Dissertations / Theses: 'Infection, Immunity and Inflammation'

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Phan, Quang Tien. "Innate immune response to tissue-specific infection : notochord infection in the zebrafish embryo." Thesis, Montpellier, 2016. http://www.theses.fr/2016MONTT082/document.

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Lors des infections bactériennes, selon les tissus infectés, et selon la nature des pathogènes, l’organisme répond en mobilisant différents acteurs. Nous avons décidé d’utiliser le modèle du zebrafish ou Danio rério pour étudier la réponse immunitaire innée dans les situations d’infection bactérienne où les phagocytes professionnels ne peuvent pas venir au contact direct des bactéries. Pour cela, j’ai développé un modèle d’infection de la notochorde del’embryon de zebrafish. Lors de l’injection des bactéries dans ce compartiment, les bactéries se retrouvent protégées par une épaisse gaine de collagènes que les phagocytes ne peuvent pas pénétrer. Alors que les mycobactéries,protégées par la gaine de collagène ne sont pas détectées par les phagocytes, les bactéries E. coli sont immédiatement détectées ce qui déclenche une importante inflammation locale autour de la notochorde. Alors que les bactéries E. coli, bien qu’inaccessibles à la phagocytose sont éliminées dans les première 24 heures qui suivent l’injection, l’inflammation dure plusieurs jours.J’ai étudié les mécanismes qui conduisent à cette inflammation persistante et ses conséquences à long terme sur le développement du poisson. J’ai montré le rôle central de la cytokine IL1b dans ce processus, et j’ai développé une lignée transgénique qui permet d’étudier l’induction de cette cytokine in vivo chez le poisson.J’ai ensuite étudié le rôle des deux principales populations de phagocytes dans l’élimination des bactéries E coli. J’ai montré que les macrophages ne sont pas impliqués dans la disparition des bactéries alors que les neutrophiles, bien qu’incapable de pénétrer à l’intérieur de la gaine de collagène sont nécessaires à l’élimination des bactéries.J’ai ensuite montré que la myelopéroxidase et le monoxyde d’azote ne sont pas impliqués dans l’élimination des bactéries alors que les espèces réactives de l’oxygène produites par les neutrophiles sont nécessaires pour éradiquer l’infection
In bacterial infections, according to the infected tissue and the nature of pathogens, the body responds by mobilizing various actors. I decided to use zebrafish or Danio rerio model to study the innate immune response to bacterial infection in the situations that professional phagocytes cannot come in direct contact with the bacteria. For this, I developed a model of infection in the notochord of zebrafish embryo. Upon injection of bacteria in this compartment, the microbes find themselves protected by the thick collagensheath where the phagocytes cannot penetrate. While mycobacteria are not detected by phagocytes; E. coli bacteria are sensed and a significant local inflammation around the notochord is mounted. The E. coli, although inaccessible to phagocytosis are eliminated within the first 24 hours after injection, the inflammation lasts several days.I studied the mechanisms that lead to this persistent inflammation and its long term consequences on the development of the fish. I showed the central role of the cytokine IL1B in this process, and I developed a transgenic line that allows studying in vivo the induction of this cytokine in fish.I then studied the roles of the two main populations of phagocytes in the elimination of E. coli. I revealed that macrophages are not involved in the removal of bacteria but neutrophils, although unable to penetrate inside the collagen casing, are necessary for the bacterial elimination. I also confirmed that myeloperoxidase and nitrogen monoxide are not involved in the removal of bacteria, rather the reactive oxygen species produced by neutrophils are needed to eradicate the infection

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Ragheb, Ramy. "Etude de l'intéraction entre inflammation et infection chez la drosophile." Thesis, Aix-Marseille, 2016. http://www.theses.fr/2016AIXM4104.

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In mammals, both sterile wounding and infection induce inflammation and activate the innate immune system, and combining both challenges can lead to severe health defects, revealing that the balance between the intensity and resolution of the inflammatory response is central for the organism's fitness. The underlying mechanisms remain however elusive. Using Drosophila as a model, we show that a sterile wounding induces a reduced resistance to a bacterial challenge and is accompanied by an increased host mortality upon infection. We further investigate the underlying molecular mechanisms of flies susceptibility to bacterial infection by comparing the transcriptome landscape of SH flies (Simple Hit: infection only), DH flies (Double Hit: trauma + infection) and control flies (sterile trauma alone) during the early steps. We observed that genes with increased expression in DH flies compared to SH ones are significantly enriched for stress related annotations, including members of the JNK pathway and demonstrate that the JNK pathway plays a central role in the DH phenotype. In addition, the CrebA/Creb3-like transcription factor and its targets are up regulated in SH flies and we show that CrebA is required for mounting the innate immune response. We also investigated the potential role of the TNF receptor grnd in SH and DH flies. Our results reveal its function in innate immune response since flies with reduced grnd function display reduced viability upon infection. Drosophila thus appears as a relevant model to investigate the complex interactions between inflammation and infection and allows to unravel key pathways involved in the acquisition of a hyper-inflammatory state

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Lajunen, T. (Taina). "Persistent Chlamydia pneumoniae infection, inflammation and innate immunity." Doctoral thesis, University of Oulu, 2008. http://urn.fi/urn:isbn:9789514289965.

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Abstract Chlamydia pneumoniae is an obligatory intracellular pathogen that causes upper and lower respiratory tract infections. Like other Chlamydial species, also C. pneumoniae has a tendency to cause persistent infections, which have been associated with different cardiovascular, neurological, and respiratory diseases. In addition, a few studies have reported an association between C. pneumoniae seropositivity and an elevated body mass index (BMI), and it has been shown that C. pneumoniae is capable of infecting preadipocytes and adipocytes. The main aims of this study were to study if certain gene polymorphisms regulate the serum levels of innate immunity and inflammation proteins, and if the polymorphisms are associated with markers of C. pneumoniae infection; to compare different methods in detection of C pneumoniae in atherosclerotic tissue; and to study if serum levels of chlamydial LPS (cLPS) are associated with BMI. The serum levels of inflammatory and innate immunity markers, namely interleukin 6 (IL-6), C-reactive protein (CRP), LPS-binding protein (LBP), and soluble CD14, in apparently healthy individuals were found to correlate with each other and possibly be regulated by the polymorphisms of genes important in inflammation and innate immunity. Especially the serum LBP levels may be regulated by the LBP (rs2232618) and toll-like receptor 4 (rs4986790) polymorphisms. The IL-6 (rs1800795) polymorphism was found to be associated with C. pneumoniae antibody positivity. C. pneumoniae DNA and cLPS could be found from atherosclerotic tissue. A new, cLPS enzyme immunoassay method was developed in this study, and it might provide a standardized, commercial method for the detection of chlamydia in tissue samples, if the sensitivity of the method could be increased e.g. by testing multiple pieces of tissue. In situ hybridization method was found to be complicated by technical problems and the repeatability of polymerase chain reaction was poor. C. pneumoniae IgG positivity and elevated serum cLPS and CRP levels were associated with an elevated BMI. There was also a strong association between cLPS levels and inflammation as measured by CRP levels. The lack of association between serum total endotoxin activity and BMI implies that the association between infection and an elevated BMI may be specific to certain pathogens.

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Thursfield, Rebecca Marie. "Infection, inflammation & innate immunity in the paediatric CF airway." Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/43757.

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This thesis focuses on infection and immunity within the airways in cystic fibrosis (CF), particularly the role of the antimicrobial peptides (part of the innate immune system) and their relationship to vitamin D status. Vitamin D response elements have been identified in the genes encoding the antimicrobial peptides cathelicidin (LL37) and human β defensins (HBD-2) and in-vitro vitamin D significantly induces expression of these peptides in both CF and non-CF bronchial epithelial cells. As innate defence is pivotal to airway health and is one of the proposed ways that vitamin D deficiency contributes to worsening respiratory health, this thesis will consider first immunity of the normal airway and the interactions with vitamin D and then discuss the pathophysiology of CF and the role of vitamin D on the innate immune system within CF. The role of vitamin D on infection and inflammation in the airways of infants with CF is explored and the impact of Vitamin D levels seen immunologically and functionally over the first year of life is described. Finally the role of vitamin D as an immunomodulatory molecule is explored in a greater range of CF disease severity and age. Through the various parameters explored, in different CF patient populations, the conclusion remains the same; vitamin D deficiency is not associated with increased infection, greater inflammation nor a worse clinical outcome. The possible reasons for the lack of any relationship are discussed in the final chapter; either a missed signal because the levels studied were on the low or high flat parts of a 2 sigmoid relationship thus effects seen only in really severe deficiency or because supra-high levels are needed to see any effect, the effect being lost in the inflammation seen within the CF airway or a true lack of relationship.

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Blackshaw, Sasha. "The manipulation of inflammation, immunity and infection by novel derivatives of halichlorine." Thesis, Manchester Metropolitan University, 2017. http://e-space.mmu.ac.uk/618825/.

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Halichlorine 1 is a marine spirocyclic alkaloid, which has shown to exhibit anti-inflammatory properties.1 Due to the complexity of this structure, and the low abundance in nature, the development of total and partial syntheses of this compound have become of interest to the organic chemist. This project aimed to evaluate the therapeutic potential of this class of compounds by producing a library of simplified halichlorine derivatives by addition of Grignard reagents onto a key spironitrone that maps onto the core structure of halichlorine and thence to monitor potential bioactivity by conducting a series of biological assays to determine what effects these compounds have on human U937 cells. Addition of a wide range of Grignard reagents to spironitrone 128 was successful and generally proceed with high diastereoselectivity. In addition, reductive cleavage of the resulting N-hydroxyspirocycles with Zn/AcOH provided a host of N-acetyl-C7-substiuted spirocyclic derivatives 167-172. Reduction with indium provided free amines 173-181. As additions to spironitrone 128 proceeded with undesired stereoselectivity attempts were made to access O-protected spironitrone 204 by oxidation of spiroamines such as 199. This strategy was unsuccessful. In order to explore alternative spirocyclic derivatives, synthetic studies were also directed in attempts to access un-substituted derivatives by ring closing metathesis (RCM) of diene precursors 222-224. While RCM substrates were accessed cyclisation of these did not proceed. It was discovered that heating 6,5-spiroisoxazolidine 102 under pressure in a microwave reactor provided access to the corresponding 6,6-isomer 164 which maps onto the core structure of the amphibian toxin histrionicotoxin (HTX). Oxidation to 6,6-spironitrone 192, as followed by conversion to cycloadducts 193-195, which represent new analogues of the HTX family of alkaloids. Grignard additions to this nitrone, did not proceed in general. Biological screenings using undifferentiated and LPS activated U937 cells helped to identify a number of biologically active derivatives, when tested in the NO and growth and viability assays. The NO assay using LPS activated cells, identified that the adducts containing larger alkyl or aryl chains, particularly the pentyl, hexyl and benzyl adducts, expressed significant differences in NO inhibition at both 10-4 M and 10-5 M concentrations tested, compared to the untreated cells.

