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Millhouse, Emma. "Microbial biofilm composition influences the host immune response." Thesis, University of Glasgow, 2015. http://theses.gla.ac.uk/6848/.
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Periodontal disease (PD) is a multifactorial disease of the oral cavity affecting the majority of the population. Although not a direct cause of mortality, PD is a health concern because it affects the majority of the population and has a negative impact on oral health, ability to chew, appearance, quality of life, dental care costs and can lead to tooth loss. Dental plaque is a microbial biofilm, which is necessary but not sufficient for the development of periodontitis. The interactions between the biofilm and the host cells, both local tissue and immune cells, can lead to tissue destruction and ultimately tooth loss. Clinical management of periodontitis involves mechanical removal of plaque from the tooth surface. Treatment is time consuming, in some patients only partially successful and recurrence is common. Therefore, understanding how the host interacts with microbial biofilms in both health and PD will help improve treatments and identify novel targets for therapeutic and preventative strategies. The hypothesis of this thesis is that the bacterial composition of oral biofilms may modulate host cell responses which contribute to the pathogenicity of PD. The overarching aim of this research was to develop an in vitro co-culture model system to study how biofilm composition can influence the host immune response. The studies document the development of health-associated, intermediate and disease-associated biofilms with host tissue and immune cells, and the use of these models to test antimicrobial and anti-inflammatory compounds as potential treatments for PD. The biofilms developed were assessed for survival in cell culture conditions and batch reproducibility by PCR and morphology visualised using SEM. The health-associated biofilm included Streptococcus mitis, S. intermedius and S. oralis (3-species); the intermediate biofilm additionally included Veillonella dispar, Actinomyces naeslundii, Fusobacterium nucleatum and F. nucleatum spp. Vincentii (7-species); and the disease-associated biofilm included further addition of Porphyromonas gingivalis, Prevotella intermedia, and Aggregatibacter actinomycetemcomitans (10-species). These biofilms were co-cultured with an oral epithelial cell line and primary gingival epithelial cells, as well as neutrophils and a myeloid cell line. Host cell viability was assessed by AlamarBlue®/LDH and changes in mRNA and protein expression of chemokines and cytokines were assessed by quantitative PCR and ELISA/Luminex®, respectively. Cellular responses were further evaluated by microscopy and flow cytometry. Generally, co-culture of health associated biofilms with host cells resulted in minimal impact on cell viability and generally low inflammatory gene expression and protein release, with some genes including CXCL5 and CCL1 being downregulated compared to the cells only control. Intermediate biofilms caused some cell death and a marked upregulation of inflammatory genes and protein release, including a 302.7 fold increase of epithelial cell IL-8 gene expression compared to the cells only control. These intermediate biofilms elicited significant upregulation of CD40 and CD69 expression on the monocyte cell line compared with untreated controls. Co-culture of the 10 species disease associated biofilms with host cells resulted in significant host cell death of both epithelial cells and monocytes. The 10 species biofilm caused significantly increased pro-inflammatory gene expression, but only low levels of protein could be detected in the supernatants. Similar trends in upregulation of inflammatory gene expression but low levels of protein release was observed in co-culture with differentiated pro-monocytes, whereas upregulation of inflammatory gene expression and protein release in neutrophil co-cultures was observed. The effect of antimicrobial and anti-inflammatory compounds, resveratrol and chlorhexidine, was evaluated using this model system. Prior treatment of epithelial cells with resveratrol and biofilm with chlorhexidine significantly reduced IL-8 release from epithelial cells in co-culture with biofilms for 4 and 24 hours. In conclusion, this research has developed and validated 3 complex multi-species biofilms to study host: biofilm interactions in vitro. Furthermore, using these models in co-culture with multiple host cell types, clear differences in the host response to different biofilms were observed. The variations in inflammatory response of host cells and oral biofilms observed in this study help further understanding of the complex host: biofilm interactions within the oral cavity which contribute to PD. This model demonstrated its potential as a platform to test novel actives, highlighting its use a tool to study how actives can influence host: biofilm interactions within the oral cavity. Future use of this model will aid in greater understanding of host: biofilm interactions. Such findings are applicable to oral health and beyond, and may help to identify novel therapeutic targets for the treatment of PD and other biofilm associated diseases.
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Tattermusch, Sonja. "The host immune response to HTLV-1 infection." Thesis, Imperial College London, 2012. http://hdl.handle.net/10044/1/9916.
