiotic-free spacer and COL injections (12 mg/kg im), or the combination of the two, or COL injections with COL-impregnated cement spacer associated or not with MRP injections (80 mg/kg im). The treatment lasted 7 days. All control rabbits were infected at D15, with median and interquartile range (IQR) bone bacterial count of 6.17 [5.69, 7.04] CFU/g of bones. In contrast to local COL, systemic COL alone or combined with MRP was more effective than control on bacterial counts in bone at the end of treatment. The combination of COL local + systemic was significantly more effective than control group on bacterial counts. Interestingly it was the only effective regimen on the number of rabbits with sterile bone and at the limit of significance vs systemic treatment alone. One COL-resistant strain was detected in the COL local treatment alone but not with the combination of local and systemic COL.Direct inoculation modes are most effective in reproducing an acute PJI. The experimental studies allow testing innovative treatments in particular for the infections with multi-resistant bacteria

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Sumaria, Nital. "The relevance of specific molecular and cellular effectors during murine cytomegalovirus infection". University of Western Australia. School of Biomedical, Biomolecular and Chemical Sciences, 2008. http://theses.library.uwa.edu.au/adt-WU2008.0116.

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[Truncated abstract] The design and development of effective anti-viral immunotherapies requires a comprehensive understanding of the cellular and molecular processes that are involved in the generation and regulation of immune responses. The fundamental objective of the immune system is to successfully complete the task of eliminating/controlling the invading pathogen without causing overt pathology. Cytomegaloviruses (CMVs) are large DNA viruses that are able to evade immune attack and persist lifelong within the host. In a healthy host, CMV causes an asymptomatic infection, but in instances of decreased immune functions, such as in newborns, acquired immunodeficiency syndrome (AIDS) patients and transplant recipients, the infection can result in serious morbidity and mortality. Thus, human CMV (HCMV) is a clinically important pathogen and an understanding of the pathogenesis, mechanisms of immune subversion and, importantly the cascade of immune events that ensue following infection is highly relevant. The studies presented in this thesis have provided useful insight into various aspects of viral immunity and it is hoped that they will assist in the design of more effective therapies against viruses of clinical importance. Genetic variability in humans can greatly influence anti-viral immune responses and the outcome of viral infection. ... Furthermore, these studies provide novel evidence that NK cells are also crucial for the control of virus in some organs of susceptible mice during early acute infection. The data reveals that both NK cells and CD8+ T cells utilise perforin- and IFN-? dependent control of MCMV. Furthermore, these studies provide novel evidence that protection mediated by Ly49H+ NK cells in resistant mice is dependent on perforin. Chapter 3 focuses on the biological relevance of Grz during MCMV infection. These studies found that GrzA and GrzB are essential components of the machinery involved in limiting MCMV during acute infection. These analyses also provide the first evidence suggesting that GrzM plays a role, albeit minor, in controlling MCMV replication. Furthermore, the current studies suggest that Grz can mediate direct antiviral activities independent of the induction of cell death in conjunction with perforin. Interestingly, in the absence of both GrzA and GrzB (GrzAB), mice were as susceptible to MCMV infection as perforin-deficient mice. However, unlike perforin-deficient mice, GrzAB-deficient mice controlled and survived the infection. In Chapter 4 the roles of perforin, GrzA and GrzB in anti-viral immunity and immunopathology during MCMV infection were examined. These studies show that NK cell-derived perforin is required to eliminate infected targets as well as activated effector cells, suggesting that NK cells are crucial not only in defensive immunity but also in limiting the immune activation that follows MCMV infection. In summary, the studies presented in this thesis define the significant role played by specific effector molecules in limiting MCMV replication during different stages of this viral infection. Furthermore, these studies provide novel evidence that perforin, GrzA and GrzB play distinct roles in defensive immunity and limiting immunopathology during MCMV infection.

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Li, Jinan. "Multifunctional roles of plasmin in inflammation : Studies of animal models on rheumatoid arthritis, multiple sclerosis, wound healing and infection". Doctoral thesis, Umeå : Dept. of medical biochemistry and biophysics, Univ, 2005. http://www.diva-portal.org/umu/theses/abstract.xsql?dbid=422.

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Cunningham, Dawn Anne. "Human lysosomal associated membrane protein-2 (LAMP-2) : a molecular bridge between infection and autoimmunity in an animal model of focal necrotising and crescentic glomerulonephritis (FNCGN)". Thesis, University of Aberdeen, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.485684.

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Pauci-immune focal necrotising and crescentic glomerulonephritis (FNCGN) is a severe form of kidney disease often associated with anti-neutrophil cytoplasmic antibodies (ANCA). Well pocumented . ANCA target proteins . include myeloperoxidase (MPO) and proteinase 3 (PR3), both contained in the Iysosomes of neutrophils. A study by Kain et al (1995) identified a novel ANCA target; lysosomal associated membrane protein 2 (LAMP-2) (Kain et aI., 1995) recognised by FNCGN patient sera. An immunodominant epitope shares sequence homology with a peptide found on bacterial adhesion protein fimH (Kain et aI., Manuscript in Preparation). The aim of this work has been to evaluate the pathogenic potential of cross reactive antibodies that bind to both LAMP-2 and fimH to provide an explanation of how persistent infection can drive chonic inflammatory responses that underpin autoimmune disease. A WKY rat model of FNCGN was used to examine this concept of molecular mimicry by using both passive and active immunisation schedules. Recombinant fragments of human and rat LAMP-2 and bacterial fimH were generated and purified Ã‚Â·following expression in plasmid vectors. The WKY rat model was first passively immunised with rabbit antibodies specific for human LAMP-2 (hLAMP-2) to confirm that they had the ability to cross-react with sequence homologous rat LAMP-2 (rLAMP-2). Indirect immunofluorescence (IIF) and ELISA confirmed cross reactivity and further indicated that antihLAMP- 2 resulted in tissue damage similar to that observed in human FNCGN. Further, active immunisation with hLAMP-2 in the presence of adjuvant was sufficient to break tolerance, generating a pathogenic antibody response specific for both human and rat LAMP-2.

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Tanner, Anne. "Human Herpesvirus 6A Infection and Immunopathogenesis in Humanized Rag2^-/-γc-/- Mice and Relevance to HIV/AIDS and Autoimmunity". BYU ScholarsArchive, 2016. https://scholarsarchive.byu.edu/etd/6078.