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Maurer, Kirk J. "A systematic evaluation of the role of infection, immunity and inflammation in cholesterol gallstone pathogenesis." Thesis, Massachusetts Institute of Technology, 2007. http://hdl.handle.net/1721.1/39917.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Biological Engineering Division, 2007.
Includes bibliographical references.
Cholesterol gallstones are exceptionally common and cost nearly 10 billion U.S. dollars annually. Despite a half-century of basic and clinical research questions still remain about cholesterol gallstone pathogenesis. The purpose of the study presented herein is to analyze the roles of infection, and immunity in cholelithogenesis. The first two aims of this work were to analyze the role of enterohepatic Helicobacter spp. and the human gastric pathogen H. pylori in cholesterol gallstone formation. To test this, we prospectively infected C57UJ mice with a variety of Helicobacter spp. and fed infected and uninfected mice a lithogenic diet for eight weeks and analyzed biliary phenotype. Mice infected with H. bilis or coinfected with H. hepaticus and H. rodentium and fed a lithogenic diet developed cholesterol gallstones at 80% prevalence compared with approximately 10% in uninfected controls (P<0.05). Monoinfections with H. hepaticus, H. cinaedi, H. rodentium, and H. pylori gave a cholesterol gallstone prevalence of 40% (P<0.05), 30%, 20% and 20%, respectively; with the exception of H. hepaticus, cholesterol gallstone formation in these groups did not differ significantly from uninfected animals.
(cont.) These findings suggest that some Helicobacter spp. play a role in the cholesterol gallstone formation in mice and perhaps humans. We further hypothesized that inflammation and immunity were important in cholesterol gallstone formation and that cholelithogenic bacteria were promoting gallstones through immune stimulation. To test this we utilized BALB/c and isogenic Rag2-/- mice. When fed a lithogenic diet for eight-weeks, wild-type mice developed cholesterol gallstones (27-80% prevalence) significantly more than Rag2-/- mice (~5%, P<0.05). Transfer of functional splenocytes, or T-lymphocytes to Rag2-/- mice markedly increased cholesterol gallstone formation (26% and 40% respectively, P<0.05) whereas transfer of B-cells did not (13%). The presence of T-cells and solid cholesterol monohydrate crystals induced proinflammatory cytokine expression in the gallbladder. These studies indicate that T-cells are critical in murine cholelithogenesis and function by promoting gallbladder inflammation. In summary, these results illustrate that microbial pathogens can influence cholesterol gallstone formation; this most likely occurs by modulating the immune response with T-cells being a critical component in this immunomodulation.
by Kirk J. Maurer.
Ph.D.

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Wachholz, Kristina Lora Catherine. "Placental Infection by Salmonella Typhimurium in a Murine Model: The Role of Innate Immune Mediators in Cell Death at the Fetal-Maternal Interface." Thesis, Université d'Ottawa / University of Ottawa, 2016. http://hdl.handle.net/10393/34190.

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Maternal tolerance during pregnancy increases the risk of infection with certain intracellular pathogens such as Salmonella enterica serovar Typhimurium (S.Tm). Systemic S.Tm infection during pregnancy in normally resistant 129X1/SvJ mice, with a functional natural resistance-associated macrophage protein-1 (Nramp1), leads to severe placental infection followed by fetal and maternal death. We hypothesized infection-induced inflammatory trophoblast cell death contributes to adverse pregnancy outcomes. We therefore investigated the kinetics of systemic and oral S.Tm infection in wild-type and gene deficient mice with defects in specific inflammatory pathways. Systemic infection with S.Tm resulted in preferential placental replication compared to other tissues in Nramp1+/+ mice. At 24 hours, <25% of individual placentas per mouse were infected, progressively increasing to >75% by 72 hours which correlated with a steady increase in resorption rates. Moreover, placental infection was associated with increased neutrophils, macrophages and natural killer cells whereas neutrophil numbers in the spleen remained unchanged, suggesting dichotomous modulation of inflammation in the systemic compartment compared to the feto-maternal interface. Oral infection resulted in systemic dissemination of the bacteria, substantial placental colonization and fetal loss five days post-infection in C57BL/6J mice. Systemic infection in pregnant cell death deficient Rip3-/-Nramp1+/+ mice (with defective necroptosis) resulted in decreased fetal demise relative to Nramp1+/+ and Caspase-1,11-/-Nramp1+/+ mice (with defective pyroptosis) suggesting a role for necroptotic inflammation. This study provides insight into the kinetics and mechanism of inflammation and cell death during placental S.Tm infection. Such studies may assist in the rational management of foodborne pathogens contracted during pregnancy.

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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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Sävykoski, née Huittinen T. (Tiina). "Chlamydia pneumoniae infection, inflammation and heat shock protein 60 immunity in asthma and coronary heart disease." Doctoral thesis, University of Oulu, 2003. http://urn.fi/urn:isbn:9514269853.

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Abstract Chlamydia pneumoniae is a common respiratory pathogen worldwide. It does not only cause acute respiratory infections, but is also associated with chronic inflammatory diseases, such as asthma and coronary heart disease (CHD). Chlamydial heat shock protein 60 (Hsp60) is associated with the development of immunopathological damage following C. trachomatis infections, but the role of Hsp60 in C. pneumoniae infections is unclear. A slightly elevated level of C-reactive protein (CRP), as a marker of systemic inflammation, predicts cardiovascular events, but its role in asthma has not been studied. The aim of this study was to develop an EIA method for the measurement of Hsp60 antibodies and for studying the host immune responses to C. pneumoniae and chlamydial and human Hsp60 proteins, CRP levels and their interactions in asthma and CHD. Elevated levels of serum IgA antibodies to the Hsp60 protein of C. pneumoniae were associated with asthma and decreased pulmonary function. CRP levels were also higher in the asthma patients than in the controls. The patients with moderate asthma had higher CRP levels than those with mild asthma. The patients with a CRP level over 2 mg/l had higher levels of serum IgA antibodies to C. pneumoniae and chlamydial Hsp60 than the patients with lower CRP levels. A prospective nested case-control study was carried out, to study the role of Hsp60 antibodies as coronary risk predictors, and their association with C. pneumoniae infection and inflammation. The participants were obtained from the Helsinki Heart Study: 241 myocardial infarctions or coronary deaths occurred during the 8.5-year period among dyslipidemic middle-aged men. An elevated level of human Hsp60 IgA antibodies in baseline serum predicted the occurrence of a coronary event several years later, especially when present simultaneously with a high C. pneumoniae IgA antibody level and an elevated CRP level. Further studies showed that only persistently, not transiently, elevated levels predicted coronary events. The risk associated with elevated antibody levels increased markedly in the presence of an elevated CRP level, and vice versa. In conclusion, these results suggest that chlamydial Hsp60 is involved in the association between C. pneumoniae infection and asthma, while autoimmunity to human Hsp60 is implicated in the association between C. pneumoniae infection and CHD. Inflammation evidently plays an important role in these associations. It can also be concluded that IgA antibodies, compared to IgG antibodies, against C. pneumoniae and Hsp60 are better markers of chronicity, especially when they are persistently elevated.

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Marshall, Benjamin Giles. "Genetically modified mycobacteria as potential anti-tuberculous vaccines : an investigation of the links between inflammation, immunity and fibrosis in mycobacterial disease." Thesis, Imperial College London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.324918.

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Auma, Ann Winniefred Nangobi. "THE IMPACT OF DIRECT-ACTING ANTI-VIRAL THERAPY ON NAIVE CD4+ T CELL LYMPHOPENIA AND CELLULAR IMMUNE ACTIVATION IN HCV INFECTION AND HCV/HIV CO-INFECTION." Case Western Reserve University School of Graduate Studies / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=case1625764728651756.

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Janczy, John Roger. "Mechanisms for activation and inhibition of inflammasomes." Diss., University of Iowa, 2014. https://ir.uiowa.edu/etd/1643.

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Activation of the cysteine protease caspase-1 and the subsequent processing and secretion of the pro-inflammatory cytokines IL-1Β and IL-18 is central to the inflammatory response as well as the induction of adaptive immune responses. Caspase-1 is activated as a part of a high-molecular weight multi-protein complex termed the inflammasome. The NLRP3 inflammasome is by far the best studied of these complexes, and it is the most promiscuous in terms of activating signals. The diversity of NLRP3 activating signals makes it likely that NLRP3 does not recognize each agonist directly, rather it detects a molecule that is generated, revealed, or altered by cellular stress. Recent studies have indicated that mitochondrial dysfunction is crucial for NLRP3 inflammasome activation, yet the activating ligand has not yet been identified. Appropriate and timely activation of this inflammatory pathway is required for host immunity to a variety of pathogens, however dysregulated activation leads to autoinflammation and potentially autoimmunity. Hence it is important to identify mechanisms for inflammasome activation and regulation. Therefore, this dissertation has focused on investigating the mechanisms for activation and regulation of the NLRP3 inflammasome, and the biological consequences of these changes. We show that the mitochondrial lipid cardiolipin is required for NLRP3 inflammasome activation. We have also identifying a novel mechanism by which inflammasome activation is regulated. Data presented in this dissertation shows that IgG immune complexes effectively suppress inflammasome activation and the subsequent processing and secretion of IL-1Α and IL-1Β. Furthermore we show that immunization with IgG immune complexes suppresses both Th2 and Th17 immune responses. Together these data provide novel insights into the activating and regulatory pathways of both the innate and adaptive immune systems.

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Gumbi, Pamela. "HIV pathogenesis in the female genital tract during chronic HIV infection : the impact of inflammation, T cell memory differentiation status and homeostatic cytokines on mucosal T cell immunity." Doctoral thesis, University of Cape Town, 2010. http://hdl.handle.net/11427/10501.

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Includes bibliographical references (leaves 124-150).
The female genital tract serves as the major portal of entry for human immunodeficiency virus (HIV). Local immune factors unique to the mucosal micro-environment such as the genital tract cytokine milieu or the activation/differentiation status of T cells may play a significant role in heterosexual transmission of HIV and subsequent pathogenesis. Elucidation of the mechanisms underlying the persistent recruitment, activation and differentiation of mucosal T cells will give crucial insight into potential therapeutic targets to restore effective local immunity.

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Karmarkar, Dipti. "Modulators of the Acute Inflammatory Response: A Dissertation." eScholarship@UMMS, 2013. https://escholarship.umassmed.edu/gsbs_diss/656.

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Acute inflammatory response is caused by the rapid recruitment of leukocytes, mainly neutrophils and monocytes, from blood to the tissue site. Diverse agents, including invading pathogens, injured or dead cells, and other irritants, may stimulate this response. In the ensuing inflammatory response, the recruited leukocytes and their secreted molecules help in eliminating or containing the injurious agents and promoting tissue regeneration. But often this response is imprecise and can lead to bystander tissue damage. Unchecked neutrophil activation is implicated in the pathology of many inflammatory conditions. An in-depth understanding of the pathways regulating this response, therefore, becomes critical in identifying therapeutic targets for these diseases. In this study, we investigate the role of intestinal commensal bacteria in regulating the acute inflammatory response. Furthermore, we examine the mechanism by which Interleukin-1 (IL-1) controls the inflammatory response to sterile agents. Inflammatory responses have been studied in the context of host defense against pathogens. However, we report that the innate immune system needs to be primed by intestinal flora to enable neutrophil recruitment to diverse microbial or sterile inflammatory signals. This priming requires myeloid differentiation primary response gene (88) (MyD88) signaling. In antibiotic-treated mice, which have depleted intestinal flora, we show that neutrophils get released into the blood from the bone marrow, but have a specific defect in migration into the inflammed tissue. This deficiency can be restored by pre-stimulating the mice with a purified MyD88 ligand. Despite having reduced number of infiltrating neutrophils, antibiotic-treated mice make higher levels of pro-inflammatory cytokines in the tissue, after inflammatory challenge. This suggests that antibiotic-treated mice produce some anti-inflammatory molecule(s) that counteract the effect of the pro-inflammatory cytokines. However, this effect is not due to the overproduction of the anti-inflammatory cytokine, Interleukin-10 (IL-10). In summary, our findings highlight the role of commensals in the development of acute inflammatory responses to microbial and sterile particles. The inflammatory response to sterile dead cells has been shown to be critically dependent upon IL-1. However, several key aspects of the IL-1 signaling cascade including the source of IL-1 and the cellular target of IL-1 were unresolved. We find that in most cases, the injured cells are not a major contributor of IL-1 that is required to propagate the inflammatory signal. On the contrary, we demonstrate that both the isoforms of IL-1, IL-1α/IL-1β are generated by bone marrow-derived, tissue-resident responding cells, upon sensing the injury. We also sought to determine the identity of the cellular target of IL-1 signaling. Previous studies have shown that for cell death-induced neutrophil recruitment, interleukin-1 receptor (IL-1R) expression is required on parenchymal cells. To identify this parenchymal cell, we are currently in the process of making the conditional knockout mouse of IL-1R. The latter would facilitate the parenchymal tissue-specific deletion of IL-1R. In summary, this study reports our progress in unraveling key aspects of IL-1 signaling during sterile inflammation. Taken together, we have identified key modulators of the acute inflammatory response and their mechanisms of regulation. These findings would facilitate the development of new therapies for inflammatory diseases triggered by both microbe and sterile agents.