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Human T-lymphotropic virus Type 1 (HTLV-1) is a retrovirus that persists lifelong in the host. In ~4% of infected people, HTLV-1 causes a chronic disabling neuroinflammatory disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The pathogenesis of HAM/TSP is unknown and treatment remains ineffective. In this study we aimed to identify patterns in frequencies of peripheral leukocyte populations and blood gene expression profiles of HTLV-1 carriers that suggest new hypotheses as to the mechanisms of HTLV-1 persistence and HAM/TSP pathology. Flow cytometric immunophenotyping of peripheral blood leukocytes revealed abnormal activation and maturation profiles of effector T cells but not antigen-presenting cells. High frequencies of circulating granzyme and perforin-rich CD8+ T cells were associated with an increased probability of HAM/TSP. However, the cytolytic capacity of these T cells is not known as although they accumulated cytolytic proteins, granzyme mRNA levels were down-regulated in patients with HAM/TSP. Furthermore, presence of HAM/TSP was associated with an expansion of CD56-negative NK cells, which are thought to have decreased cytolytic functions. Blood gene expression profiles identified perturbations of the p53 signalling pathway as a hallmark of HTLV-1 infection. In contrast, a subset of interferon (IFN)-stimulated genes was over-expressed in patients with HAM/TSP but not in asymptomatic HTLV-1 carriers or patients with the clinically similar disease multiple sclerosis. The IFN-inducible signature was present in all circulating leukocytes and its intensity correlated with the clinical severity of HAM/TSP. Leukocytes from patients with HAM/TSP were primed to respond strongly to stimulation with exogenous IFN. However, while type I IFN suppressed expression of the HTLV-1 structural protein Gag it failed to suppress the highly immunogenic viral transcriptional transactivator Tax. Based on our findings we hypothesise that impaired NK cell and T cell-mediated immune responses result in high HTLV-1 proviral loads but that the over-expression of a subset of IFN-stimulated genes contributes to the development of HAM/TSP.
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Verma, Meghna. "Modeling Host Immune Responses in Infectious Diseases." Diss., Virginia Tech, 2019. http://hdl.handle.net/10919/96019.
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Infectious diseases caused by bacteria, fungi, viruses and parasites have affected humans historically. Infectious diseases remain a major cause of premature death and a public health concern globally with increased mortality and significant economic burden. Unvaccinated individuals, people with suppressed and compromised immune systems are at higher risk of suffering from infectious diseases. In spite of significant advancements in infectious diseases research, the control or treatment process faces challenges. The mucosal immune system plays a crucial role in safeguarding the body from harmful pathogens, while being constantly exposed to the environment. To develop treatment options for infectious diseases, it is vital to understand the immune responses that occur during infection. The two infectious diseases presented here are: i) Helicobacter pylori infection and ii) human immunodeficiency (HIV) and human papillomavirus (HPV) co-infection. H pylori, is a bacterium that colonizes the stomach and causes gastric cancer in 1-2% but is beneficial for protection against allergies and gastroesophageal diseases. An estimated 85% of H pylori colonized individuals show no detrimental effects. HIV is a virus that causes AIDS, one of the deadliest and most persistent epidemics. HIV-infected patients are at an increased risk of co-infection with HPV, and report an increased incidence of oral cancer. The goal of this thesis is to elucidate the host immune responses in infectious diseases via the use of computational and mathematical models. First, the thesis reviews the need for computational and mathematical models to study the immune responses in the course of infectious diseases. Second, it presents a novel sensitivity analysis method that identifies important parameters in a hybrid (agent-based/equation-based) model of H. pylori infection. Third, it introduces a novel model representing the HIV/HPV coinfection and compares the simulation results with a clinical study. Fourth, it discusses the need of advanced modeling technologies to achieve a personalized systems wide approach and the challenges that can be encountered in the process. Taken together, the work in this dissertation presents modeling approaches that could lead to the identification of host immune factors in infectious diseases in a predictive and more resource-efficient manner.Doctor of Philosophy
Infectious diseases caused by bacteria, fungi, viruses and parasites have affected humans historically. Infectious diseases remain a major cause of premature death and a public health concern globally with increased mortality and significant economic burden. These infections can occur either via air, travel to at-risk places, direct person-to-person contact with an infected individual or through water or fecal route. Unvaccinated individuals, individuals with suppressed and compromised immune system such as that in HIV carriers are at higher risk of getting infectious diseases. In spite of significant advancements in infectious diseases research, the control and treatment of these diseases faces numerous challenges. The mucosal immune system plays a crucial role in safeguarding the body from harmful pathogens, while being exposed to the environment, mainly food antigens. To develop treatment options for infectious diseases, it is vital to understand the immune responses that occur during infection. In this work, we focus on gut immune system that acts like an ecosystem comprising of trillions of interacting cells and molecules, including membars of the microbiome. The goal of this dissertation is to develop computational models that can simulate host immune responses in two infectious diseases- i) Helicobacter pylori infection and ii) human immunodeficiency virus (HIV)-human papilloma virus (HPV) co-infection. Firstly, it reviews the various mathematical techniques and systems biology based methods. Second, it introduces a "hybrid" model that combines different mathematical and statistical approaches to study H. pylori infection. Third, it highlights the development of a novel HIV/HPV coinfection model and compares the results from a clinical trial study. Fourth, it discusses the challenges that can be encountered in adapting machine learning based computational technologies. Taken together, the work in this dissertation presents modeling approaches that could lead to the identification of host immune factors in infectious diseases in a predictive and more resourceful way.
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Watret, Karen Christine. "Graft-versus-host reaction and the mucosal immune response." Thesis, University of Edinburgh, 1990. http://hdl.handle.net/1842/19395.
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Post, Frank A. "Mycobacterial strain diversity : impact on the host immune response." Doctoral thesis, University of Cape Town, 2003. http://hdl.handle.net/11427/2717.
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Rowland, Caroline A. "Characterisation of host immune responses to Burkholderia mallei." Thesis, Open University, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.439229.
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Anderson, J. J. "The immune response to respiratory syncytial virus in an animal model." Thesis, University of Newcastle Upon Tyne, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.380769.