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Human herpesvirus 6A (HHV-6A) has yet to be definitively linked to a specific disease. This is due in part to the ubiquitous nature of the virus. Humanized Rag2-/-γc-/- (Rag-hu) mice were tested to determine if these were a suitable animal model to study the virus. Both cell-free and cell-associated virus was used for infection and both were found to be efficient at infecting the mice. Viral DNA was found in the plasma and cellular blood fractions, bone marrow, lymph node, and thymus, indicating successful infection and propagation of the virus in vivo. The CD3+CD4- population was depleted, while the CD3-CD4+ was increased in infected animals. The CD3-CD4+CD8- and CD3+CD4+CD8- populations were depleted and the CD3+CD4+CD8+ population increased when analysis was gated upon CD4+ cells. The CD3-CD4+CD8+ population expanded and the CD3-CD4+CD8- population was reduced when analysis was gated on the CD3- population. Additional flow cytometry analysis revealed increases in CD4+CD8+ double positive cells in the peripheral blood of cell-free infected mice, which could indicate improper T cell selection and a premature departure of these cells from the thymus, possibly contributing to autoimmunity. Previous research has shown that HIV and HHV-6A may have a synergistic effect on one another and that HHV-6A may act as a cofactor in the progression to AIDS. After determining the Rag-hu mouse model was suitable for studying HHV-6A infection, a coinfection of HHV-6A and HIV-1 was performed. Coinfected mice had fewer thymocytes when compared with the HIV-1 only, mock-infected, and to a lesser extent HHV-6A only groups which could indicate increased cell death in the coinfected group as well as possible disruptions in migration of cells, either causing cells to be sequestered in the bone marrow and unable to migrate to the thymus, or causing premature egress of the cells in the thymus due in part to premature upregulation of CCR7, both of which would explain the smaller cellular populations found in the coinfected mouse thymi. Additional studies were performed to determine if a preferential targeting existed between HHV-6A and HIV-1 as these viruses are found simultaneously coinfecting the same cell. Preferential targeting was not observed by cell-associated migration assay, but increased migration of HHV-6A-infected cells was observed in a CCL21 dependent manner. These studies have provided useful information about HHV-6A and its relevance to HIV/AIDS as well as a possible mechanism of the involvement of HHV-6A in multiple sclerosis (MS) and other autoimmune diseases.

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Schlosser, Josephine [Verfasser]. "Transmission and pathogenesis of hepatitis E virus infection in European wild boar and domestic pigs, and the establishment of a small animal model for hepatitis E / Josephine Schlosser". Hannover : Bibliothek der Tierärztlichen Hochschule Hannover, 2015. http://d-nb.info/1073931005/34.

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Duan, Yue. "A cultivable primate calicivirus causes enteric infections in gnotobiotic piglets". The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1366250409.

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Guerrero, Israel. "A Comparison of Chikungunya Virus Infection, Dissemination, and Cytokine Induction in Human and Murine Macrophages and Characterization of RAG2-/-γc-/- Mice as an Animal Model to Study Neurotropic Chikungunya Disease". BYU ScholarsArchive, 2020. https://scholarsarchive.byu.edu/etd/8430.

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Chikungunya virus (CHIKV) is classified as an alphavirus in the Togaviridae family. This virus is known to rely on Aedes arthropod vectors for its dissemination. Human infection is characterized by rash, high fever, and severe chronic polyarthritis that can last for years. Recently, efforts in developing animal models have been made in an attempt to better understand CHIKV pathogenesis. CHIKV infection starts with a 7 to 10 day long febrile acute phase, in which most of the symptoms occur (rash, fever, and incapacitating pain in joints and muscle). Once the immune system clears most of the viral infection, a chronic phase starts in as many as 70% of the infected patients. Long term virus-related polyarthralgia is the hallmark of the CHIKV chronic phase. It is believed that CHIKV-infected macrophages infiltrate the joints during the acute phase, and CHIKV infects joint tissue and persists in it. Research into the effects of CHIKV infection in human and murine macrophages revealed that CHIKV-infected human macrophages produce high amounts of virions as well as induce the production of pro-inflammatory cytokines and monocyte recruiting chemokines. This contrasts with murine macrophage infection where low quantities of the virus were detected as well as lower production of pro-inflammatory cytokines. This may contribute to the lack of polyarthritis in murine animal models. Current literature suggests that CHIKV’s viral proteins bind and interact with human host cell machinery promoting viral replication more efficiently in humans than in mice. CHIKV-related neuropathology is not the most common outcome of the disease. However, recent outbreaks suggest that this pathology is becoming more prevalent, affecting as many as 30% of confirmed patients. The role of adaptive and innate immunity in CHIKV disease amelioration has been extensively, yet separately, explored. A RAG2-/-γc-/- Balb/c mouse model was used to study the role of these immune pathways and their associated immune cells in CHIKV infection. The mice in this study developed local arthritis at the site of inoculation as well as showed signs of viral invasion in the brain. This study added to the hypothesis that both innate and adaptive immune responses are necessary to ameliorate the disease and that the lack of adequately matured lymphocytes and STAT6-activation deficient macrophages may result in more severe pathologies.

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Gicquel, Mireille. "Relations pharmacocinetiques pharmacodynamiques des antibiotiques : developpement d'un modele d'etude des quinolones chez le porc (doctorat : pharmacologie experimentale)". Nantes, 1999. http://www.theses.fr/1999NANT19VS.

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Jacops, Eliza. "Effects Of Invasion Timing In A One-Dimensional Model Of Competing Species With An Infectious Disease". University of Akron / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=akron1462802187.

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Keller, Andrea. "Avaliação morfológica-funcional da recuperação do endométrio eqüino através da infusão de neutrófilos imunocompetentes criopreservados baseado em um modelo experimental definido". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2004. http://hdl.handle.net/10183/10838.