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Karmarkar, Dipti. "Modulators of the Acute Inflammatory Response: A Dissertation." eScholarship@UMMS, 2002. http://escholarship.umassmed.edu/gsbs_diss/656.

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Acute inflammatory response is caused by the rapid recruitment of leukocytes, mainly neutrophils and monocytes, from blood to the tissue site. Diverse agents, including invading pathogens, injured or dead cells, and other irritants, may stimulate this response. In the ensuing inflammatory response, the recruited leukocytes and their secreted molecules help in eliminating or containing the injurious agents and promoting tissue regeneration. But often this response is imprecise and can lead to bystander tissue damage. Unchecked neutrophil activation is implicated in the pathology of many inflammatory conditions. An in-depth understanding of the pathways regulating this response, therefore, becomes critical in identifying therapeutic targets for these diseases. In this study, we investigate the role of intestinal commensal bacteria in regulating the acute inflammatory response. Furthermore, we examine the mechanism by which Interleukin-1 (IL-1) controls the inflammatory response to sterile agents. Inflammatory responses have been studied in the context of host defense against pathogens. However, we report that the innate immune system needs to be primed by intestinal flora to enable neutrophil recruitment to diverse microbial or sterile inflammatory signals. This priming requires myeloid differentiation primary response gene (88) (MyD88) signaling. In antibiotic-treated mice, which have depleted intestinal flora, we show that neutrophils get released into the blood from the bone marrow, but have a specific defect in migration into the inflammed tissue. This deficiency can be restored by pre-stimulating the mice with a purified MyD88 ligand. Despite having reduced number of infiltrating neutrophils, antibiotic-treated mice make higher levels of pro-inflammatory cytokines in the tissue, after inflammatory challenge. This suggests that antibiotic-treated mice produce some anti-inflammatory molecule(s) that counteract the effect of the pro-inflammatory cytokines. However, this effect is not due to the overproduction of the anti-inflammatory cytokine, Interleukin-10 (IL-10). In summary, our findings highlight the role of commensals in the development of acute inflammatory responses to microbial and sterile particles. The inflammatory response to sterile dead cells has been shown to be critically dependent upon IL-1. However, several key aspects of the IL-1 signaling cascade including the source of IL-1 and the cellular target of IL-1 were unresolved. We find that in most cases, the injured cells are not a major contributor of IL-1 that is required to propagate the inflammatory signal. On the contrary, we demonstrate that both the isoforms of IL-1, IL-1α/IL-1β are generated by bone marrow-derived, tissue-resident responding cells, upon sensing the injury. We also sought to determine the identity of the cellular target of IL-1 signaling. Previous studies have shown that for cell death-induced neutrophil recruitment, interleukin-1 receptor (IL-1R) expression is required on parenchymal cells. To identify this parenchymal cell, we are currently in the process of making the conditional knockout mouse of IL-1R. The latter would facilitate the parenchymal tissue-specific deletion of IL-1R. In summary, this study reports our progress in unraveling key aspects of IL-1 signaling during sterile inflammation. Taken together, we have identified key modulators of the acute inflammatory response and their mechanisms of regulation. These findings would facilitate the development of new therapies for inflammatory diseases triggered by both microbe and sterile agents.

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Tu, Fei. "Roles of Endothelial Cell Heat Shock Protein A12B and β-glucan, a reagent for trained Immunity in the Regulation of Inflammation in Sepsis." Digital Commons @ East Tennessee State University, 2020. https://dc.etsu.edu/etd/3792.

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Sepsis is dysregulated host immune response to infection causing life-threatening organ dysfunction. Endothelial cell dysfunction and uncontrolled inflammatory responses are two contributors for sepsis-induced mortality. The crosstalk between endothelial and immune cells plays a critical role in the pathophysiology of sepsis. Therefore, understanding the mechanism of interaction between endothelial and immune cells will provide novel information to develop therapeutic strategies for sepsis. Pathogen associated moleculear patterns (PAMPs) and/or damage associated molecular patterns (DAMPs) produced during sepsis, activate endothelial cells to increase the expression of adhesion molecules, attracting immune cell infiltration into the tissues. Uncontrolled inflammatory responses during the early phase of sepsis contribute to organ failure and lethality. Over 100 clinical trials, targeting inflammatory responses in sepsis, have failed in the past three decades. Thereby, developing novel therapeutic strategies for sepsis are urgent. Heat shock protein A12B (HSPA12B), as one member of HSP70 family, predominately expressed in the endothelial cells, plays important roles in many pathophysiological processes. Currently, we observed endothelial cell specific HSPA12B deficiency (HSPA12B-/-) exacerbates mortality in sepsis induced by cecal ligation puncture (CLP). HSPA12B-/- septic mice exhibits increased expressions of adhesion molecule and infiltrated macrophages in the myocardium and activated macrophages in the peritoneal cavity. In vitro studies show that HSPA12B could be secreted from endothelial cells via exosome. HSPA12B carried by exosomes can be uptaken by macrophages to downregulate macrophage NF-kB activation and pro-inflammatory cytokine production. Trained immunity, induced by β-glucan, causes immune memory in innate immune cells, with an altered response towards another challenge. We have found that mice received β-glucan seven days before CLP sepsis exhibit attenuated mortality with decreased pro-inflammatory responses. We found that β-glucan significantly increased the levels of HSPA12B in endothelial cells and endothelial exosomes. β-glucan induced endothelial exosomes markedly suppress macrophage NF-kB activation and pro-inflammatory responses. The current data suggests that HSPA12B plays a novel role in the regulation of immune and inflammatory responses and that HSPA12B could be an important mediator for the crosstalk between endothelial cells and macrophages during sepsis. β-glucan regulates endothelial cell functions and immune/inflammatory responses, thus improving survival outcome in CLP sepsis.

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Tu, Fei. "Roles of Endothelial Cell Heat Shock Protein A12B and β-glucan, a reagent for trained Immunity in the Regulation of Inflammation in Sepsis." Digital Commons @ East Tennessee State University, 2008. https://dc.etsu.edu/etd/3792.

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Sepsis is dysregulated host immune response to infection causing life-threatening organ dysfunction. Endothelial cell dysfunction and uncontrolled inflammatory responses are two contributors for sepsis-induced mortality. The crosstalk between endothelial and immune cells plays a critical role in the pathophysiology of sepsis. Therefore, understanding the mechanism of interaction between endothelial and immune cells will provide novel information to develop therapeutic strategies for sepsis. Pathogen associated moleculear patterns (PAMPs) and/or damage associated molecular patterns (DAMPs) produced during sepsis, activate endothelial cells to increase the expression of adhesion molecules, attracting immune cell infiltration into the tissues. Uncontrolled inflammatory responses during the early phase of sepsis contribute to organ failure and lethality. Over 100 clinical trials, targeting inflammatory responses in sepsis, have failed in the past three decades. Thereby, developing novel therapeutic strategies for sepsis are urgent. Heat shock protein A12B (HSPA12B), as one member of HSP70 family, predominately expressed in the endothelial cells, plays important roles in many pathophysiological processes. Currently, we observed endothelial cell specific HSPA12B deficiency (HSPA12B-/-) exacerbates mortality in sepsis induced by cecal ligation puncture (CLP). HSPA12B-/- septic mice exhibits increased expressions of adhesion molecule and infiltrated macrophages in the myocardium and activated macrophages in the peritoneal cavity. In vitro studies show that HSPA12B could be secreted from endothelial cells via exosome. HSPA12B carried by exosomes can be uptaken by macrophages to downregulate macrophage NF-kB activation and pro-inflammatory cytokine production. Trained immunity, induced by β-glucan, causes immune memory in innate immune cells, with an altered response towards another challenge. We have found that mice received β-glucan seven days before CLP sepsis exhibit attenuated mortality with decreased pro-inflammatory responses. We found that β-glucan significantly increased the levels of HSPA12B in endothelial cells and endothelial exosomes. β-glucan induced endothelial exosomes markedly suppress macrophage NF-kB activation and pro-inflammatory responses. The current data suggests that HSPA12B plays a novel role in the regulation of immune and inflammatory responses and that HSPA12B could be an important mediator for the crosstalk between endothelial cells and macrophages during sepsis. β-glucan regulates endothelial cell functions and immune/inflammatory responses, thus improving survival outcome in CLP sepsis.

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Alanio, Bréchot Cécile. "Impact d'une infection virale chronique sur le répertoire T CD8 préimmun : à quel moment perd-on sa naiveté?" Thesis, Paris 6, 2015. http://www.theses.fr/2015PA066376/document.

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Le répertoire T CD8 préimmun correspond aux lymphocytes T spécifiques d'antigène circulant en périphérie, et n'ayant pas encore été activés. Ces cellules sont très rares, et de ce fait, n'ont jusqu'ici pas pu être étudiées de façon approfondie. Nous avons dans un premier temps développé un protocole d'enrichissement basé sur la technologie des tétramères. Nous avons pu détecter et énumérer des lymphocytes T CD8 naïfs spécifiques d'antigènes dans le sang de sujets sains. Nous avons ensuite utilisé cet outil pour évaluer le répertoire T préimmun de patients chroniquement infectés par le virus de l'hépatite C (cHCV). Nous avons démontré que celui-ci est significativement perturbé, avec des cellules hypersensibles à l'activation TCR et une proportion importante de lymphocytes T de phénotype mémoire alors qu'ils n'ont pourtant pas rencontré leur antigène cible. Ces anomalies disparaissent après résolution de l'infection, soulignant l'intérêt d'instaurer précocément un traitement antiviral chez ces patients. Enfin, nous avons observé dans un modèle de souris transgéniques (OTI) une proportion importante de T inexpérimentés de phénotype mémoire chez les animaux non-immunisés déficients en cxcr3. Nos travaux démontrent que les lymphocytes T inexpérimentés peuvent perdre leur naïveté dans différentes situations pathologiques. Ces résultats devraient être pris en considération pour l'optimisation de futures stratégies d'immunothérapie, notamment lorsque des patients dits "inflammatoires" sont la cible de vaccinations. Enfin, nos résultats soulignent la difficulté d'interpréter les données d'immunophénotypage en l'absence d'information sur la spécificité antigénique
The CD8 preimmune repertoire is defined as the set of circulating antigen-specific T CD8 lymphocytes that have not been activated yet by their cognate antigen. Because those cells are very rare, they have not been evaluated in humans. We developed a tetramer-based enrichment protocol that allowed for the first time direct detection and enumeration of those rare naive antigen-specific CD8 T cells in healthys. We then used this tool to characterize the CD8 preimmune repertoire in patients with chronic hepatitis C viral infection. We found that their naive CD8 T cells are dysregulated, being hypersensitive to TCR signals, and with increased proportions of memory-phenotype (MP) cells in inexperienced populations. These perturbations are reversible after viral clearance, highlighting the added benefit of early antiviral treatment. Finally, using a transgenic model (OTI), we observed high proportions of MP inexperienced T cells in the blood of cxcr3-deficient unimmunized mice. This suggests that CXCR3-dependent lymphocyte trafficking could account for some preimmune repertoire alterations. Altogether, our work demonstrates that inexperienced T cells can lose their naiveté in several pathological situations. The impact of these findings will need to be considered when designing future immunotherapeutic strategies - especially when « inflammatory » patients are being targeted. Additionally, we highlight the challenge of interpreting T-cell immunophenotyping studies without getting knowledge into antigen-specific populations

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Hopewell, Emily. "Enhancing the immune response through IKKbeta-induced activation of NF-kappaB." Scholar Commons, 2012. http://scholarcommons.usf.edu/etd/4078.