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Smith, A. L. "Immunity response to Eimeria vermiformis infection in the mouse." Thesis, University of Nottingham, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.284111.
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Parsa, Venkata Laxmi Kishore. "Molecular mechanisms of host cell response to Francisella infection." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1195584597.
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Ringqvist, Emma. "Host-Pathogen Responses during Giardia infections." Doctoral thesis, Uppsala universitet, Mikrobiologi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-108980.
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Giardia lamblia is a eukaryotic parasite of the upper small intestine of humans and animals. The infecting trophozoite cells do not invade the epithelium lining of the intestine, but attach to the brush border surface in the intestinal lumen. The giardiasis disease in humans is highly variable. Prior to this study, the molecular mechanisms involved in establishment of infection or cause of disease were largely uncharacterized. In this thesis, the molecular relationship between Giardia and the human host is described. The interaction of the parasite with human epithelial cells was investigated in vitro. Changes in the transcriptome and proteome of the parasite and the host cells, and changes in the micro-environment of the infection have been identified using microarray technology, and 1- and 2-Dimensional SDS-PAGE protein mapping together with mass spectrometry identification. The first large-scale description of cellular activities within host epithelial cells during Giardia infection is included in this thesis (Paper I). We identified a unique activation of the host immune response and induction of apoptosis upon infection by Giardia. Four important virulence factors of the parasite, directly linked to the success of Giardia infection, were characterized and are presented in Papers II and III. The parasite was shown to have immune-modulating capacities, and to release proteins during host-interaction that facilitate the establishment of infection. Additional putative virulence factors were found among Giardia genes transcriptionally up-regulated during early infection (Paper IV). In summary, this thesis provides important insights into the molecular mechanisms of the host-parasite interaction.
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Contreras, Garcia Irazú. "Modulation of the host innate immune response by «Leishmania» parasites." Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=95096.
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Leishmania parasites have evolved sophisticated mechanisms to subvert macrophage immune responses in order to survive inside the mammalian host. Among these mechanisms are the rapid activation of phosphatases that in turn will inactivate protein kinases and transcription factors, causing abrogation of nitric oxide (NO) production and induction of immunosuppressive molecules. This doctoral thesis discusses novel mechanisms of how the parasite modulates the immune response of macrophages and dendritic cells. Herein, we describe the role of Myeloid Related Proteins (MRPs) 8 and 14 during Leishmania infection. MRPs 8/14 are produced by neutrophils and are able to induce microbicidal activity in macrophages. We present data that shows that priming macrophages with MRP 8/14 before infection induces their activation. However, infection with L. major prior to MRP stimulation significantly decreases their activation. In vivo studies showed that abrogation of MRPs resulted in an increased parasitic burden, whereas injection of recombinant MRPs (rMRPs) reduced the size of the lesion and the parasitic load. One of the main mechanisms that Leishmania parasites utilize to subvert the innate immune response is the alteration of transcription factors (TFs). In this thesis, we have shown that upon Leishmania infection, AP-1 activity is abolished and this correlates with the nuclear degradation of AP-1 subunits. Of interest, c-Jun, the main AP-1 activator is degraded and cleaved by Leishmania inside the nucleus in a GP63 dependent manner. Despite the fact that macrophages have been considered as preferred hosts for Leishmania parasites, other cells have been described as possible hosts. Finally, we discuss the effect of Leishmania infection in dendritic cells (DCs) and how this pathogen affects their maturation and capacity to present antigen. In addition, we found that Leishmania is able to activate phosphatases to inactivate signalling pathways in these cells. Collectively, oLe parasite Leishmania a su développer des mécanismes sophistiqués lui permettant de déjouer les réponses immunitaires des macrophages dans le but de survivre à l'intérieur de son hôte mammifère. Parmi ces mécanismes, notons l'activation rapide de phosphatases, qui inactiveront des protéines kinases et des facteurs de transcription, causant ainsi l'abrogation de la production d'oxyde nitrique, de même que l'induction de molécules immunosuppressives. Cette thèse doctorale discute de nouveaux mécanismes utilisés par le parasite afin de moduler la réponse immunitaire des macrophages et des cellules dendritiques. Dans le présent rapport, nous décrirons le rôle des MRPs (Myeloid Related Proteins) 8 et 14 lors de l'infection par Leishmania. Produites par les neutrophiles, les MRPs 8/14 ont la capacité d'induire l'activité microbicide des macrophages. Nos résultats montrent qu'une sensibilisation active pré-infection des macrophages avec les MRPs 8/14 induit leur activation. Par contre, lorsque l'infection à L.major est antérieure à la stimulation avec les MRPs, l'activation des macrophages est significativement réduite. Les études in vivo démontrent quant à elles que l'abrogation des MRPs a entraîné une augmentation de la charge parasitaire, alors que l'injection de MRPs recombinantes réduit la taille de la lésion, de même que la charge parasitaire. Un des principaux mécanismes qu'utilisent les parasites Leishmania, afin de déjouer la réponse immunitaire innée, est l'altération de facteurs de transcription. À l'aide de nos résultats, nous démontrons que l'activité d'AP-1 est abolie suite à l'infection par Leishmania, ceci concordant avec la dégradation au noyau des protomères d'AP-1. Il est d'ailleurs à souligner que c-Jun, le principal activateur d'AP-1, est dégradé et clivé par Leishmania à l'intérieur du noyau, et ce de façon GP63 dépendante. Malgré le fait que les macrophages sont considérés comme les cell
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Yadev, Nishant. "Investigating the host innate immune response mechanisms to Candida albicans." Thesis, University of Sheffield, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.575466.