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A endometrite é uma importante causa de subfertilidade na égua. Infecções uterinas repetidas ou persistentes poderiam levar ao desenvolvimento de fibrose periglandular. Os objetivos deste trabalho foram avaliar se os processos degenerativos do endométrio são influenciados por infecções bacterianas experimentais sucessivas; realizar uma avaliação histopatológica das biópsias endometriais para documentar os efeitos de diferentes tratamentos sobre o endométrio após infecções experimentais. Foram utilizadas vinte éguas resistentes, com histórico reprodutivo desconhecido, e cinco éguas susceptíveis, com histórico de endometrites recorrentes e subfertilidade. As vinte e cinco éguas foram classificadas nos seguintes grupos, de acordo com o grau de endometrite e endometrose: GI (n=4), GIIA (n=10), GIIB (n=8) e GIII (n=3). Após o primeiro exame histopatológico (amostra pré-infecção), as éguas foram sincronizadas com prostaglandina. Na fase estral, as éguas foram infectadas com 1 x 109 Streptococcus equi subsp. zooepidemicus. Constatada a presença de sinais clínicos de endometrite, os grupos de éguas foram distribuídos entre cinco diferentes tratamentos: leucócitos frescos, leucócitos congelados, leucócitos lisados, Interleucina-8 (Il-8) e grupo controle.As éguas foram tratadas diariamente, por, no máximo, quatro dias, ou até que o exame bacteriológico não evidenciasse o crescimento de Streptococcus. No quinto dia, as éguas eram submetidas a novo exame histopatológico (amostra pós-infecção) e no sétimo dia, todas as éguas eram tratadas com penicilina, independentemente de terem eliminado a infecção ou não. Sete dias após, as éguas eram novamente submetidas a exame histopatológico e sincronizadaspara realizar uma nova infecção e novo tratamento. As biópsias foram avaliadas quanto à endometrose e endometrite. Não se observaram diferenças significativas entre os graus de endometrose observados antes e no quinto dia após as cinco infecções experimentais. Da mesma forma, não foram observadas variações no grau de endometrose entre as biópsias realizadas antes das infecções, bem como entre as biópsias coletadas no quinto dia após a infecção. Não houve influência dos tratamentos sobre os graus de endometrose durante as 5 infecções experimentais. Entretanto, verificou-se variação significativa entre as diferentes éguas no grau de endometrose das biópsias uterinas coletadas antes e após a infecção experimental. Observou-se, nas éguas resistentes, neutrofilia e eosinofilia significativas nas biópsias do 5º dia pós-infecção, quando comparadas com as biópsias pré-infecção. Nas éguas susceptíveis, somente foi detectada eosinofilia, não se observando aumento do número de neutrófilos. Não houve aumento do número de linfócitos e plasmócitos nas biópsias pós-infecção, quando comparadas às pré- infecção, nas éguas susceptíveis e resistentes. Os tratamentos não influenciaram, nas éguas resistentes e susceptíveis, a migração de neutrófilos no quinto dia, quando comparada com a observada antes da infecção. Conclui-se que infecções experimentais sucessivas durante 13 meses não influenciaram o grau médio de endometrose, apesar da variabilidade ocorrida entre as éguas. Esta variação provavelmente se deva a uma baixa representatividade de uma única amostra de biópsia na avaliação somente do grau de degeneração endometrial. Conclui-se, também, que éguas susceptíveis à endometrite, com presença de Streptococcus no útero, não apresentam neutrofilia cinco dias após a infecção. Provavelmente, o menor tempo de eliminação bacteriana observada nos tratamentos com leucócitos frescos e congelados deva-se a outros fatores que não o efeito quimioatraente leucocitário.
Endometritis is an important cause of subfertility in the mare. Repetitive or persistent uterine infections could lead to the development of periglandular fibrosis. The objectives of this study were: - to evaluate if degenerative endometrial diseases are influenced by repetitive experimental bacterial infections; - to determine the effect of different treatments on the endometrium after experimental infections by means of histopathological evaluation of endometrial biopsies. Twenty resistant mares, with unknown reproductive history, and five susceptible mares, with history of recurrent endometritis and subfertility, were used. Mares were classified, according to the degree of endometritis and endometrosis, within the following groups: GI (n=4), GIIA (n=10), GIIB (n=8) and GIII (n=3). Cycles were synchronized with prostaglandin after the first histopathological examination (pre-infection sample). During estrus, mares were infected with 1 x 109 Streptococcus equi subsp. zooepidemicus. Twenty four hours after the inoculation, clinical, bacteriological and cytological examinations were performed. When endometritis clinical signs were detected, the groups of mares were distributed into five different treatments: fresh leukocytes, frozen leucocytes, lysed leucocytes, Interleukin-8 (Il-8) and control group. Mares were treated on a daily basis for no more than four days, or until there was no Streptococcus growth in bacteriological examination. On the fifth day, mares were submitted to a new histopathological examination (post-infection sample) and, on the seventh day, all the mares were treated with penicillin, independently of having eliminated infection, or not. Seven days after, mares were submitted to a new histopathological examination and synchronized in order to proceed to a new infection and a new treatment. Biopsies were evaluated for endometritis and endometrosis. Therewas no significant difference regarding the degree of endometrosis before and on the fifth day after the five infections. Similarly, there was no difference regarding the degree of endometrosis among biopsies performed before infections and among biopsies performed on the fifth day after infections. Treatments did not influence the degree of endometrosis during the five experimental infections. Anyway, there was a significant variation between different mares, according to the degree of endometrosis, in biopsies collected before, as well as in biopsies collected after experimental infection. Resistant mares showed significant neutrophilia and eosinophilia in biopsies collected on the fifth day after infection, compared to pre-infection samples. Susceptible mares showed eosinophilia, but no growth in neutrophil number. There was no growth in lymphocyte and plasma cell number in post-infection biopsies, if compared to pre-infection biopsies, either in susceptible, or in resistant mares. In the same way, treatments did not influence neutrophil migration on the fifth day post-infection, if compared to pre-infection, either in susceptible, or in resistant mares. It was concluded that repetitive experimental infections do not influence the average degree of endometrosis, in spite of the variability between mares. This variability is probably due to the low representation of one single biopsy sample in the evaluation of the degree of endometrial degeneration. It was also concluded that susceptible mares showing Streptococcus in uterus do not present with neutrophil growth five days after infection. The shorter time required for bacterial elimination when fresh and frozen leukocytes were used is probably due to other factors than leukocyte chemoattractive effect.

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Månsson, Lisa. "Visualizing the dynamic interplay between the host and bacterial pathogen : a real-time study of renal infection /". Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-218-7/.

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Suzuki, Saori. "Basic research for the development of hepatitis C vaccine". 京都大学 (Kyoto University), 2016. http://hdl.handle.net/2433/215372.

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Contents of the present thesis were published in the following articles. 1. Suzuki S, Mori K, Higashino A, Iwasaki Y, Yasutomi Y, Maki N, Akari H. 2016. Persistent replication of a hepatitis C virus genotype 1b-based chimeric clone carrying E1, E2 and p6 regions from GB virus B in a New World monkey. Microbiol Immunol 60:26-34. Copyright © 1999-2016 John Wiley & Sons, Inc.2. Yoshida T, Suzuki S, Iwasaki Y, Kaneko A, Saito A, Enomoto Y, Higashino A, Watanabe A, Suzuki J, Inoue K, Kuroda T, Takada M, Ito R, Ito M, Akari H. 2013. Efficient in vivo depletion of CD8+ T lymphocytes in common marmosets by novel CD8 monoclonal antibody administration. Immunol Lett 154:12-17.Copyright © 2013 Elsevier B. V.
Kyoto University (京都大学)
0048
新制・課程博士
博士(理学)
甲第19546号
理博第4206号
新制||理||1604(附属図書館)
32582
京都大学大学院理学研究科生物科学専攻
(主査)教授明里宏文, 教授岡本宗裕, 教授中村克樹
学位規則第4条第1項該当

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Lemaitre, Julien. "Heterogeneity of polymorphonuclear neutrophils in HIV-1 infection. Study of SIV-infected cynomolgus macaque model". Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS267.