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Nuclear factor-κB (NF-κB) is one of the main regulators of inflammatory and immune responses. It is a family of transcription factors composed of five members: RelA, RelB, cRel, NF-κB1 (p105/p50), and NF-κB2 (p100/p52). Homo- and hetero-dimers of family members are inhibited by inhibitor of &klappaB (IκB) family members and activated by IκB kinase (IKK) family members. The IKK family is comprised of IKKα, IKKΒ, and IKKγ. The focus of my dissertation delves into the role of NF-κB activation by IKKΒ in both an immunotherapy setting and its role in T cell mediated anti-tumor immune responses. A central focus of immunotherapy is to develop vaccine adjuvants that are capable of enhancing a protective adaptive immune response. Microbial adjuvants in vaccines activate key transcription factors, including NF-κB and interferon response factors (IRF). The individual role of these transcription factors in successful vaccines is not clear. We used constitutively active IKKΒ (CA-IKKΒ) expressed in an adenoviral vector (AdIKK) to determine the role of classical NF-κB activation in a vaccine-induced immune response. In an in vivo model, AdIKK induced rapid and sustained NF-κB-driven inflammation in the lungs compared to the control virus. AdIKK infection had no impact on the magnitude of T cell activation as measured by IFN-γ production; however pulmonary inflammation resulted in increased cellularity of draining lymph nodes (LN) at early timepoints resulting in increased early antibody and T cell responses. Taken together, these findings show that IKKΒ-induced NF-κB activation of an inflammatory response affects the kinetics, but not the magnitude of the adaptive immune response. NF-κB is activated in many tumor types and contributes to the progression of cancer by suppressing apoptosis, and enhancing proliferation, angiogenesis and metastasis. NF-κB is also activated in other cells within the tumor microenvironment and promotes inflammation initiated by neutrophils and macrophages. In addition to inflammatory cells, T cells can be found within the tumor microenvironment and are associated with improved patient survival. Using CA-IKKΒ, we sought to determine if NF-κB activation in tumor cells could promote T cell mediated tumor immunity. In both primary tumors and a metastatic tumor model, we found that NF-κB expression in tumors rendered immunogenic through expression of Kb-OVA led to tumor rejection or growth suppression. Tumor regression was mediated by increased CD8 T cell recruitment by chemokines. Microarray results showed increases in T cell chemokines, including CCL2 and CCL5. Knock-down of CCL2 by Lentiviral shRNA in LLC-OVA-IKK cells resulted in abrogation of tumor regression. These results suggest that NF-κB is capable of promoting immune surveillance in tumors through increased recruitment of T cells. Overall, my dissertation highlights beneficial roles of IKKΒ-induced activation of NF-κB in two separate systems: vaccine induced immune responses and tumor immune surveillance.

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Rantala, A. (Aino). "Susceptibility to respiratory tract infections in young men: the role of inflammation, mannose-binding lectin, interleukin-6 and their genetic polymorphisms." Doctoral thesis, University of Oulu, 2010. http://urn.fi/urn:isbn:9789514262937.

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Abstract Respiratory tract infections are the most common acute illnesses, and innate immunity and inflammation are important in defence against these infections. Mannose-binding lectin (MBL) mediates innate immune defences by recognising microbial structures. MBL deficiency caused by polymorphisms in the MBL2 gene has been associated with susceptibility to recurrent infections. Interleukin-6 (IL-6) is a mediator of inflammatory response. Polymorphisms in the IL-6 and IL-6 receptor (IL-6R) genes have been previously associated mainly with metabolic disorders and cardiovascular diseases. Chlamydia pneumoniae is a common pathogen in acute respiratory tract infections, but it also has a tendency to cause persistent infections, which have been associated with cardiovascular diseases and its risk factors, such as obesity. The aims of this study were to investigate if selected polymorphisms of the MBL2, IL-6 and IL-6R genes are associated with respiratory tract infections and markers of C. pneumoniae infection, and to study if persistent C. pneumoniae infection is connected with an elevated body mass index (BMI) in 893 Finnish male military conscripts. Respiratory tract infections were followed during their military service and serum samples were collected at the beginning and end of their service and during each infectious episode. A variation in serum MBL levels between different MBL2 genotypes and a MBL deficiency in homozygous exon 1 variant genotypes (at codons 52, 54 and 57) were observed. Low MBL levels and MBL2 polymorphisms in exon 1 and promoter region were found to be risk factors for susceptibility to respiratory tract infections as well as for positivity and a rise in C. pneumoniae antibodies during military service. Associations between IL-6R gene polymorphisms in the promoter region (-183G/A) and in intron 1 and respiratory tract infections were found. In addition, the IL-6 -174G/C polymorphism was associated with persistently elevated C. pneumoniae antibodies and with slightly elevated serum C-reactive protein (CRP) levels, pointing to chronic C. pneumoniae infection. Furthermore, persistent C. pneumoniae antibodies as a suggestive marker of chronic infection, and elevated serum CRP levels as a marker of systemic inflammation, were associated with an elevated BMI. In conclusion, the findings support the role for MBL in susceptibility to infections and provide new information about the association between MBL and common respiratory tract infections. The results also suggest that the 5’ area of the IL-6R gene may be a possible candidate region for respiratory tract infection susceptibility, and that IL-6 genetics may be associated with C. pneumoniae infection. The study also provides new information about the role of possible chronic C. pneumoniae infection in obesity
Tiivistelmä Hengitystieinfektiot ovat yleisimpiä äkillisiä sairauksia, ja synnynnäisellä immuunivasteella ja tulehduksella on tärkeä rooli puolustuksessa näitä infektioita vastaan. Synnynnäiseen immuniteettiin kuuluva mannoosia sitova lektiini (MBL) tunnistaa infektioita aiheuttavien mikrobien rakenteita. MBL2-geenin polymorfismien aiheuttaman MBL-proteiinin puutteen on todettu altistavan toistuville infektioille. Interleukiini-6 (IL-6) on tulehduksen välittäjänä toimiva sytokiini. IL-6- ja IL-6-reseptori (IL-6R) -geenien polymorfismit on aikaisemmin yhdistetty lähinnä metabolisiin häiriöihin sekä sydän- ja verisuonitauteihin. Chlamydia pneumoniae eli keuhkoklamydia on yleinen hengitystieinfektioiden aiheuttaja, mutta se voi myös aiheuttaa kroonisia infektioita, jotka on yhdistetty sydän- ja verisuonitauteihin sekä niiden riskitekijöihin kuten lihavuuteen. Työn tarkoituksena oli tutkia tiettyjen MBL2-, IL-6- ja IL-6R-geenien polymorfismien yhteyttä hengitystieinfektiohin ja keuhkoklamydiavasta-ainetasoihin sekä keuhkoklamydiainfektion yhteyttä painoindeksiin 893 suomalaisella varusmiehellä. Hengitystieinfektioita seurattiin palveluksen aikana, ja seeruminäytteet kerättiin palveluksen alussa, lopussa ja jokaisen infektion aikana. Tutkimuksessa havaittiin vaihtelua seerumin MBL-pitoisuudessa eri MBL2-genotyyppien välillä sekä MBL:n puute homotsygooteissa eksoni 1 -alueen varianttigenotyypeissä (kodoneissa 52, 54 ja 57). Alhaiset MBL-tasot sekä MBL2-geenin polymorfismit eksoni 1 -alueella ja säätelyalueella olivat riskitekijöitä hengitystieinfektioalttiudelle sekä keuhkoklamydiavasta-aineiden esiintymiselle ja vasta-aineiden nousulle palveluksen aikana. IL-6R-geenin polymorfismit säätelyalueella (-183G/A) ja introni 1 -alueella liittyivät hengitystieinfektioihin. Lisäksi IL-6-geenin -174G/C polymorfismi oli yhteydessä jatkuvasti kohonneisiin keuhkoklamydiavasta-aineisiin sekä seerumin C-reaktiivisen proteiinin (CRP) tasoihin, jotka mahdollisesti osoittaisivat kroonista keuhkoklamydiainfektiota. Lisäksi krooniseen keuhkoklamydia-infektioon viittaavat vasta-ainetasot sekä tulehdukseen liittyvä kohonnut CRP-pitoisuus olivat yhteydessä ylipainoon. Tutkimuksen tulokset tukevat aikaisemmin havaittua MBL:n vaikutusta infektioalttiuteen ja lisäksi antavat uutta tietoa MBL:n yhteydestä tavallisiin hengitystieinfektioihin. Tulokset viittaavat myös siihen, että IL-6R-geenin 5’-alueella voi olla yhteyttä hengitystieinfektioalttiuteen ja että IL-6-polymorfismi olisi yhteydessä keuhkoklamydiainfektioon. Tutkimus antaa myös uutta tietoa mahdollisen kroonisen keuhkoklamydiainfektion liittymisestä ylipainoon

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Kheir, Saadé. "Etude d'une thérapie cellulaire par transplantation intrapulmonaire de macrophages dans le traitement d'une infection aigue à pseudomonas aeruginosa." Thesis, Université de Paris (2019-....), 2019. http://www.theses.fr/2019UNIP7085.

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Pseudomonas aeruginosa (P.a) est un bacille Gram négatif responsable d’infections chroniques associées à une mortalité élevée due à la prédilection de la bactérie à développer une résistance aux antibiotiques et l’inefficacité des thérapies actuelles. Notre groupe a montré dans un modèle d’infection aigue chez la souris, que l’élastase B (LasB), un facteur de virulence de P.a, dégrade la cytokine IL-6 et la molécule antimicrobienne Elafine et que la surexpression de ces deux médiateurs confère une protection aux souris en diminuant l’inflammation et augmentant la réparation. Les macrophages alvéolaires représentent la population myéloïde la plus abondante dans l’espace alvéolaire et jouent un rôle clé dans le maintien de l’homéostasie, l’initiation & la résolution de l’inflammation. Compte tenu de leur importance, ils sont très étudiés dans le cadre de développement de nouvelles approches de thérapie cellulaire. Nous avons donc émis l’hypothèse que le macrophage alvéolaire qui est également cible de P.a et de LasB plus particulièrement, puisse être un outil adéquat pour le transfert de la protection IL-6- et Elafine-médiée. L’objectif principal de ce travail est de modifier le macrophage avec des vecteurs adénoviraux permettant la surexpression de l’IL-6 et de l’Elafine, et de l’utiliser comme un outil thérapeutique dans un modèle de transplantation intrapulmonaire suivie d’une infection par P.a. Nous montrons que le transfert de macrophages génétiquement modifiés avec l’IL-6 et l’Elafine est protecteur. L’Elafine induit dans le macrophage une signature IL6/IL10/peptides antimicrobiens qui, en synergie avec l’IL-6, confère un phénotype régulateur à l’unité alvéolaire
Pseudomonas aeruginosa (P.a) is a Gram-negative bacillus responsible for chronic infections associated with high mortality due to the bacterium's predilection for developing antibiotic resistance and the inefficacy of current therapies. Our group showed in a model of acute infection in mice that Elastase B (LasB), a virulence factor of Pa, degrades the cytokine IL-6 and the antimicrobial molecule Elafine and that the overexpression of these two mediators provides protection to mice by decreasing inflammation and increasing repair. Alveolar macrophages represent the most abundant myeloid population in the alveolar space and play a key role in maintaining homeostasis, initiation and resolution of inflammation. Given their importance, they are very much studied in the development of new approaches to cell therapy. We therefore hypothesized that the alveolar macrophage which is also targeted by P.a and LasB more particularly, may be an adequate tool for the transfer of IL-6- and Elafine-mediated protection. The main objective of this work is to modify the macrophage with adenoviral vectors allowing the overexpression of IL-6 and Elafine, and to use it as a therapeutic tool in an intrapulmonary transplantation model followed by a Pa infection We show that the transfer of genetically modified macrophages with IL-6 and Elafine is protective. Elafine induces in the macrophage an IL6 / IL10 / antimicrobial peptide signature which, in synergy with IL-6, confers a regulatory phenotype to the alveolar unit

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Stoicov, Calin. "Pathogenesis of the Helicobacter Induced Mucosal Disease: A Dissertation." eScholarship@UMMS, 2010. https://escholarship.umassmed.edu/gsbs_diss/477.