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Candida albicans is a commensal fungal organism that forms part of the normal human oral microbial flora. Although very few individuals will ever develop infection from C. albicans, it has the potential to cause a range of serious mucocutaneous infections. In healthy individuals, C. albicans is able to colonise mucosal surfaces as a commensal organism. However, in certain susceptible individuals changes occur within the host to enable C. albicans to go from being a commensal to a pathogen. Little is known about the local host innate immune defence mechanisms of the oral mucosa that are important in providing protection and maintenance of a commensal relationship. The majority of in vitro studies to investigate the host - C. albicans interaction have used an oral mucosal model based on the TR146 buccal cancer cell line, which lacks the presence of a fibroblast containing connective tissue. This mucosa model was compared for suitability against two full thickness oral mucosa models based upon primary cells seeded onto a fibroblast containing connective tissue; one generated 'in house' and the other a commercially available model (MatTek). Normal oral mucosa was used as a comparison. Immunohistochemical staining and infection studies showed that the mucosal model based upon the TR146 buccal cancer cell line resembled least the oral mucosa in vivo, whilst both full thickness oral mucosal models were more advanced and more closely resembled the oral mucosa in vivo. Infection of the full thickness oral mucosa models with a mutant strain of C. albicans, in which morphogenic properties could be controlled, was performed. Over 48 hours, hyphal-infected models displayed high levels of C. albicans invasion and showed a time-dependent increase in cell death compared to yeast-infected models. In addition, hyphal-infected models demonstrated a rapid host response by inducing cytokine release and affecting the expression of a large number of genes, as shown by microarray analysis, in particular those involved with a pro-inflammatory response. In comparison yeast-infected models caused a slower cytokine release response and affected the expression of fewer genes. The hyphal-infected tissue also demonstrated a greater host antimicrobial peptide (human l3-defensin) response when compared to yeast-infected tissue. Overall this study showed that the oral mucosa responds differently to yeast and hyphal forms of C. albicans with respect to gene, cytokine and antimicrobial peptide expression. These data suggested that the oral mucosa may have detected yeast and hyphae using different mechanisms that may initiate different intracellular signalling XI
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Thullen, Timothy D. "Analyzing the host immune response to pneumocystis utilizing two rat." Cincinnati, Ohio : University of Cincinnati, 2003. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=ucin1066676759.
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Hicks, Daniel Jake. "Characterisation of the host immune response to European bat Lyssavirus infection." Thesis, Royal Veterinary College (University of London), 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.559029.
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Ke, Qi. "Negative Regulation of Host Innate Immune Signaling and Response Pathways by Viral and Host Regulatory Factors." University of Toledo / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1470185159.
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Hollingsworth, Rosalind C. "An investigation of host and viral factors which may influence the rate of progression and clinical outcome of hepatitis C virus infection." Thesis, University of Nottingham, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.363931.
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Fors, Lisa. "Ecology and evolution in a host-parasitoid system : Host search, immune responses and parasitoid virulence." Doctoral thesis, Stockholms universitet, Institutionen för ekologi, miljö och botanik, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-115243.
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In host-parasitoid systems, there is a continuous coevolutionary arms race where each species imposes a strong selection pressure on the other. The host needs to develop defence strategies in order to escape parasitism and the parasitoid must evolve counter-defence strategies in order to overcome the host’s immune defence and successfully reproduce. This makes host-parasitoid systems excellent model systems for understanding evolutionary processes underlying host race formation and speciation. In order to gain a better understanding of the complexity of host-parasitoid interactions several aspects must be considered, such as search behaviour and host selection in the parasitoid, the development of immune responses in the host and counter-defence strategies in the parasitoid. In this thesis, I investigate interactions and coevolution in a natural host-parasitoid system, consisting of five species of Galerucella leaf beetles and three species of Asecodes parasitoids, by combining behavioural ecology with chemical ecology and immunology. In the studies performed, I found that pheromone production and responses in the beetles are connected to the phylogenetic relatedness between the Galerucella species (Paper I). I found no evidence that Asecodes exploits the adult pheromone to locate host larvae, but observed an ability in the parasitoids to distinguish a better host from a less suitable one based on larval odors (Paper II). The studies also revealed large differences in immune competence between the Galerucella species, which were linked to differences in hemocyte composition in the beetle larvae (Paper III, IV). Further, the results suggest that parasitism success in polyphagous Asecodes is strongly affected by former host species of the parasitoid (Paper IV). In conclusion, the results of this thesis suggest an on-going evolution in both parasitoid virulence and host immune responses in the Asecodes-Galerucella system.At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 4: Manuscript.
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Blanc, Mathieu. "Sterol biosynthesis pathway is part of the interferon host defence response." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5556.