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La persistance du VIH-1 est associée au maintien de l’inflammation chronique chez les patients infectés, malgré la mise en place de combinaison de traitements antirétroviraux. L’inflammation chronique est associée à un risque augmenté de développer des comorbidités, non associées au SIDA. Les polynucléaires neutrophiles (PNN) sont des cellules myéloïdes qui ont été impliqués dans de multiples maladies inflammatoires chroniques. Néanmoins, leur rôle dans l’infection par le VIH-1 est moins bien connue. Afin de pallier ce manque de connaissances, nous avons évalué l’hétérogénéité des PNNs dans le modèle macaque cynomolgus infecté par le SIVmac251. L’analyse phénotypique par cytométrie de masse a révélé la circulation de PNNs immatures en phase chronique de l’infection. En caractérisant l’hétérogénéité des PNNs au cours de l’infection par le SIV, nous avons observé une augmentation des fréquences des neutrophiles immatures et activés dans le sang dès la primo-infection. En phase chronique, les PNNs immatures et activés étaient toujours significativement augmentés dans le sang et la moelle osseuse. Au cours de l’infection, les PNNs avaient une fonction immunostimulatrice envers la prolifération et la sécrétion cytokinique des lymphocytaire T. L’initiation d’un traitement antirétroviral précoce a permis de restaurer le phénotype des PNNs. Les PNNs sont des cellules à fort potentiel pro-inflammatoire abondantes qui devraient être ainsi considérés comme de nouveaux effecteurs de l’inflammation chronique associée au VIH-1
Even under combinational antiretroviral treatments (cART), HIV-1 persistence is associated with chronic inflammation in infected patients, leading to an increased risk of non-AIDS-related comorbidities. Polymorphonuclear neutrophils (PMN), have been less studied in HIV infection whereas they were associated with chronic inflammation diseases. To evaluate PMN heterogeneity in SIVmac251 nonhuman primate infection model, we first performed multiparameter single-cell phenotyping by mass cytometry giving a global vision of the immune system. This analysis demonstrated circulation of immature PMN with impaired during chronic infection. Then, we characterized neutrophils heterogeneity in the course of SIV infection. In primary infection, there was an increased frequency of CD10- immature and CD62L-low primed PMNs in peripheral blood. In chronic phase, CD10- immature PMNs were significantly higher in bone marrow and blood, maintaining a primed profile. During SIV infection, PMNs demonstrated variable immunomodulatory function against T cells proliferation and cytokine production. Early cART allowed to restore PMN phenotype. In this study, we provide unprecedented insight into PMN heterogeneity in the course of SIV infection. Since PMN represent 40-70% of circulating leukocytes and primed PMN are more potent to release pro-inflammatory cytokines and to transmigrate, they should be considered as a new player in HIV-1 chronic inflammation

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Andrews, Daniel Mark. "Effects of murine cytomegalovirus infection on dendritic cell functionality and natural killer cell responses". University of Western Australia. Centre for Ophthalmology and Visual Science, 2004. http://theses.library.uwa.edu.au/adt-WU2005.0003.

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Cytomegaloviruses (CMVs) are ubiquitous in nature, having evolved over many millenia with their hosts. While in healthy hosts most infections with CMV are asymptomatic, the virus can cause severe disease in immunocompromised hosts. Thus, the increase in organ transplantation and the HIV/AIDS pandemic have established human CMV (HCMV) as a clinically important pathogen. Indeed, HCMV infections are now the major cause of morbidity and mortality among immunocompromised patients, which has led to more research targeting CMV for effective anti-viral treatment. The discovery that cytomegaloviruses encode several genes which are involved in immune escape has prompted a new area of research, aimed at understanding immune escape mechanisms for exploitation as potential anti-viral therapeutics. By targeting the viral proteins directly, or their receptors in the host, it may be possible to treat CMV disease by agonistic/antagonistic therapy. The first part of this thesis describes the first demonstration of anti-NK1.1 staining in situ to identify NK cells using a modified in vivo perfusion/fixation method. Using this method, we have compared the acute NK1.1+ cellular response to wild-type MCMV infection in the visceral organs of genetically susceptible intra-NK complex recombinant BALB.B6-CT6 (Cmv1s, NK1.1+) mice with resistant C57B⁄J (Cmv1r, NK1.1+) and BALB.B6-Cmv1r mice (Cmv1r, NK1.1+). Expression of viral antigens and the consequences of infection on other cellular subsets, were also analyzed in this study. The data show that in susceptible mice (Cmv1s) MCMV infection is predominent in the marginal zone of splenic white pulp, resulting in local changes in various cellular constituents, including macrophages, NK cells and DC. In the liver, distinct foci of infection were comprised of large numbers of macrophages and NK1.1+ cells surrounding infected cytomegalic cells. In resistant mice (Cmv1r), 6 MCMV infection predominantly affected the red-pulp of the spleen and was associated with increased accumulation of NK1.1+ cells and macrophages at sites of viral infection

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Zou, Weiping. "Production et role des cytokines au cours de l'infection par les virus de l'immunodeficience des primates (vih/siv)". Paris 11, 1997. http://www.theses.fr/1997PA11T022.

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Luo, Karen Yao. "Assessment of the Effect of Induced Hypothermia in Experimental Sepsis Using a Cecal Ligation and Perforation Mouse Model". Thèse, Université d'Ottawa / University of Ottawa, 2011. http://hdl.handle.net/10393/20119.

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Sepsis-induced organ failure is associated with high morbidity and mortality rates. The onset of an exaggerated host response to microbial invasion and/or trauma, is believed to be the primary cause of excessive inflammation and the subsequent tissue hypoperfusion observed in patients with severe sepsis. In our mouse model of sepsis induced by cecal ligation and perforation (CLP), symptoms indicative of the disease, including diarrhea, increased ventilation and persistent hypothermia, are present at six hours after the surgery (T6). In the untreated CLP mice, mortality occurs starting at T15. As induced hypothermia has shown to exert immunomodulatory effects, this study is aimed at assessing its potential in attenuating inflammation and improving survival in experimental sepsis. Our data has shown that deep hypothermia initiated at T6, by means of cold chamber-induced cooling, prolongs survival. Plasma cytokine quantification by enzyme-linked immunosorbent assays (ELISA) also reveals that induced deep hypothermia reduces tumour necrosis factor(TNF)-α and interleukin (IL)-6 production in untreated CLP mice. In contrast, induced moderate hypothermia does not have such effect. Antibiotic (cefotaxime) and saline resuscitation initiated immediately following CLP ensures survival. However, when these supportive treatments are initiated at T6, >50% mortality is observed in the CLP mice with or without induced hypothermia. In summary, this preliminary study provides proof for a downregulated inflammatory response mediated by external cooling. However, to achieve a survival benefit, treatment strategies in addition to cooling and antibiotics may be required.