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Helicobacter pylori causes chronic gastritis, peptic ulceration and gastric cancer. This bacterium is one of the most prevalent in the world, but affects mostly the populations with a lower socioeconomical status. While it causes gastric and duodenal ulcers in only 20% of infected patients, less then 1% will develop gastric adenocarcinoma. In fact, H. pylori is the most important risk factor in developing gastric cancer. Epidemiological studies have shown that 80% of gastric cancer patients are H. pylori positive. The outcome of the infection with this bacterium depends on bacterial factors, diet, genetic background of the host, and coinfection with other microorganisms. The most important cofactor in H. pylori induced disease is the host immune response, even though the exact mechanism of how the bacterium is causing disease is unknown. The structural complexity of Helicobacter bacteria makes us believe that different bacterial factors interact with different components of the innate immunity. However, as a whole bacterium it may need mainly the TLR2 receptor to trigger an immune response. The type of adaptive immunity developed in response to Helicobacter is crucial in determining the consequences of infection. It is now known for decades that a susceptible host will follow the infection with a strong Th1 immune response. IFNγ, IL-12, IL-1β and TNF-α are the key components of a strong adaptive Th1 response. This is further supported by our work, where deficient T-bet (a master regulator for Th1 response) mice were protected against gastric cancer, despite maintaining an infection at similar levels to wild type mice. On the other hand, a host that is resistant to Helicobacter develops an infection that is followed by a Th2 response sparing the mucosa from severe inflammation. Human studies looking at single nucleotide polymorphism of cytokines, like IL-1β, IL-10 and TNF-α have clearly demonstrated how genotypes that result in high levels of IL-1β and TNF-α, but low IL-10 expression may confer a 50-fold higher risk in developing gastric cancer. The outcome of Helicobacter infection clearly relies on the immune response and genetic background, however the coinfection of the host with other pathogens should not be ignored as this may result in modulation of the adaptive immunity. In studying this, we took advantage of the Balb/C mice that are known to be protected against Helicobacter induced inflammation by mounting a strong Th2 polarization. We were able to switch their adaptive immunity to Th1 by coinfected them with a T. gondii infection (a well known Th1 infection in mice). The dual infected mice developed severe gastritis, parietal cell loss and metaplastic changes. These experiments have clearly shown how unrelated pathogens may interact and result in different clinical outcomes of the infected host. A strong immune response that results in severe inflammation will also cause a cascade of apoptotic changes in the mucosa. A strict balance between proliferation and apoptosis is needed, as its disruption may result in uncontrolled proliferation, transformation and metaplasia. The Fas Ag pathway is the leading cause of apoptosis in the Helicobacter-induced inflammation. One mechanism for escaping Fas mediating apoptosis is upregulation of MHCII receptor. Fas Ag and MHCII receptor interaction inhibits Fas mediated apoptosis by an impairment of the Fas Ag receptor aggregation when stimulated by Fas ligand. Because H. pylori infection is associated with an upregulation of the MHCII levels on gastric epithelial cells, this indeed may be one mechanism by which cells escape apoptosis. The link between chronic inflammation and cancer is well known since the past century. Helicobacter infection is a prime example how a chronic inflammatory state is causing uncontrolled cell proliferation that results in cancer. The cell biology of “cancer” is regarded not as an accumulation of cells that divide without any control, but rather as an organ formed of cancer stem cells, tumor stromal support cells, myofibroblasts and endothelial cells, which function as a group. The properties of the cancer stem cells are to self-renew and differentiate into tumor cells thus maintaining the tumor grow, emphasizing that a striking similarity exists between cancer stem cells and tissue stem cells. We looked into what role would BMDCs play in chronic inflammation that causes cancer. Using the mouse model of Helicobacter induced adenocarcinoma we discovered that gastric cancer originates from a mesenchymal stem cell coming from bone marrow. We believe that chronic inflammation, in our case of the stomach, sets up the perfect stage for bone marrow stem cells to migrate to the stomach where they are exposed to inflammatory stimuli and transform into cancer stem cells. One of the mechanism by which the MSC migrate to the inflammation site is the CXCR4/SDF-1 axis. Our work sheds new light on Helicobacter induced gastric cancer pathogenesis. I hope that our findings will promote the development of new therapies in the fight against this deadly disease.

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Ghosh, Sreya. "Different Journeys, Same Destination: Exploring the Role of a PYHIN Protein and Involvement of Caspase-8 in the Regulation and Activation of Inflammasomes." eScholarship@UMMS, 2009. http://escholarship.umassmed.edu/gsbs_diss/928.

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Interferon-inducible PYHIN protein family includes the DNA-binding proteins, AIM2 and IFI16, which form ASC-caspase 1 dependent inflammasomes, important in immunity against cytosolic bacteria, DNA viruses and HIV. The role of other members of this family in the recognition of DNA and/or regulation of immune responses is unclear. We identified an immune regulatory function of p205, another member of the PYHIN family, in the transcriptional control of immune genes. Knockdown of p205 in macrophages revealed that inflammasome activation due to dsDNA and ligands that engage the NLRP3 inflammasome were severely compromised. Detailed mechanistic analysis showed that loss of p205 was associated with a decrease in Asc mRNA and protein levels. p205 knockdown resulted in reduced RNA Polymerase II-mediated endogenous Asc gene transcription and mRNA processing, suggesting a co-transcriptional control of Asc gene expression. Ectopically expressed p205 induced expression of an Asc gene-luciferase reporter and collaborated with other transcription factors, such as c/EBPβ, p65/RelA, to further enhance expression. p205 knockdown also affected the expression of the immune genes Cd86, Cox2, Cxcl2, Il1α, Il10, Il12α, Il6 and Ifnα in LPS-stimulated macrophages. Together these findings suggest that p205 regulates inflammation through control of Asc gene expression, and other immune genes. Fungal infections activate both caspase 1-dependent and -independent inflammasomes. In an independent study, we show that Paracoccidioides brasiliensis fungal infection also induces caspase 8-dependent non-canonical inflammasome. Caspase 8-dependent IL-1β processing required dectin-1, Syk and Asc. Rip3-/- Casp8-/- mice infected with P. brasiliensis displayed increased fungal load and showed worse disease progression compared to wild type and Rip3-/- mice. These results revealed the importance of caspase 8 in activating and regulating inflammasome responses during fungal infection in vivo.

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Ghosh, Sreya. "Different Journeys, Same Destination: Exploring the Role of a PYHIN Protein and Involvement of Caspase-8 in the Regulation and Activation of Inflammasomes." eScholarship@UMMS, 2017. https://escholarship.umassmed.edu/gsbs_diss/928.

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Interferon-inducible PYHIN protein family includes the DNA-binding proteins, AIM2 and IFI16, which form ASC-caspase 1 dependent inflammasomes, important in immunity against cytosolic bacteria, DNA viruses and HIV. The role of other members of this family in the recognition of DNA and/or regulation of immune responses is unclear. We identified an immune regulatory function of p205, another member of the PYHIN family, in the transcriptional control of immune genes. Knockdown of p205 in macrophages revealed that inflammasome activation due to dsDNA and ligands that engage the NLRP3 inflammasome were severely compromised. Detailed mechanistic analysis showed that loss of p205 was associated with a decrease in Asc mRNA and protein levels. p205 knockdown resulted in reduced RNA Polymerase II-mediated endogenous Asc gene transcription and mRNA processing, suggesting a co-transcriptional control of Asc gene expression. Ectopically expressed p205 induced expression of an Asc gene-luciferase reporter and collaborated with other transcription factors, such as c/EBPβ, p65/RelA, to further enhance expression. p205 knockdown also affected the expression of the immune genes Cd86, Cox2, Cxcl2, Il1α, Il10, Il12α, Il6 and Ifnα in LPS-stimulated macrophages. Together these findings suggest that p205 regulates inflammation through control of Asc gene expression, and other immune genes. Fungal infections activate both caspase 1-dependent and -independent inflammasomes. In an independent study, we show that Paracoccidioides brasiliensis fungal infection also induces caspase 8-dependent non-canonical inflammasome. Caspase 8-dependent IL-1β processing required dectin-1, Syk and Asc. Rip3-/- Casp8-/- mice infected with P. brasiliensis displayed increased fungal load and showed worse disease progression compared to wild type and Rip3-/- mice. These results revealed the importance of caspase 8 in activating and regulating inflammasome responses during fungal infection in vivo.

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Textoris, Julien. "Réponse à l'infection : apport du transcriptome." Phd thesis, Université de la Méditerranée - Aix-Marseille II, 2011. http://tel.archives-ouvertes.fr/tel-00723077.

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Avant propos L'objectif de cette thèse est d'explorer l'inflammation et l'infection au niveau du transcriptome, à l'aide de la technologie des puces à ADN. Pour cela, nous avons dans un premier temps travaillé sur des données publiques. Nous avons construit une base de données de signatures transcriptionnelles annotées, et développé un logiciel modulaire d'analyse. Ce logiciel permet d'explorer aisément les données publiques en effectuant des recherches par nom de gène ou par mots-clés. Nous avons ensuite exploré la modulation temporelle de l'expression des gènes du parenchyme pulmonaire dans un modèle murin d'inflammation aiguë par injection d'acide oléique. Dans un second modèle murin d'infection par Coxiella burnetii, nous avons analysé le rôle du sexe dans la modulation de la réponse transcriptionnelle hépatique, et identifié des voies métaboliques impliquées dans le contrôle de l'infection. Dans un troisième modèle in-vitro d'infection par différentes souches du virus de la grippe, nous avons identifié une signature transcriptionnelle commune de réponse à l'infection. Par une approche bio-informatique originale, cette signature a conduit à l'identification de nouveaux anti-viraux à large spectre, dont l'efficacité a été démontrée in-vitro sur les souches utilisées pour l'analyse, et sur la souche H1N1, responsable de la dernière pandémie grippale. Enfin, nous avons analysé les modulations du transcriptome lors de pneumonies associées à la ventilation mécanique compliquant l'évolution de sujets traumatisés graves admis en réanimation.

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Rahman, Muhammad Jubayer. "Mucosal immunity against mycobacterial infection." Doctoral thesis, Stockholms universitet, Wenner-Grens institut, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-39170.