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Recently, cholesterol metabolism has been shown to modulate the infection of several viruses and there is growing evidence that inflammatory response to infection also modulates lipid metabolism. However little is known about the role of inflammatory processes in modulating lipid metabolism and their consequences for the viral infection. This study investigates host-lipid viral interaction pathways using mouse cytomegalovirus, a large double-stranded DNA genome, which represents one of the few models for a natural infection of its natural host. In this study, transcriptomic and lipidomic profiling of macrophages shows that there is a specific coordinated regulation of the sterol pathways upon viral infection or treatment with IFNγ or β (but not TNFα, IL1β or IL6) resulting in the decrease of free cellular cholesterol. Furthermore, we show that pharmacological and RNAi inhibition of the sterol pathway augments protection against infection in vitro and in vivo and we identified that the prenylation branch of the sterol metabolic network was involved in the protective response. Finally, we show that genetic knock out of IFNβ results in a partial reduction while genetic knock out of Ifnar1 completely abolishes the reduction of the sterol biosynthetic activity upon infection. Overall these results support a role for part of the sterol metabolic network in protective immunity and show that type 1 IFN signalling is both necessary and sufficient for reducing the sterol metabolic network upon infection; thereby linking the sterol pathway with IFN defence responses.
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Lee, Katherine Shi-Hui. "The host immune response to Streptococcus pneumoniae : bridging innate and adaptive immunity /." Download the dissertation in PDF, 2006. http://www.lrc.usuhs.mil/dissertations/pdf/lee2006.pdf.
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Auld, Stuart Kenneth John Robert. "Fitness consequences of cellular immunity : studies with Daphnia magna and its sterilizing bacterial parasite." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5779.
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Immune responses are presumed to contribute to host fitness, either by fighting off infections or via immunopathology. Research in this thesis sought to relate the magnitude of a putative immune response to infection and host and parasite fitness. The experiments and field studies presented here all focus on the interactions between the freshwater crustacean, Daphnia magna and its sterilizing bacterial endoparasite, Pasteuria ramosa, using the number of circulating haemocytes as a measure of host immune activity. I found substantial genetic variation in Daphnia’s cellular response to P. ramosa, and that Daphnia genotypes that mount the strongest cellular responses are the most likely to get infected and suffer sterilization. Thus, a strong cellular response is associated with low, as opposed to high host fitness potential. There were also some host genotypes that mounted a weaker cellular response and did not go on to suffer infection, and some that lacked a cellular response and also never suffered infection with P. ramosa. These findings led to a heuristic two-stage model for infection, where the parasite has to (1) pass from the host gut to haemolymph and then (2) successfully overcome haemolymph-based immune effectors to reproduce and achieve fitness. I also demonstrate that both the magnitude of host cellular response and likelihood of infection increases with initial parasite dose in susceptible host genotypes, and that host cellular response is associated with likely infection under both host and parasite genetic variation. Parasitised Daphnia also have substantially more circulating haemocytes than their healthy counterparts in both the laboratory and in the wild, where there is substantial genetic and environmental variation. This is one of the very few examples of how an immune response designates low host and high parasite fitness potential in a wild system. Finally, using a mixture of field study and common garden experiment, I demonstrate evolution in parasite infection traits over the course of an epidemic in a wild population, and that this evolution is associated with a decline in host abundance.
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Smyth, Robin. "Role of Protein Kinase R in the Immune Response to Tuberculosis." Thesis, Université d'Ottawa / University of Ottawa, 2021. http://hdl.handle.net/10393/41842.
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Tuberculosis (TB) is a deadly infectious lung disease caused by the pathogenic bacterium Mycobacterium tuberculosis (Mtb). The identification of macrophage signaling proteins exploited by Mtb during infection will enable the development of alternative host-directed therapies (HDT) for TB. HDT strategies will boost host immunity to restrict the intracellular replication of Mtb and therefore hold promise to overcome antimicrobial resistance, a growing crisis in TB therapy. Protein Kinase R (PKR) is a key host sensor that functions in the cellular antiviral response. However, its role in defense against intracellular bacterial pathogens is not clearly defined. Herein, we demonstrate that expression and activation of PKR is upregulated in macrophages infected with Mtb. Immunological profiling of human THP-1 macrophages that overexpress PKR (THP-PKR) showed increased production of IP-10 and reduced production of IL-6, two cytokines that are reported to activate and inhibit IFNy-dependent autophagy, respectively. Indeed, sustained expression and activation of PKR reduced the intracellular survival of Mtb, an effect that could be enhanced by IFNy treatment. We further demonstrate that the enhanced anti-mycobacterial activity of THP-PKR macrophages is mediated by a mechanism dependent on selective autophagy as indicated by increased levels of LC3-II that colocalize with intracellular Mtb. Consistent with this mechanism, inhibition of autophagolysosome maturation with bafilomycin A1 abrogated the ability of THP-PKR macrophages to limit replication of Mtb, whereas pharmacological activation of autophagy enhanced the anti-mycobacterial effect of PKR overexpression. As such, PKR represents a novel and attractive host target for development of HDT for TB, and our data suggest value in the design of more specific and potent activators of PKR.
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McLauchlan, P. E. "Host-parasite interactions : cellular immune responses and modulation by cyclosporin A." Thesis, University of Aberdeen, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.593084.