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Mallick, Emily M. "A New Murine Model For Enterohemorrhagic Escherichia coli Infection Reveals That Actin Pedestal Formation Facilitates Mucosal Colonization and Lethal Disease: A Dissertation". eScholarship@UMMS, 2012. https://escholarship.umassmed.edu/gsbs_diss/601.

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Enterohemorrhagic Escherichia coli (EHEC) colonizes the intestine and produces the phage-encoded Shiga toxin (Stx) which is absorbed systemically and can lead to hemolytic uremic syndrome (HUS) characterized by hemolytic anemia, thrombocytopenia, and renal failure. EHEC, and two related pathogens, Enteropathogenic E. coli (EPEC), and the murine pathogen, Citrobacter rodentium, are attaching and effacing (AE) pathogens that intimately adhere to enterocytes and form actin “pedestals” beneath bound bacteria. The actin pedestal, because it is a unique characteristic of AE pathogens, has been the subject of intense study for over 20 years. Investigations into the mechanism of pedestal formation have revealed that to generate AE lesions, EHEC injects the type III effector, Tir, into mammalian cells, which functions as a receptor for the bacterial adhesin intimin. Tir-intimin binding then triggers a signaling cascade leading to pedestal formation. In spite of these mechanistic insights, the role of intimin and pedestal formation in EHEC disease remains unclear, in part because of the paucity of murine models for EHEC infection. We found that the pathogenic significance of EHEC Stx, Tir, and intimin, as well as the actin assembly triggered by the interaction of the latter two factors, could be productively assessed during murine infection by recombinant C. rodentium expressing EHEC virulence factors. Here we show that EHEC intimin was able to promote colonization of C. rodentium in conventional mice. Additionally, previous in vitro data indicates that intimin may have also function in a Tir-independent manner, and we revealed this function using streptomycin pre-treated mice. Lastly, using a toxigenic C. rodentium strain, we assessed the function of pedestal formation mediated by Tir-intimin interaction and found that Tir-mediated actin polymerization promoted mucosal colonization and a systemic Stx-mediated disease that shares several key features with human HUS.

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Martinet, Jérémie. "Cellules dendritiques plasmocytoïdes et infections virales : rôle physiopathologique et potentiel vaccinal". Phd thesis, Université de Grenoble, 2012. http://tel.archives-ouvertes.fr/tel-00843008.

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La réponse immune lors d'une infection par le VHB est essentielle pour éliminer le virus. Le virus module le système immunitaire pour échapper à son contrôle. Le mécanisme par lequel le virus module l'immunité est encore mal connu. Les cellules dendritiques plasmocytoides (pDC) jouent un rôle crucial dans l'immunité antivirale de part leur capacité à capturer et apprêter les antigènes viraux afin d'induire une réponse immune adaptative. Les pDCs représentent un bon potentiel pour restaurer une immunité anti-VHB fonctionnelle, mais le VHB pourrait moduler les pDCs pour échapper au contrôle immunitaire. Dans une première partie, nous avons évalué le potentiel des pDCs à restaurer l'immunité anti-VHB en contexte d'hépatite B chronique. Nous avons utilisé une lignée de pDCs HLA-A*0201+ chargée avec des peptides HLA-A*0201 restreints dérivés des antigènes HBc et HBs du virus afin d'amplifier des lymphocytes T spécifiques ex vivo à partir de cellules de patients atteints d'hépatite B chronique. Nous avons ensuite établi un modèle de souris humanisées (Hepato-HuPBL) afin d'évaluer le potentiel thérapeutique de la stratégie in vivo. La stimulation de PBMC ou de lymphocytes infiltrant le foie (LIL) issus de patients HLA-A*0201+ par la lignée de pDC chargée avec le peptide HBc a permis d'amplifier des lymphocytes T spécifiques de HBc et fonctionnels dans 45,8% des cas. Le groupe de non répondeurs était caractérisé par la présence d'Ag HBe ou un plus fort niveau de lymphocytes T régulateurs. L'efficacité thérapeutique du vaccin de pDC a été évaluée dans un modèle de souris NOD-SCID β2m-/- reconstituées avec des PBMC issus de patient VHB et xenotransplantées avec des hépatocytes humains transfectés avec le VHB. La vaccination de ces souris avec la lignée de pDC chargée avec les peptides HBc et HBs a permis l'amplification de lymphocytes T CD8 spécifiques du VHB capables de lyser spécifiquement les hépatocytes infectés in vivo. Ainsi, la lignée de pDC chargée avec des peptides dérivés du VHB est capable d'amplifier des lymphocytes T CD8 spécifiques du VHB et fonctionnels in vitro et in vivo. Cette nouvelle stratégie d'immunothérapie pourrait donc restaurer une immunité antivirale et permettre l'élimination du virus chez les patients atteints d'hépatite B chronique. Dans une deuxième partie, nous avons évalué le rôle physiopathologique des pDCs au cours de l'infection chronique par le VHB et les conséquences fonctionnelles sur le cross-talk pDC/NK. Des défauts fonctionnels des pDCs et des cellules NK ont été observé chez les patients atteints d'hépatite B chronique. Cependant le cross-talk pDC/NK ainsi que les mécanismes en jeu n'ont pas encore été élucidé. Nous avons étudié le phénotype et la capacité de répondre à une stimulation TLR-L des pDCs de patients comparé aux pDCs de donneurs sains puis nous avons étudié les conséquences sur le cross-talk entre pDCs de patients (virémiques ou avirémiques) et cellules NK hétérologues. Les pDCs de patients montrent un phénotype plus activé que les pDCs de donneurs sains mais ne sont pas capables de répondre à une stimulation TLR9-L. De plus, les pDCs de patients virémiques ne sont pas capables d'activer les fonctions cytotoxiques des cellules NK. Cette perturbation du cross-talk pDC/NK semble liée à un défaut de production d'IFNα et d'expression d'OX40L par les pDCs de patients virémiques, ainsi qu'à la présence d'une quantité importante d'IP-10 dans le plasma des patients. Ainsi, le VHB pourrait échapper à l'immunité en altérant la fonction des pDCs et perturbant le cross-talk pDC/NK par un mécanisme dépendant de IP-10, OX40L et IFNα.