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This thesis aimed to the identification of immune biomarkers of mycobacterial infection for better diagnosis of tuberculosis (TB) and also focused on new vaccination strategies with a particular emphasis on the immune responses in the respiratory tract using murine models. Since the lung is the natural habitat for the M. tuberculosis, we reasoned that immune responses detected locally in the lungs would be good correlates of infection (Paper I). Likewise, immune responses induced in the respiratory tract following immunization would be more effective against mycobacterial infection. We showed that cytokines (IL-12, TNF, and IFN-γ) and cytokine receptors (sTNFR1 and sTNFR2) together with specific antibodies in the respiratory tract correlated better with the bacterial burden in the organs. In Paper II, we investigated the role of the BCG vaccination as a priming vaccine in a heterologous prime-boost immunization protocol. The results showed that the neonatal BCG vaccination primed the immune system for a relevant antigen and showed a generalized adjuvant effect. Using this immunization protocol, protective immune responses in the lungs were generated independently of the route used for the booster immunization. In Paper III, We showed that exposure to mycobacterial antigens during the gestational period led to antigen transportation from the mother to the fetus and this resulted in an early priming of the fetal immune system. Immunization with the same antigen during the postnatal life increased antigen-specific recall IFN-γ responses and protection against infection. We examined the role of innate immunity for the induction of acquired immune responses upon immunization with mycobacterial antigens using TLR2 deficient mice (Paper IV). Our data indicated that suboptimal innate immune responses in the TLR2-/- mice might compromise the induction of acquired immune responses. Overall, the current findings suggested that a better understanding of the mucosal immunity would be useful for the improvement of diagnostic procedures and the development of efficient vaccines against TB.
At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript

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Permpoonpattana, Patima. "Clostridium difficile : infection and immunity." Thesis, Royal Holloway, University of London, 2013. http://repository.royalholloway.ac.uk/items/33009ec4-7815-0803-d39b-f968c8d9cdbb/7/.

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Clostridium difficile is a Gram positive pathogen of significant importance in the UK, Europe and the USA. No vaccine has been developed and current treatments are focused on hospital management and the use of antibiotics. The disease is spread in hospitals in the spore form and the role of spores in C. difficile infecton is poorly understood. In this project spores of C. difficile have been characterised. The proteins from the outermost layers of the spore were identified and the genes cloned. Three of these surface proteins have unique enzymatic properties that maybe important for symptoms of disease. The ability of C. difficile spores to adhere to intestinal cells was found to be far greater than with live cells and through this we have identified that the spore may play an important role in colonisation. The regulation of spore coat gene expression during sporulation was also examined and temporal phases of genes expression identified. A major part of this project was to develop a mucosal vaccine to C. difficile. The approach used was to clone the C-terminus of toxin A onto the surface of Bacillus subtilis spores and use these recombinant spores to immunise mice and hamsters. We found that oral delivery of these spores conferred 75% protection to C. difficile infection in a hamster model of infection. Further, parenteral immunisation of the same antigens (toxin A and B) failed to generate mucosal responses and this showed that mucosal immunisation is critical for good protection. Finally, we found that antibodies to the C-terminus of toxin A were cross reactive to the C-terminus of toxin B. This showed that mucosal delivery of just the C-terminus of toxin A is sufficient to confer protection in an animal model of infection. The outcome of this work is that we have shown the parameters for successful immunisation and vaccination against C. difficile.

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Wuttge, Dirk Marcus. "Cellular immunity and inflammation in atherosclerosis /." Stockholm : Karolinska Univ. Press, 2001. http://diss.kib.ki.se/2001/91-7349-051-2/.

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Salzano, Sonia. "Redox regulation of inflammation and immunity." Thesis, University of Brighton, 2013. https://research.brighton.ac.uk/en/studentTheses/f28a2a37-9169-4b2a-abe8-ee83c6bfe86f.

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Inflammation is a consequence of the activation of innate immunity and represents an important component of several pathological conditions, including not only the complication of infections but also sterile and autoimmune diseases. An early event in inflammation is represented by the production of proinflammatory cytokines and both their production and action have often been associated to oxidative stress. The redox status of the cell is therefore a key regulator of inflammation and glutathionylation (formation of mixed disulphides between cysteine residues of proteins and glutathione) is considered an important mechanism of this regulation. While most of the studies in the past focused on glutathionylation of intracellular proteins and transcription factors, the main goal of this project was to verify whether glutathionylated proteins are released by inflammatory cells and if these have a biological role. Using redox proteomics, we identified several proteins in the supernatants from Raw 264.7 cells (murine macrophages) stimulated with bacterial lipopolysaccharide (LPS). Among the identified proteins, we focused our attention on Peroxiredoxin 2 (Prx2), an antioxidant enzyme involved in cells protection against oxidative stress by removing H2O2. Released Prx2 was also detected in supernatant from human peripheral blood mononuclear cells (PBMC) and human macrophages. Prx2 levels were also increased in the serum of LPS-treated mice. We could confirm that Prx2 is released in the glutathionylated form. Moreover it was observed that the intracellular level of glutathione affects Prx2 release suggesting a role for glutathionylation in the mechanism of its release. The second part of the project was to verify whether released glutathionylated proteins may act as mediators of inflammation. To this purpose, the possible inflammatory role of released Prx2 was studied. The results showed that extracellular Prx2 induced an increase of TNF-α production in Raw 264.7 cells and in human macrophages. In conclusion, Prx2 is released during inflammation in a redox-dependent manner, in addition to its well-known intracellular role as enzyme, Prx2, in its released form, can also play a role in inflammatory response.

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Silvera, Peter. "Immunity to Simian Imunodeficiency Virus infection." Thesis, Open University, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.242518.

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Holm, Angelika. "Aquaporins in Infection and Inflammation." Doctoral thesis, Linköpings universitet, Avdelningen för mikrobiologi och molekylär medicin, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-127500.

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The ability of eukaryotic cells to change their shape and to migrate directionally is highly dependent on active volume regulation in cells building up tissues as well as in individual cells. Transmembrane fluxes of water via specialized water channels, called aquaporins (AQPs), facilitate the changes of volume and shape, which additionally require a complex interplay between the plasma membrane and the cytoskeleton. AQPs have been shown to be involved in the development of inflammatory processes and diseases. The aims of the studies underlying this thesis were to further elucidate the expression and function of AQPs in both bacterial and viral infections as well as in the inflammatory disease, microscopic colitis. For this, molecular techniques qPCR, immunoblotting and live, holographic, confocal and super-resolution imaging were used. When cells of the innate immune system encounter pathogens they need to respond and prepare for migration and phagocytosis and do so through volume regulatory processes. The Gramnegative bacterium Pseudomonas aeruginosa utilizes a small molecule-based communication system, called quorum sensing (QS) to control the production of its virulence factors and biofilms. We found that P. aeruginosa with a complete QS system elicits a stronger phagocytic response in human blood-derived macrophages compared to its lasI-/rhlI- mutant lacking the production of the QS molecules N-butyryl-L-homoserine lactone (C4-HSL) and N-3-oxododecanoyl-L-homoserine lactone (3O-C12-HSL). Infection with P. aeruginosa further increases the expression of AQP9 and induces re-localisation of AQP9 to the front and trailing ends of macrophages. Moreover, the 3O-C12-HSL alone elevates the expression of AQP9, redistribute the water channel to the front and rear ends and increases the cell area and volume of macrophages. Both infection with the wild type P. aeruginosa and the treatment with 3OC12-HSL change the nano-structural architecture of the AQP9 distribution in macrophages. Viruses use the intracellular machinery of the invaded cells to produce and assemble new viral bodies. Intracellular AQPs are localised in a membranes of cellular organelles to regulate their function and morphology. C3H10T1/2 fibroblasts transiently expressing green fluorescent protein (GFP)-AQP6 show a reduced expression of AQP6 after Hazara virus infection and an increased cell area. Overexpressing AQP6 in C3H10T1/2 cells reduces the infectivity of Hazara virus indicating that AQP6 expression has a protective role in virus infections. Ion and water channels in the epithelial cell lining tightly regulate the water homeostasis. In microscopic colitis (MC), patients suffer from severe watery diarrhoeas. For the first time, we have shown that the expression of AQP1, 8 and 11 and the sodium/hydrogen exchanger NHE1 are reduced in colonic biopsies from MC patients compared to healthy control individuals. Following treatment with the glucocorticoid budesonide the patients experienced a rapid recovery and we observed a restored or increased expression of the AQPs and NHE1 during treatment, suggesting a role for AQPs in the diarrhoeal mechanisms in MC. Taken together, this thesis provides new evidence on the importance of water homeostasis regulation through AQPs during infections and inflammation and opens up a door for further investigations of roles for AQPs in inflammatory processes.

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Thorpe, Callum. "Immunity and pathology to Chlamydia pneumoniae infection." Thesis, Imperial College London, 2006. http://hdl.handle.net/10044/1/11264.

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Xie, Fang. "Infection and immunity in pregnancy and preeclampsia." Thesis, University of British Columbia, 2010. http://hdl.handle.net/2429/30063.

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Preeclampsia is a hypertensive disorder of pregnancy, which shares similar risk factors with atherosclerosis. There is increasing evidence to suggest that Chlamydia pneumoniae (C. pneumoniae) and cytomegalovirus (CMV) are linked with atherosclerosis and may trigger inflammation during pregnancy. However, the roles of these two microbes and the underlying immune mechanism remain unclear. Case control studies were preformed to examine the evidence of C. pneumoniae and CMV infection, immune response and Toll like receptor (TLR) gene variations in women with preeclampsia compared with normotensive intrauterine growth restriction (nIUGR), and normal pregnancy and non-pregnancy controls. At each stage, a systematic review and data synthesis methodology are applied to place our findings within the context of published studies in the area of C. pneumoniae and CMV infection and TLR gene variations in preeclampsia to clarify apparent discrepancies in these studies. In the first paper, an increase of C. pneumoniae genomic DNA loads was detected in preeclampsia when compared with normal pregnancy and non-pregnancy controls. Data synthesis indicated C. pneumoniae IgG seropositivity was more prevalent in preeclampsia patients. The second paper detected that preeclampsia had higher CMV IgG antibody level than normal pregnancies. Further, anti-CMV IgG seropositivity was more prevalent in women with preeclampsia than nIUGR and normal pregnancy controls. The third paper discussed up-regulated neutrophil TLR2 and TLR4 protein as well as mRNA expression in preeclampsia where the difference was more markedly in an early-onset preeclampsia condition. Early-onset preeclampsia was associated with elevated mRNA expression of cryopyrin, NF-kappaBp50, NF-kappaBp65 and IL-1β, as well as increased pro- versus anti-inflammatory cytokine ratios (TNF-α/IL-10 and IL-6/IL-10). Finally, in the fourth paper, data synthesis has suggested that gene variations in TLR2 or TLR4 were associated with early-onset preeclampsia. In summary, our findings indicated that infection with C. pneumoniae and CMV may trigger the maternal inflammation crossing the threshold development of preeclampsia. A better understanding of immunology and genetic basis of preeclampsia may reveal therapeutic opportunities for treatment of this disorder and lead to improved health for both mother and fetus.

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Noursadeghi, Mahdad. "Studies of innate immunity to bacterial infection." Thesis, Imperial College London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.406424.

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Nixon, Douglas F. "Cytotoxic T cell immunity in HIV infection." Thesis, University of Oxford, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.291435.

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Lobbermann, Jens. "Regulation of immunity during viral lung infection." Thesis, Imperial College London, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.544288.

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Westman, Gabriel. "Herpesvirus Infection and Immunity in Neurocognitive Disorders." Doctoral thesis, Uppsala universitet, Infektionssjukdomar, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-247187.