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The role of cyclosporin A (CsA) as an immunomodulatory and antiparasitic drug was examined. The immune responses in various host:parasite relationships were examined giving an insight into the complicated nature of this relationship. In addition, analogues of CsA were screened to investigate the antiparasitic mode of action of cyclosporins. Expulsion of intestinal parasites has been proposed to involve the cellular immune response but its precise role is unknown. In CBA/ca mice infected with Hymenolepsis diminuta, peak intestinal mucosal mast cell (IMMC) numbers and release of mast cell protease (mMCP-I) correlated with parasite expulsion. Immunosuppression by cyclosporin A (CsA) treatment abrogated the response and allowed H. diminuta to survive to maturity. In contrast, H. microstroma survived long-term in MF1 mice, despite a significant and sustained IMMC response and mMCP-I release. It is proposed that the protease has different roles in these hymenolepid infections. Goblet cell proliferation did not occur in either infection. Adult Schistosoma mansoni are less susceptible to CsA than juveniles and reduced drug efficacy correlates with the onset of egg deposition and pathology in the liver of the host. This may alter metabolism of CsA and prevent the production of an active metabolite. CsA and metabolites were identified in mice tissues using reverse phase HPLC but problems with background peaks and low drug recovery prevented examination of the metabolite profile. CsA is antiparasitic against a range of protozoa and helminths but its mode of action is unknown. One possibility is that it involves the binding protein, cyclphilin (CyP). Three analogues of CsA, B-5-49, CsH and CsA-acetate (CsA-A) were screened against H. microstroma in vitro, which is susceptible to CsA. All analogues induced drug damage comparable to CsA. However, only B-5-49 bound to H. microstroma cytosolic CyP, suggesting that CyP is not necessary for the antiparasitic action of cyclosporins. Schistosomes suppress the activity of the internal defence system in their host in order to ensure their survival.
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Ortiz, Marty Rebecca Josefina. "Staphylococcus aureus virulence factors dictate host signaling pathways and immune responses." Diss., Virginia Tech, 2011. http://hdl.handle.net/10919/77299.
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Staphylococcus aureus causes nosocomial- and community- acquired infections. This versatile pathogen expresses virulence factors (VF) that enhance establishment of infection and immune evasion. Our research focused on defining the roles of S. aureus VF on host immune responses during intracellular or extracellular infections. Accessory gene regulator (agr) controls VF expression and intracellular survival. Our goal was to determine mammary epithelial cells (MEC) responses to intracellular infection and subsequent polymorphonuclear leukocyte (PMN) responses. Intracellular S. aureus increased thrombomodulin expression by MEC and activated protein C (APC) production. APC inhibited PMN chemotaxis. Findings depicted an indirect role for VF on PMN responses, so next we determined signaling pathways and cytokine responses of PMN to S. aureus toxins. Live S. aureus infections increased activation of stress signaling pathways and highlighted a role for agr-regulated genes in MAPK p38 phosphorylation and α-hemolysin in ERK phosphorylation and IL-8 expression in PMN. Continuing our studies of VF, chemotaxis inhibitory protein of S. aureus (CHIPS) inhibits monocyte chemotaxis. We hypothesized that CHIPS inhibited C5a receptor (C5aR) signaling. Monocytes pretreated with CHIPS did not inhibit C5aR signaling. Nevertheless, signaling pathways can reduce PMN function in models such as glucocorticoid treatment. Immunosuppressive effects of glucocorticoids on PMN are restored with OmniGen-AF® supplementation. Glucocorticoid receptor and Toll-like receptor signaling potentially crosstalk to restore PMN function. OmniGen-AF® supplementation restored dexamethasone-induced immunosuppression in a MyD88-dependent manner. Overall, this research focused on characterizing immune responses to S. aureus infections and PMN signaling pathways and how it is key to understanding pathogenesis.Ph. D.
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Djomkam, Leopold Tientcheu. "Differences between host immune responses to `Mycobacterium tuberculosis' and 'Mycobacterium africanum'." Thesis, London School of Hygiene and Tropical Medicine (University of London), 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.590516.
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Lopes, Carolina Schultz. "Regulação do desenvolvimento e resposta imune de lagartas de Diatraea saccharalis (Fabricius) (Lepidoptera: Crambidae) por Cotesia flavipes (Cameron) (Hymenoptera: Braconidae)." Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/11/11146/tde-16092008-161549/.