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Dhondt, Kévin. "Etude des mécanismes de haute pathogénicité des Henipavirus". Thesis, Lyon, École normale supérieure, 2014. http://www.theses.fr/2014ENSL0954/document.

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Les Henipavirus sont des paramyxovirus zoonotiques émergents hautement pathogènes. Ils sont capables d’infecter un large spectre d’hôtes incluant notamment la chauve-souris frugivore (réservoir naturel), le porc et l’homme. Etant donné leur très grande dangerosité et en l’absence de traitements curatifs ou prophylactiques efficaces, ces virus doivent être manipulés dans un laboratoire de classe P4. Dans une première partie, nous étudions l’effet de composés glyco-amino-glycanes sur l’infection par les Henipavirus ainsi que leur potentielle application en tant que traitement. Dans une seconde partie, nous nous attachons à comprendre les interactions entre le système immunitaire de l’hôte et le virus. Afin de mieux comprendre ces interactions, nous avons utilisé une approche basée sur l’utilisation de souris déficientes pour certaines voies de l’immunité. En effet, bien que les récepteurs cellulaires au virus (EFN B2 et B3) soient fonctionnels chez la souris, celle-ci est résistante à l’infection par voie intrapéritonéale. Nous avons analysé la susceptibilité au virus Nipah (NiV) de souris privées de différentes voies du système immunitaire inné et adaptatif. Les résultats obtenus permettent d’envisager certaines lignées de ces souris comme nouveaux modèles animaux pour l’étude de l’immunopathogénèse du NiV. Cette étude suggère aussi que le système interféron de type I joue un rôle crucial dans la limitation de la propagation virale vers le cerveau et que les lymphocytes T sont nécessaires à la complète élimination du virus. Les macrophages jouent, quant à eux, un rôle central et indispensable, à l’interface entre système inné et adaptatif. Enfin, nous abordons les prémices d’un projet visant à identifier les différences d’interactions au niveau moléculaire entre les protéines non-structurales du virus et les protéines du système immunitaire inné chez l’Homme et la souris afin de voir s’il se dégage des différences d’interactions pouvant expliquer les différences de pathogénie. Ces travaux ont donc permis d’identifier de nouveaux modèles animaux et de mieux caractériser les interactions entre le pathogène et le système immunitaire de l’hôte, de l’échelle moléculaire à l’échelle de l’organisme entier. Néanmoins, les mécanismes précis de ces interactions restent à élucider et permettront certainement de mieux comprendre la grande diversité de pathogénie des Henipavirus
Henipaviruses are highly pathogenic emerging zoonotic paramyxoviruses. They can infect a broad spectrum of mammals including flying foxes (Pteropus fruit bats), its reservoir, pigs and humans. As there are neither therapeutic drugs nor efficient prophylactic treatment towards these highly lethal viruses, they have to be manipulated in biosafety level-4 laboratories. In the first part of this thesis, we study the role of glyco-amino-glycans on Henipavirus infection and their potential use as treatment. In the second part, we describe the interaction between the host immune system and the pathogen. To investigate these interactions, we took advantage of different transgenic mouse models deficient for some immune pathways. Indeed, although mice possess the viral entry receptor for Henipaviruses, they do not succumbed to intraperitoneal infection. We analyzed the susceptibility to Nipah virus (NiV) infection of mice deleted for different components of innate and adaptive immune systems. Obtained results showed that some of these mice can be used as new models for NiV immunopathogenesis study. This study also suggests that type I interferon system plays a major role in limitation of viral spreading to the brain and that T cells are necessary for full viral clearance. Macrophages act at the crossroad of immunity, between innate and adaptive system. Finally, we deal with the preliminary phases of a project which aims to identify the differences, at a molecular level, of interaction between non-structural viral proteins and innate immunity proteins in mice and human. Such differences could explain the different clinical patterns that are observed in these species. In conclusion, this thesis allowed to identify new animal models and to better characterize host-pathogen interactions, from molecular to whole organism level. However, the precise mecanisms of these interactions remain to be elucidated and would probably help to understand the great diversity of pathogeny of Henipaviruses

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O’Meara, Connor Patrick. "The development of an effective vaccine against Chlamydia : utilisation of a non-toxic mucosal adjuvant to generate a protective mucosal response". Thesis, Queensland University of Technology, 2012. https://eprints.qut.edu.au/61614/1/Connor_O%27Meara_Thesis.pdf.

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Chlamydia is responsible for a wide range of diseases with enormous global economic and health burden. As the majority of chlamydial infections are asymptomatic, a vaccine has greatest potential to reduce infection and disease prevalence. Protective immunity against Chlamydia requires the induction of a mucosal immune response, ideally, at the multiple sites in the body where an infection can be established. Mucosal immunity is most effectively stimulated by targeting vaccination to the epithelium, which is best accomplished by direct vaccine application to mucosal surfaces rather than by injection. The efficacy of needle-free vaccines however is reliant on a powerful adjuvant to overcome mucosal tolerance. As very few adjuvants have proven able to elicit mucosal immunity without harmful side effects, there is a need to develop non-toxic adjuvants or safer ways to administered pre-existing toxic adjuvants. In the present study we investigated the novel non-toxic mucosal adjuvant CTA1-DD. The immunogenicity of CTA1-DD was compared to our "gold-standard" mucosal adjuvant combination of cholera toxin (CT) and cytosine-phosphate-guanosine oligodeoxynucleotide (CpG-ODN). We also utilised different needle-free immunisation routes, intranasal (IN), sublingual (SL) and transcutaneous (TC), to stimulate the induction of immunity at multiple mucosal surfaces in the body where Chlamydia are known to infect. Moreover, administering each adjuvant by different routes may also limit the toxicity of the CT/CpG adjuvant, currently restricted from use in humans. Mice were immunised with either adjuvant together with the chlamydial major outer membrane protein (MOMP) to evaluate vaccine safety and quantify the induction of antigen-specific mucosal immune responses. The level of protection against infection and disease was also assessed in vaccinated animals following a live genital or respiratory tract infectious challenge. The non-toxic CTA1-DD was found to be safe and immunogenic when delivered via the IN route in mice, inducing a comparable mucosal response and level of protective immunity against chlamydial challenge to its toxic CT/CpG counterpart administered by the same route. The utilisation of different routes of immunisation strongly influenced the distribution of antigen-specific responses to distant mucosal surfaces and also abrogated the toxicity of CT/CpG. The CT/CpG-adjuvanted vaccine was safe when administered by the SL and TC routes and conferred partial immunity against infection and pathology in both challenge models. This protection was attributed to the induction of antigen-specific pro-inflammatory cellular responses in the lymph nodes regional to the site of infection and rather than in the spleen. Development of non-toxic adjuvants and effective ways to reduce the side effects of toxic adjuvants has profound implications for vaccine development, particularly against mucosal pathogens like Chlamydia. Interestingly, we also identified two contrasting vaccines in both infection models capable of preventing infection or pathology exclusively. This indicated that the development of pathology following an infection of vaccinated animals was independent of bacterial load and was instead the result of immunopathology, potentially driven by the adaptive immune response generated following immunisation. While both vaccines expressed high levels of interleukin (IL)-17 cytokines, the pathology protected group displayed significantly reduced expression of corresponding IL-17 receptors and hence an inhibition of signalling. This indicated that the balance of IL-17-mediated responses defines the degree of protection against infection and tissue damage generated following vaccination. This study has enabled us to better understand the immune basis of pathology and protection, necessary to design more effective vaccines.