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Herpesviruses have co-speciated with several vertebrate and invertebrate animals throughout the history of evolution. In the immunocompetent human host, primary infection is usually benign, whereafter the virus is brought into life-long latency. Viral reactivation can however cause severe disease in immunocompromised, and rarely also in immunocompetent, patients. The overall aim of this thesis was to study the immunologic effects of cytomegalovirus (CMV) and herpes simplex type 1 (HSV-1) infection in neurocognitive disorders. CMV is known to promote T-cell differentiation towards a more effector-oriented phenotype, similar to what is seen in the elderly. We have addressed the frequency of CMV-specific CD8+ T-cells in Alzheimer's disease (AD). Furthermore, we have investigated whether AD patients present with a different CMV-specific immune profile, overall CD8 phenotype or inflammatory cytokine response to anti-CD3/CD28 beads, CMV pp65 and amyloid beta. Subjects with AD presented with a lower proportion of CMV-specific CD8+ T-cells compared to non-demented (ND) controls, but no differences in overall CD8 differentiation were seen. Overall, AD subjects presented with a more pro-inflammatory peripheral blood mononuclear cell (PBMC) phenotype. When PBMCs were challenged with CD3/CD28-stimulation, CMV seropositive AD subjects presented with more IFN-γ release than both CMV seronegative AD subjects and CMV seropositive ND controls. For effective screening of humoral herpesvirus immunity, both in research and in clinical practice, efficient immunoassays are needed. We have addressed the methodology of multiplex herpesvirus immunoassays and related bioinformatics and investigated antibody levels in AD patients and ND controls. Subjects with AD presented with lower levels of human herpesvirus 6 (HHV-6) IgG. However, there was no difference in HHV-6 DNA levels in PBMCs between the groups. Herpes simplex encephalitis (HSE) is a devastating disease, where antiviral treatment has greatly decreased mortality but not eliminated the associated long-term neurocognitive morbidity. We have investigated the correlation between N-Methyl-D-Aspartate Receptor (NMDAR) autoimmunity and recovery of neurocognitive functions after HSE. Approximately one quarter of all HSE cases developed NMDAR autoantibodies within 3 months after onset of disease. Antibody development was associated with an impaired neurocognitive recovery during the two year follow-up and could become an important therapy guiding factor in the future.

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Glover, Maya. "Trickle infection and immunity to Trichuris muris." Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/trickle-infection-and-immunity-to-trichuris-muris(0add74f1-05de-49a1-b54c-2dff9b523422).html.

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Trichuris trichiura is a gastrointestinal helminth infection causing global morbidity and economic burden. The mouse species Trichuris muris is a well established laboratory model to study infection and immunity. Studies investigating the immune response to T. muris revealed that resistance is dependent on CD4+ Th2 cells and the production of IL-13 that mediates worm expulsion mechanisms. The majority of experimental studies follow infection and immunity after a single dose infection, however individuals are naturally infected with repeated low doses resulting in the slow development of partial immunity. Therefore to replicate a more natural infection regime in the laboratory, mice were infected repeatedly with low doses of T. muris, so called trickle infection and the developing immune response was investigated. Trickle infection of C57BL/6 mice resulted in the slow build up of worm burden followed by a significant decrease in adult worms and early larval stages, thus partial immunity was established. Flow cytometry revealed that a reduction in worm burden was associated with an increase in CD4+ Th2 cell populations that coincided with an increase in IL-13 and worm expulsion mechanisms, including goblet cell hyperplasia, Muc5ac production and increased epithelial cell turnover. Depletion of CD4+ T cells confirmed their importance in the development of resistance following trickle infection. Challenge experiments confirmed that resistance developed following trickle infection was long lasting. Additionally, trickle infection resulted in a microbiome dysbiosis that recovered following the development of resistance. Group 2 innate lymphoid cells (ILC2s) have been shown to be essential for resistance following N. brasiliensis infection, therefore ILC responses were investigated during T. muris infection. Analysis of ILC populations by flow cytometry during single dose and trickle T. muris infection suggested there was no significant response during infection. Depletion of ILC2s in ICOS-T mice confirmed they were not essential for the development of resistance following a single high dose T. muris infection or a T. muris trickle infection. Together the data presented here demonstrates the need for natural infection regimes to be used in the laboratory for animal helminth models to become more applicable to human infections.

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Muir, Peter. "Cytomegalovirus infection and immunity in homosexual men." Thesis, University of Edinburgh, 1985. http://hdl.handle.net/1842/20040.

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Lubaki, Ndongala. "HIV-specific immunity Acute Infection Early disease (AIED)." Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=86794.

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An estimated 33 millions of individuals are currently infected with HIV worldwide; the majority of them lives in Sub-Saharan Africa and do not have access to antiretroviral treatment despite all efforts from the international community. Despite efforts made in the area of prevention and treatment, the virus is still continuing to infect people worldwide. It is therefore believed that a safe, effective and affordable vaccine is the best solution to the global HIV epidemic. Unfortunately, despite recent advances in our understanding of HIV-1 pathogenesis and immunology, this goal remains elusive.
Vaccination started with Edward Jenner's success with smallpox immunization in 1796. Since then, a number of successful vaccines have been developed including, polio, measles, mumps, rubella, hepatitis B and influenza. The quest for an effective HIV-1 vaccine has proved to be very difficult because of specific characteristic of the virus, the lack of understanding of correlates of protection from infection and disease progression and the inadequacy of assays currently used to evaluate immune responses.
This thesis focuses on characterizing the qualitative and quantitative features of HIV-specific T cell immune responses in individuals in primary infection as well as their fate in progressive HIV disease. The rationale for studying individuals in primary HIV infection is that events during this phase of infection are believed to set the stage for the subsequent course of infection. We first developed an ELISPOT assay able to detect both IFN-γ and IL-2 secretion simultaneously. This assay was used for the comprehensive screening and characterization of responses to the entire HIV proteome in individuals during primary and chronic infections.
We showed that the dual color ELISPOT assay developed in our laboratory is capable of detecting 3 functional lymphocyte populations: single IFN-γ, dual IFN-γ/IL-2 and single IL-2 secreting cells. We demonstrated that this assay is sensitive, reproducible and able to detect both CD4+ and CD8+ T cell responses. We found that the breadth and magnitude of responses directed against the entire HIV proteome was not associated with control of viremia. Interestingly, we found an association between Gag p55-, and particularly Gag p24-specific responses, with concurrent and set point VL, for all 3 functional subsets detected. We also showed that the contribution of IFN-γ/IL-2 secreting cells to the total HIV-specific response as well as their proliferative capacity was reduced by the 2nd year of HIV infection.
Taken together, we believe that the results presented in this thesis contribute to furthering our understanding of immune correlates of protection from disease progression. These results suggest that vaccine strategies designed to focus immune responses against Gag may have a better chance of controlling HIV viral replication to levels that slow disease progression and reduce HIV transmission both at the individual and the population levels.
A ce jour, près de 33 millions d'individus sont infectés par le virus du VIH à travers le monde, parmi lesquels la majorité non seulement se retrouvent dans les pays de l'Afrique au Sud du Sahara mais aussi n'ont pas accès aux médicaments antiviraux, malgré les efforts soutenus de la communauté internationale.
Le meilleur moyen pour contrôler la pandémie serait la mise au point d'un vaccin efficace et bon marché. Jusqu'à ce jour, la mise au point de ce vaccin s'est avéré plutôt difficile car les corrélats de protection contre l'infection et le contrôle de la maladie ne sont pas encore élucidés.
Pour étudier la réponse immunitaire anti-VIH à médiation cellulaire, la communauté scientifique a besoin des tests plus adéquats. C'est ainsi que nous avons commencé par mettre au point une nouvelle stratégie basée sur l'ELISPOT qui consiste à détecter simultanément la sécrétion d'IFN-γ et d'IL-2 par les cellules VIH-spécifiques. Cette strategie permet d'étudier trois sous-populations des cellules T, aussi bien les cellules CD8+ que les cellules CD4+, les quelles réponses correspondent aux déterminants génétiques exprimés par le virus dans son entièreté.
En ce qui concerne les corrélats de protection contre l'évolution de la maladie, la contribution principale de ce travail de recherche est décrite dans le chapitre 3 de cette thèse. En effet, nous avons montré que la réponse VIH-spécifique reconnaissant le Gag p55 et plus spécifiquement le Gag p24 est associée au control de la virémie aussi bien pendant la primo infection qu'au set point. Ceci suggère que l'efficacité de la réponse immunitaire à médiation cellulaire naturellement acquise ou induite par vaccination dépend primordialement de la capacité de cibler cette portion du virus. En d'autres termes, la mise au point d'un vaccin efficace contre le virus VIH devrait essentiellement viser le développement des réponses cellulaires de forte magnitude dirigées contre le Gag du virus VIH
Dans le chapitre 3 de cette thèse, nous avons étudié l'évolution des différentes sous-populations des cellules VIH-spécifiques telles que détectées par l'ELISPOT à deux couleurs décrits dans le chapitre 2. Dans le même ordre d'idées, nous avons aussi étudié la capacité proliférative de ces sous-populations lymphocytaires pendant la primo infection et l'infection chronique. Nous avons montré que la contribution de la réponse immunitaire sécrétrice d'IFN-γ et d'IL-2 ainsi que leur capacité proliférative sont essentiellement réduites 2 ans après l'infection VIH.
En guise de conclusion, au regard des résultats décrits dans cette thèse, nous estimons avoir contribué à une meilleure compréhension des corrélats de protection contre l'évolution de la maladie. Nous avons en outre mis au point un test qui peut être utilisé pour détecter et analyser des réponses immunitaires à médiation cellulaire contre le VIH et cette stratégie peut être modifiée et adaptée en vue d'étudier la réponse immunitaire à médiation cellulaire contre d'autres virus ou des bactéries infectant les humains. Les résultats décrits dans ce travail de recherche suggèrent que la réponse VIH-spécifique induite par vaccination devrait viser particulièrement la portion Gag du virus en vue de réduire la réplication virale à des faibles taux. Ce qui devrait avoir un impact sur la progression de la maladie ainsi que la transmissibilité à l'échelle individuelle et collective.

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Chowdhury, Abeed. "Infection and immunity in health and surgical disease." Thesis, University of Nottingham, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.665483.

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Advances in surgical technology, critical care and antimicrobial therapy have improved outcomes for patients undergoing major abdominal surgery. However, for some patients, the risk of complications remains considerably high. It is recognised that sepsis due to bacterial infection is a major aetiological factor leading to postoperative major organ dysfunction. Current therapies to combat rates of infection rely far too heavily on antibiotics, to which there is growing resistance, leading to the demand for novel or alternative strategies The aim of this series of studies was to demonstrate the influence of bacteria and their products on human immune responses in both health and surgical disease. Previous studies indicate a potential role for probiotic bacteria in the treatment of infective disorders of the gastrointestinal tract. In this thesis, it is demonstrated using meta-analytical methods, that probiotic and synbiotic bacteria reduce the risk of infective complications following major abdominal surgery. It is proposed that some of the beneficial effects of probiotics involve modulation of host immune responses. In this thesis, it is demonstrated that probiotic treatment in healthy volunteers confers changes in the expression of Foxp3, the transcription factor characteristic of T regulatory cells. In addition, expression of cell surface proteins on dendritic cells (DCs) following synbiotic treatment has indicated expansion of mature DC subsets with altered phenotype.

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Michalopoulou, Eleni. "'Chlamydophila abortus' : infection, persistence and immunity in sheep." Thesis, Royal Veterinary College (University of London), 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.415215.

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Wilson, R. J. "Natural adaptive immunity to Streptococcus pneumoniae lung infection." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1417184/.

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Streptococcus pneumoniae is an important respiratory pathogen and a leading cause of community-acquired pneumonia. As well as invasive disease S. pneumoniae also colonises the nasopharynx. Colonisation with S. pneumoniae is nearly universal in infants, dropping to 10% in adulthood. This frequent exposure has potential for developing and boosting natural adaptive immune responses. However naturally-acquired immune responses that protect against subsequent lung infection with S. pneumoniae are not fully understood. This thesis investigates the targets and function of naturally-acquired IgG to S. pneumoniae in humans and additionally the mechanisms of protection from lung infection following experimental colonisation in mice. The target and function of naturally-acquired IgG in human sera and pooled intravenous immunoglobulin (IVIG) preparations was assessed. IVIG, pooled from >1000 adult donors provides a tool to investigate the natural antibody responses to S. pneumoniae within a population. Data indicate that naturally-acquired human IgG predominantly binds to non-capsular antigens on the surface of S. pneumoniae and can target surface exposed protein antigens. In vitro assays indicate that antibodies to non-capsular targets may be functional, enhancing phagocytosis and killing of S. pneumoniae. In vivo human IgG protected against lung infection. Cellular depletion demonstrated that protection within the lung required neutrophils and clearance of S. pneumoniae from the blood required macrophages. A model of lung infection in the absence of bacteraemia using S. pneumoniae strain EF3030 was developed. This model allowed assessment of the immune responses to S. pneumoniae colonisation of the nasopharynx that protect against re-infection specifically within the lung. Prior nasal colonisation with S. pneumoniae EF3030 was protective against subsequent lung infection. Cellular depletion strategies and challenge in antibody-deficient mice demonstrated that protection against lung infection required the development of both humoral and cell-mediated immunity.