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Cotesia flavipes (Cameron) (Hym.: Braconidae), como outros cenobiontes, é capaz de regular seu hospedeiro, criando um ambiente que sustenta e promove o desenvolvimento de suas larvas, comumente em detrimento do hospedeiro. Substâncias derivadas do trato reprodutivo das fêmeas (proteínas ovarianas, veneno e polidnavírus) são injetadas no hospedeiro, afetando a resposta imune e outros processos fisiológicos com o propósito de regular os níveis hormonais, nutrição e comportamento. O presente trabalho teve por objetivo avaliar o papel dessas substâncias no crescimento e desenvolvimento de Diatraea saccharalis (Fabricius) (Lepidoptera: Crambidae), e avaliar como o parasitismo afeta a resposta imune do hospedeiro. Todas as substâncias derivadas da fêmea foram obtidas após a dissecação do parasitóide, através da coleta do reservatório de veneno ou dos ovários (proteínas ovarianas e polidnavírus) em tampão resfriado. As secreções foram processadas adequadamente e injetadas logo após a coleta. O veneno e as proteínas ovarianas + polidnavírus (PDV) foram injetados juntos ou separadamente em lagartas entre 0-12h do 6º instar. O efeito de cada um dos componentes isolados do parasitóide no desenvolvimento e crescimento do hospedeiro foi avaliado através de observações no ganho de peso, duração e viabilidade da fase larval e pupal. Os efeitos do parasitismo na resposta imune do hospedeiro foram avaliados tanto ao nível celular, através da contagem do número total de hemócitos e capacidade de encapsulação, como ao nível bioquímico, medindo-se a ativação da profenoloxidase e produção de óxido nítrico na hemolinfa das lagartas de D. saccharalis em diferentes estágios de desenvolvimento do parasitóide (0, 1, 3, 5, 7 e 9 dias após o parasitismo). As proteínas ovarianas do parasitóide e o PDV sozinho, ou co-injetado com o veneno, suspenderam o desenvolvimento larval do hospedeiro, enquanto que o veneno, sozinho, afetou o processo de metamorfose. A resposta imune do hospedeiro também foi afetada por C. flavipes, de maneira dependente do tempo. Lagartas parasitadas apresentaram declínio no número total de hemócitos a partir do 3º dia e a capacidade de encapsulação foi afetada ao longo do desenvolvimento do parasitóide. A atividade da fenoloxidase do hospedeiro foi alterada apenas no final do desenvolvimento imaturo do parasitóide, enquanto que o óxido nítrico foi afetado nas 24 h iniciais após parasitismo.Cotesia flavipes (Cameron) (Hym., Braconidae), as other koinobionts, is capable of regulating the host development to produce an suitable host environment to sustain and promote its own larval development at the host expenses. Female-derived substances from the reproductive tract (ovarian proteins, venom, polydnavirus) are injected into the host, affecting the host immune response and other physiological processes aiming to regulate the host hormone levels, nutrition and behavior. Our goal was to evaluate the role of these substances on Diatraea saccharalis (F.) (Lepidoptera: Crambidae) growth and development, and how the parasitism affects the host immune response. All female-derived substances were collected after parasitoid dissection by collecting the venom reservoir or the ovaries (ovarian proteins and polydnavirus). Dissections were carried out in ice-cold buffer, collected tissues were processed accordingly and the desired substances injected immediately after collection. Venom and ovarian proteins+polydnavirus (PDV) were injected jointly and separated in 0-12 hold 6th instars of D. saccharalis. The effect of these substances on host development and growth was evaluated by measuring the host weight gain, larval and pupal survivorship and developmental time. The effects of the parasitism on the host immune response was evaluated either at the cellular level, by measuring the total hemocyte count and the encapsulation capacity, and at the biochemical level, by measuring the prophenoloxidase activity and nitric oxide levels at different stages of parasitoid development (0, 1, 3, 5, 7 and 9 days after parasitism). Parasitoid ovarian proteins and PDV alone or co-injected with the venom arrested the host larval development, while the venom by itself only affected the host metamorphosis process. The host immune response was also affected by C. flavipes at a time-dependent manner. The total hemocyte count dropped at day 3 of parasitism, while the host encapsulation capacity was reduced during parasitoid development. The host prophenoloxidase activity was also affected mainly towards the end of parasitoid larval development, while the nitric oxide at the first 24 h after parasitism.
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Rehm, Kristina Roper Rachel. "The Poxvirus A35 Protein Promotes Virulence by Regulating the Host Adaptive Immune Response." [Greenville, N.C.] : East Carolina University, 2010. http://hdl.handle.net/10342/2696.
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Kumar, Ramesh Kumar al Athi. "Association of angiogenesis with the host Th1/Th2 immune response in brain tumours." Thesis, University of Hull, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.421208.
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Johnston, Claire. "Isolates of Trichuris muris : host immune response and characterisation of secreted parasite antigens." Thesis, University of Manchester, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.508261.