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Klingström, Jonas. "Hantaviruses : animal models, immunology and pathogenesis /". Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-071-0/.

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Alexandre, Youenn. "Développement d'une application oropharyngée de lactobacilles pour lutter contre les infections respiratoires à Pseudomonas aeruginosa". Thesis, Brest, 2014. http://www.theses.fr/2014BRES0046/document.

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Pseudomonas aeruginosa est un pathogène opportuniste responsable de pneumonies. Il est particulièrement impliqué dans la mortalité des patients sous ventilation mécanique et des patients atteints de la mucoviscidose. Ces infections sont difficiles à traiter en raison de l’existence de nombreuses résistances aux antibiotiques chez cette bactérie et des alternatives thérapeutiques s’avèrent donc nécessaires. Nous avons ainsi émis l’hypothèse qu’une application oropharyngée de lactobacilles pourrait permettre de limiter les infections à P. aeruginosa et leurs effets chez les patients concernés. L’objectif principal de ce travail était d’évaluer les effets d’un mélange de lactobacilles dans un modèle murin de pneumonie à P. aeruginosa. Les effets de lactobacilles isolés dans les cavités orales de volontaires sains sur la formation de biofilm et l’activité élastolytique de P. aeruginosa PAO1 ont été mesurés in vitro. Les effets des lactobacilles sélectionnés ont ensuite été évalués dans un modèle d’infection de cellules épithéliales respiratoires(A549) par P. aeruginosa PAO1 puis dans un modèle murin de pneumonie à P. aeruginosa PAO1. Les effets de 87 lactobacilles sur la formation de biofilm et l’activité élastolytique de P. aeruginosa PAO1 ont été déterminés in vitro,aboutissant à la sélection de 3 et 5 souches ayant respectivement inhibé la formation de biofilm et l’activité élastolytique de P. aeruginosa PAO1. Parmi ces souches, L. fermentum K.C6.3.1E, L. paracasei ES.D.88 et L. zeae Od.76,qui étaient les souches les plus actives contre la formation de biofilm ou l’activité élastolytique et les plus acidifiantes lors de croissances dans une salive artificielle, ont été associées dans un mélange testé dans un modèle cellulaire d’infection à P. aeruginosa PAO1. Ce mélange n’a pas eu d’effet cytotoxique et a démontré un effet cytoprotecteur vis-à-vis de l’infection à P. aeruginosa PAO1. In vivo, l’administration intratrachéale de ces mêmes bactéries de façon prophylactique a permis d’une part de réduire les charges pulmonaires en P. aeruginosa PAO1 et d’autre part de réduire ses effets pro-inflammatoires au niveau pulmonaire (IL-6, TNF-α). Ces résultats prometteurs laissent entrevoir la possibilité de nouvelles applications thérapeutiques pour les probiotiques
Pseudomonas aeruginosa is an opportunistic pathogen that causes pneumonia and which is involved in themortality of mechanically-ventilated or cystic fibrosis patients.These infections are difficult to treat because of the existence of many antibiotic resistances in P. aeruginosa and therapeutic alternatives are needed. Our hypothesis was that the use of probiotics could be an alternative to antibiotic therapy in order to reduce P. aeruginosa infections and its injurious and pro-inflammatory effects in lungs.The main goal of this work was to evaluate the effects of lactobacilli in a murine model of P. aeruginosa pneumonia.The first step of this work was to screen lactobacilli isolated from oral cavities of healthy volunteers against biofilmformation and elastolytic activity of P. aeruginosa PAO1. The effects of selected lactobacilli were then evaluated in amodel of infection of lung epithelial cells by P. aeruginosa PAO1 and in a murine model of P. aeruginosa PAO1pneumonia. Eighty-seven lactobacilli were tested in vitro, leading to the selection of 3 and 5 strains respectively active against biofilm formation and elastolytic activity. The most active strains (L. fermentum K.C6.3.1E, L. paracasei ES.D.88and L. zeae Od.76) toward biofilm formation and elastolytic activity were chosen to be tested in vitro, in a cell model of P. aeruginosa PAO1 infection. This mix showed cytoprotective effect against P. aeruginosa PAO1. Finally, the prophylactic intratracheal administration of the mix of lactobacilli in mice allowed to reduce the pulmonary loads in P.aeruginosa PAO1. In the same time, the pro-inflammatory effects(IL-6 and TNF- α) of the infection were reduced. These promising results suggest the possibility of new therapeutic applications for probiotics

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Castegren, Markus. "Modulating Organ Dysfunction in Experimental Septic Shock : Effects of Aminoglycosides, Antiendotoxin Measures and Endotoxin Tolerance". Doctoral thesis, Uppsala universitet, Infektionssjukdomar, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-149274.

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Sepsis is a common diagnose in the intensive care population, burdened with a high mortality. The systemic inflammatory reaction underlying the development of septic organ dysfunction can be modeled using Gram-negative bacterial lipopolysaccharide, endotoxin. This thesis used a porcine endotoxemic experimental sepsis model to address clinical questions difficult to answer in clinical trials; furthermore a model of secondary sepsis was developed. No additional effect on the development of renal dysfunction by tobramycin was found, indicating that a single dose of tobramycin does not further compromise renal function in inflammatory-induced acute kidney injury. Antiendotoxin treatment had no measurable effect on TNF-α-mediated toxicity once the inflammatory cascade was activated. There was an effect on the leukocyte response that was associated with improvements in respiratory function and microcirculation, making it impossible to rule out fully the beneficial effect of this strategy. However, the effects were limited in relation to the magnitude of the endotoxin concentration reduction and the very early application of the antiendotoxin measure. The lungs stood out compared to the other organ systems as having a threshold endotoxin dose for the protective effect of endotoxin tolerance. As to the development of circulatory and renal dysfunction, tolerance to endotoxin was evident regardless of the endotoxin pre-exposure and challenge dose. There was a temporal variation of endotoxin tolerance that did not follow changes in plasma TNF-α concentrations and maximal tolerance was seen very early in the course. More pronounced endotoxin tolerance at the time of maximum tolerance was associated with a more marked hyperdynamic circulation, reduced oxygen consumption and thrombocytopenia eighteen hours later. It might be of interest to use the experimental model of long-term endotoxemia followed by a second hit, which has been designed to resemble an intensive care setting, for the study of treatment effects of immunomodulating therapies in secondary sepsis.
Paper 3, previous title as submitted: "Compartmentalization of organ endotoxin tolerance in a porcine model of secondary sepsis"

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Martín, Vicente Adela. "Development of new strategies for the treatment of emerging opportunistic fungal infections". Doctoral thesis, Universitat Rovira i Virgili, 2016. http://hdl.handle.net/10803/399444.