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Widdrington, John David. "The role of mitochondria in innate immunity and inflammation." Thesis, University of Newcastle upon Tyne, 2016. http://hdl.handle.net/10443/3196.

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Deactivation of blood monocytes during sepsis is associated with increased mortality and susceptibility to secondary infections. Septic monocytes may also have mitochondrial DNA (mtDNA) depletion and mitochondrial respiratory dysfunction. Two principal approaches explored the link between these phenomena in THP-1 cells, a human leukaemia cell line resembling monocytes, to test the hypothesis that mtDNA depletion is important in the pathophysiology of monocytic cell immune deactivation. Firstly, the consequences of immune deactivation for mitochondria was assessed using an endotoxin tolerance model in which repeated exposures to lipopolysaccharide (LPS) trigger diminishing inflammatory responses. In parallel with the induction of endotoxin tolerance, LPS treatment lead to increased mitochondrial respiration due to the activation of mitochondrial biogenesis. These results could not be confirmed in healthy volunteers following inhalation of LPS as this model failed to induce endotoxin tolerance in blood monocytes. Secondly, the effects of depleting mtDNA, by treatment with ethidium bromide or transfection with short-interfering RNA targeted against mitochondrial transcription factor A, on immunity were measured. THP-1 cells with mtDNA depletion displayed the key phenotypic feature of deactivated septic monocytes, a decreased LPS-induced release of the pro-inflammatory cytokine tumour necrosis factor-α. Furthermore, there were significant alterations in the nuclear transcriptome of mtDNA-depleted THP-1 cells, with a particular inhibition of key innate immune signalling pathways and a marked blunting of the transcriptomic response to LPS. These investigations confirm that there are complex but vital links between mitochondria and innate immunity. Compensatory responses following an inflammatory insult include the simultaneous induction of mitochondrial biogenesis and shift to an anti-inflammatory phenotype. Moreover, when sepsis disrupts mitochondrial homeostasis the negative effects of mtDNA depletion on innate immunity may exacerbate monocyte immune deactivation. Further investigations should focus on exploring the fundamental processes coupling mitochondria with immunity and confirming these findings in blood monocytes during sepsis.

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Blohmke, Christoph Johannes. "Innate immunity and inflammation in cystic fibrosis lung disease." Thesis, University of British Columbia, 2011. http://hdl.handle.net/2429/34559.

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Inflammatory lung disease is the major life-limiting factor of cystic fibrosis (CF) and occurs through a self-sustaining cycle of airway obstruction, infection and inflammation. Although there is no consensus regarding the pathways responsible for the excessive inflammation, reducing lung-damaging pro-inflammatory responses are likely to be beneficial for CF patients. Using CF (IB3-1) and non-CF control (C38) respiratory cells, the host-pathogen interaction between the airway epithelium and the common CF pathogens P. aeruginosa and B. cepacia was investigated. Using purified Toll-like receptor (TLR) ligands and different knock-out strains of P. aeruginosa, TLR5 was identified as the receptor mediating much of the increased inflammatory response to CF pathogens. To validate TLR5 as an anti-inflammatory target, the disease modifying effects of the functionally relevant TLR5 c.1174C>T single nucleotide polymorphism (rs5744168) was analysed in approximately 80% of Canada’s CF population. rs5744168 encodes a premature stop codon and the T allele is associated with 45.5 – 76.3% reduction in flagellin responsiveness. CF patients carrying rs5744168 (CT or TT) had a significantly higher body mass index than CF patients homozygous for the common allele (CC) (p=0.044); however, similar improvements in lung function associated with the T allele were not statistically significant. Since TLR5 mediates much of the excessive inflammation to P. aeruginosa, it is of interest to understand the mechanisms underlying this dysregulated immune response. By combining gene expression arrays with network analyses and biochemical assays, ER stress was identified as a potential mechanism dysregulating p38 MAP kinase activity and leading to potentiated immune responses. Together, this thesis provides data underscoring the importance of TLR5-mediated excessive pro-inflammatory immune response by CF airway cells to P. aeruginosa. The association of the TLR5392STOP SNP with higher BMI in adult CF patients indicates an important role for TLR5 in CF disease severity. Finally, ER stress may potentiate the immune response to flagellin by signalling through p38 MAP kinase, supporting an emerging paradigm in which the imbalance of protein homeostasis can lead to altered signalling events. Strategies to inhibit either TLR5 signalling, ER stress signalling or to improve the cellular protein homeostasis may prove useful in treating life limiting inflammation in CF.

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Mazdai, Goudarz. "The influence of mineral nutrients on immunity and inflammation." Thesis, University of Ulster, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.281215.

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Croft, Nicholas Michael. "Investigation of gastrointestinal mucosal immunity and inflammation in children." Thesis, University of Edinburgh, 1996. http://hdl.handle.net/1842/21172.

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In this thesis I have introduced a new technique, whole gut lavage (WGL), for the study of gastrointestinal secretory immunity in children. Initially I arranged to collect specimens from control children, undergoing whole gut lavage prior to colonoscopy or surgery, at the Royal Hospital for Sick Children, Edinburgh. Whole gut lavage has been used to treat severe constipation and so I organised a study to look at the effectiveness of this, intending both these groups of children as immunologically normal controls. Analysis of specimens from the first five severely constipated children showed that the total IgA levels in all were very low. I went on to examine reasons for these low IgA levels including mucosal IgA deficiency, degradation and interference by other factors in the bowel lumen. Having collected specimens from control children I then arranged a study of intestinal secretory immunity in children with cystic fibrosis (CF). This was stimulated by a paper in the Lancet suggesting that CF children, taking high dose pancreatic enzyme supplements, had developed strictures of the ascending colon possibly due to direct toxic effects of these medications. As CF children have chronic lung infections I then studied the possible influence of respiratory secretions on assays of whole gut lavage fluid by measuring concentrations of immune factors in sputum. With the data from these patient groups I was able to analyse, in some detail, the clinical aspects of whole gut lavage in children. Although I had established that WGL could be an ethical and useful method for research in children it was clear, for clinical reasons, this could not be used for the study of acute diarrhoeal illness, one of the most common paediatric problems involving the gastrointestinal mucosal immune system. With the help of adult patients, I directly compared outputs of immune factors in faeces and whole gut lavage.

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Arnaout, Ramy A. "Mathematical models of antiviral immunity." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325989.

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49

Shawcross, Deborah Lindsay. "Ammonia, infection and inflammation in hepatic encephalopathy." Thesis, University College London (University of London), 2007. http://discovery.ucl.ac.uk/1445060/.

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For over a century, we have known that ammonia is important in the pathogenesis of hepatic encephalopathy. Studies in patients with acute liver failure have shown rapid progression to severe encephalopathy in those patients with evidence of a systemic inflammatory response, suggesting a possible link between inflammation and encephalopathy. In view of the growing evidence to support the role of inflammation in increasing the susceptibility of the brain to the effects of hyperammonemia in liver disease, 3 hypotheses were explored: 1: Inflammation and infection are important in hepatic encephalopathy. 2: Inflammation and infection act synergistically with ammonia. 3: Ammonia makes the immune system more susceptible to infection. In the first of 2 clinical studies, inflammation was shown to be an important determinant of the presence and severity of minimal hepatic encephalopathy. In a second study, significant deterioration of neuropsychological test scores in patients with cirrhosis following induced hyperammonemia during the inflammatory state, but not after its resolution, suggested that inflammation may be important in modulating the cerebral effect of ammonia in liver disease, supporting the first hypothesis. Ammonia and inflammation were shown to be synergistic in the bile duct ligated rat which showed increased brain water and astrocyte swelling exacerbated by endotoxin and accompanied by a rise in nitric oxide and brain nitrotyrosine, but not in plasma ammonia, suggesting nitric oxide may play an important synergistic role in the pathogenesis of hepatic encephalopathy. Ammonia was shown to impair neutrophil function by reducing phagocytosis, inducing spontaneous respiratory burst and cell swelling. The p38"MAPK pathway was shown to be important and a p38"MAPK agonist prevented neutrophils from swelling in the presence of ammonia and improved phagocytosis. While cultures of muscle cells were a potentially interesting direction to take to investigate the effect of inflammation on the muscle uptake of ammonia, unfortunately the resulting data demonstrated a low glutamine synthetase activity. In conclusion, these studies illustrate the important factors that modulate the manifestation of symptoms of hepatic encephalopathy in cirrhosis, the most important of which is the synergistic role of inflammation and ammonia. Furthermore, the ammonia-induced impairment of neutrophil function may, in part, account for the increased susceptibility to infection found in patients with cirrhosis.

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Wessel, Hannah Margaret. "Microbial infection and mechanisms of intestinal inflammation." Thesis, University of Glasgow, 2017. http://theses.gla.ac.uk/8377/.

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The intestinal immune system plays an essential role in maintaining the delicate balance between mounting protective responses against invading pathogens and sustaining tolerance towards self-antigens and the endogenous microbiota. Disturbing this balance leads to intestinal inflammation, such as is seen in inflammatory bowel disease (IBD). IBD is characterised by alterations in the mucosa-associated microbiota, such as the increase in adherent and invasive Escherichia coli (AIEC) species in Crohn’s disease (CD) patients. Concomitantly, the inflamed mucosa exhibits an elevated rate of apoptosis in IBD, a phenomenon that also accompanies infection with a range of enteric bacterial pathogens. While phagocytosis of apoptotic cells by dendritic cells (DC) is required for self-tolerance in the healthy intestine, there is evidence to suggest that apoptotic cell uptake during infection activates protective T cell responses. In order to investigate the link between the recognition of apoptotic cells and intestinal inflammation, we used a range of different in vivo enteric bacterial infection models. Previously published work had implicated the AIEC strain NRG857c in the induction of chronic intestinal inflammation in vivo. We did not, however, find that NRG857c caused any signs of chronic colitis in mice, either by histological examination, or in-depth analysis of both innate and adaptive immune responses in the lamina propria and mesenteric lymph nodes (MLN). Due to the important role of DC in acquiring apoptotic cell antigen and priming protective T cell responses, we next characterised the expression of apoptotic cell receptors, specifically TIM4, on DC populations in steady state mucosal tissues. We demonstrated that TIM4 expression was enriched on CD11b- CD103+ DC, which have previously been shown to cross-present apoptotic cell-derived antigen. However, upon migration in mesenteric lymph, all intestinal DC populations upregulated TIM4, and migratory CD11b+ CD103+ had the highest frequency of TIM4+ cells in the MLN. However, blocking TIM4 did not affect DC migration in vivo. We also found that infection with C. rodentium elevated the percentage of TIM4+ DC in a population-specific manner, but that TIM4 was not essential for the induction of protective T cell responses during infection with either C. rodentium or S. Typhimurium. We therefore provide a detailed analysis of the intestinal immune response to bacterial infection, focussing specifically on the role of the apoptotic cell receptor TIM4 on intestinal DC populations.

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Dissertations / Theses on the topic 'Infection, Immunity and Inflammation'

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