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Aspergillus fumigatus és el fong filamentós més freqüent i, encara que normalment és sensible als antifúngics, recentment s’han detectat aïllats resistents. Neocosmospora solani, Lomentospora prolificans, Scopulariopsis brevicaulis i Scopulariopsis brumptii són algunes de les espècies fúngiques multirresistents més importants. Les monoteràpies normalment no són eficaces, causant preocupants taxes de mortalitat. Per això és vital trobar tractaments alternatius i les combinacions d’antifúngics poden jugar un paper important. Scedosporium apiospermum és un fong que provoca infeccions al sistema nerviós central, sent el tractament el voriconazol. No obstant, no hi ha punts de tall establerts i es desconeix el paper que juga la determinació de la sensibilitat antifúngica en cas d’escedosporiosis. Els principals objectius d’aquesta tesi són evaluar l’activitat in vitro i l’eficàcia in vivo de combinacions d’antifúngics en front A. fumigatus i quatre espècies de fongs multiresistents; i avaluar l’eficàcia del voriconazol en front S. apiospermum en un model murí per tal de proposar punts de tall experimentals. Les combinacions de posaconazol amb anfotericina B o anidulafungina van ser eficaces en front A. fumigatus, suggerint que aquests tractaments poden representar una alternativa en cas d’aspergil·losi refractària. El tractament amb voriconazol va ser eficaç en front aquelles soques de S. apiospermum amb una CMI ≤2µg/ml però no en front la soca més resistent. Es va observar una bona correlació in vitro-in vivo, suggerint que els mètodes de difusió en disc i Etest poden ser ràpides alternatives per la determinació de la sensibilitat de S. apiospermum al voriconazol. Pel que respecta als fongos multiresistents, la combinació més sinèrgica va ser la d'anfotericina B i anidulafungina. La combinació triple també va mostrar un elevat percentatge de sinergisme però aquesta combinació no va mostrar avantatge sobre les dobles en front algunes soques, concloent que, en alguns casos una teràpia amb tres fàrmacs no seria millor que l’administració de dos.
Aspergillus fumigatus es el hongo filamentoso más frecuente y aunque normalmente es sensible a los antifúngicos, recientemente se han detectado aislados resistentes. Neocosmospora solani, Lomentospora prolificans, Scopulariopsis brevicaulis y Scopulariopsis brumptii son algunas de las especies fúngicas multirresistentes más importantes. Las monoterapias normalmente no son eficaces, causando alarmantes tasas de mortalidad. Por eso es crucial encontrar tratamientos alternativos y las combinaciones de antifúngicos podrían jugar un papel importante. Scedosporium apiospermum es un hongo que provoca infecciones del sistema nervioso central, siendo el tratamiento el voriconazol. Sin embargo, no hay puntos de corte establecidos y se desconoce el papel que juega la determinación de la sensibilidad antifúngica en casos de escedosporiosis. Los principals objetivos de esta tesis fueron evaluar la actividad in vitro y la eficacia in vivo de combinaciones de antifúngicos frente a A. fumigatus y cuatro especies de hongos multiresistentes; y evaluar la eficacia del voriconazol frente a S. apiospermum en un modelo murino con el propósito de proponer puntos de corte experimentales. Las combinaciones de posaconazol con anfotericina B o anidulafungina fueron eficaces frente a A. fumigatus, sugiriendo que estos tratamientos pueden representar una alternativa en caso aspergilosis refractaria. El tratamiento con voriconazol fue eficaz frente a aquellas cepas de S. apiospermum con una CMI ≤2µg/ml pero no frente a la cepa más resistente. Se observó una buena correlación in vitro-in vivo, sugiriendo que los métodos de disco-difusión y Etest pueden ser rápidas alternativas para la determinación de la sensibilidad de S. apiospermum al voriconazol. Con lo que respecta a los hongos multiresistentes, la combinación más sinérgica fue la de anfotericina B y anidulafungina. La combinación triple también mostró un alto porcentaje de sinergia, pero esta combinación no mostró ventaja sobre las dobles en algunas cepas, concluyendo que en algunos casos una terapia con tres fármacos no sería mejor la administración de dos.
Aspergillus fumigatus is the most prevalent filamentous fungal pathogen and, although it is usually susceptible to antifungal drugs, resistant isolates have been detected recently. In addition, Neocosmospora solani, Lomentospora prolificans, Scopulariopsis brevicaulis and Scopulariopsis brumptii are some of the most important multiresistant fungi. Antifungal monotherapies usually fail, causing alarming mortality rates. For this reason, it is crucial to find alternative treatments and antifungal combinations could play an important role. In addition, Scedosporium apiospermum is an important neurotropic fungus for which the first line treatment is voriconazole. However, breakpoints are not available and the role of the susceptibility determination in cases of scedosporiosis is largely unknown. The main objectives of the thesis were to test the in vitro activity and in vivo efficacy of antifungal combinations against A. fumigatus and four species of multiresistant fungi; and to test the efficacy of voriconazole against S. apiospermum in a murine model in order to propose experimental tentative cutoffs. A good efficacy of the combinations of posaconazole with either amphotericin B or anidulafungin was observed against A. fumigatus, suggesting that these combinations can play an important role in case of refractory aspergillosis. Voriconazole showed efficacy in those S. apiospermum isolates with a MIC ≤ 2µg/ml and did not against the most resistant strain. Additionally, a good correlation between in vitro methods and in vivo outcome was found, suggesting that disk diffusion and Etest can be rapid alternatives for determining voriconazole susceptibility of S. apiospermum. In the case of the combinations against multiresistant fungi, the most synergistic combination was amphotericin B plus anidulafungin. The triple combination also showed a high percentage of synergism but this combination did not always show advantage over the double ones, suggesting that the administration of three drugs would not be better than two in some cases.

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