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Gastrointestinal helminths infect over 1 billion people worldwide. While rarely causing death, intestinal helminths cause high morbidity, especially in children and result in huge economic losses each year. While antihelminthics have proven effective, in endemic areas reinfection is common and the emergence of antihelminthic resistance is a major concern. The murine intestinal nematode, Trichuris muris has been utilised as a good model for the human parasite, T. trichiura for the past 45 years and has yielded much evidence of the immune response to this caecal-dwelling nematode. Studies of the immune response to T. muris have mainly been conducted using the E isolate. Host resistance to T. muris relies upon the development of a Th2 response while susceptibility correlates with a Th1 response. In the present work, studies were conducted using the J and S isolates and the conventionally-studied E isolate. Firstly, the phylogenetic relationship between the E, J and S isolates was explored by comparing internal transcribed spacer (ITS) 2 sequences between the isolates and to other ITS2 sequences from other Trichuris species. These analyses revealed the isolates to be extremely similar at this level. Following this, the immune response elicited by the E, J and S isolates of T. muris in male AKR, C57BL/6 and BALB/c mice was characterised. In BALB/c mice, all isolates were expelled and was, with all three isolates, associated with an elevated Th2 response. In contrast, all three isolates persisted to chronicity in AKR mice but the E and S isolate elicited significantly higher IL-12 while levels in J-infected mice were equivalent to naïve. Serum MMCP-1 was significantly higher in J and E-infected mice compared with S-infected mice. Interestingly, differential worm expulsion kinetics occurred in the C57BL/6 mouse strain, with the E and J isolate expelled by d 35 p.i. but the S isolate was retained to chronicity. Furthermore, levels of Th2 cytokines were markedly lower in S-infected mice while type 1 cytokines IL-12 and IFN-γ were raised in all infected groups. The lower Th2 response in S-infected mice was reflected in a lower goblet cell hyperplasia and a lower mastocytosis and eosinophilia. IgG1 was equally raised while IgG2a was lowest in J-infected mice. In contrast, female C57BL/6 mice were able to mount a Th2 response against the S isolate and expel most worms by d 35 p.i. Furthermore, survival of the S isolate is dependent upon MyD88 thus MyD88 KO mice expelled the S isolate in a Th2-dependent manner. To begin to address the mechanism underlying S persistence, the effects of isolate-specific E/S on DC were examined. Interestingly, CD 1lc+ DC from C57BL/6 mice upregulated MHC II expression when stimulated with E and J E/S but did not with S E/S. Western blots showed parasite-specific E/S to be differentially recognised by mouse strain-specific antibody, with strong recognition of low molecular weight antigens being associated with susceptibility. Furthermore, E/S zymography revealed protease activity at approximately 20 kDa which was greatest in S isolate E/S. Inhibition studies showed differential protease activity between isolate specific E/S but all exhibited serine protease activity. Overall, these studies enhanced previous understanding of the immune response to T. muris as a whole thus highlighting the relevance parasite isolates have in parasite immunology.
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Teng, Ooiean, and 丁瑋嫣. "Identification of CLEC5A in modulating host immune response after influenza A virus infection." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/208615.
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Human infections with influenza A virus (IAV) exhibit mild to severe clinical outcomes as a result of differential virus-host interactions. C-type lectin receptors (CLRs) are pattern recognition receptors that may sense carbohydrates, proteins, or lipids derived from infected hosts or the invading microbes including bacteria, viruses, fungi, or parasites. CLR-viral interaction may lead to increased viral entry and spread; furthermore, their interactions have been reported to trigger downstream signaling that further modulates host’s innate immune responses through the induction of pro-inflammatory cytokines. To date, DC-SIGN and DC-SIGNR have been shown to mediate IAV entry; however, the potential interactions between other human transmembrane CLRs with IAV have not yet been systematically investigated. We utilized lentiviral-based pseudoparticles expressing influenza hemagglutinin (HA) to examine the binding potential between HA and a panel of human CLRs expressed in soluble form. CLEC5A was identified as a potential interacting target with the HA proteins derived from a highly pathogenic avian H5N1 virus A/VN/1203/04 (VN1203) or a human seasonal H1N1 virus A/HK/54/98 (HK5498), albeit at different binding intensity. Applying siRNA gene silencing, we confirmed that CLEC5A did not enhance influenza entry in human monocytic U937 cells that constitutively express CLEC5A or in the lentiviral-transduced stable CHO and CHO-Lec2 cells that overly expressed CLEC5A. To investigate downstream signaling upon engagement of CLEC5A to influenza virus, M-CSF or GM-CSF differentiated human macrophages with high expression levels of CLEC5A and DAP12, a known adaptor protein for CLEC5A upon phosphorylation to initiate signal transduction, was subjected to CLEC5A siRNA gene silencing followed by infection with recombinant A/PR/8/34 virus expressing HA and NA derived from either VN1203 (H5N1) or HK5498 (H1N1) viruses. RG-PR8xVN1203HA,NA (H5N1) exhibited a higher infectivity and induced higher levels of pro-inflammatory cytokines (TNF-( and IFN-α) and chemokines (IP-10, MCP-1, MIG and MIP-1α) secretion in M-CSF or GM-CSF differentiated macrophages while compared to that of the RG-PR8xHK5498HA,NA (H1N1) virus. Knocking-down CLEC5A in macrophages led to a universal reduction of cytokines and chemokines secretion after infection with either the RG-PR8xVN1203HA,NA, RG-PR8xHK5498HA,NA, RG-A/VN/1203/04 (H5N1) or A/Shanghai/2/2014 (H7N9) viruses, suggesting that CLEC5A plays a role as cytokine and chemokine amplifier after influenza infection. Since DAP12 phosphorylation is known to activate downstream signaling via Spleen tyrosine kinase (Syk), pre-incubation of M-CSF macrophages with a Syk inhibitor (Bay 61-3606) also lead to a significant reduction of TNF-α and IP-10 in infected macrophages. A higher mortality was observed in CLEC5A-/- mice while compared to the wild-type C57BL/6 mice after challenged with a lethal dose of RG-A/VN/1203/04 (H5N1) influenza virus suggesting that CLEC5A as a host innate response amplifier play a protective role upon influenza infection. In conclusion, we have identified CLEC5A as a novel host factor for influenza pathogenesis by modulating host innate inflammatory response.published_or_final_version
Public Health
Doctoral
Doctor of Philosophy
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Marsh, Elizabeth Kate. "Host-pathogen interactions in the innate immune response of the nematode Caenorhabditis elegans." Thesis, University of Birmingham, 2010. http://etheses.bham.ac.uk//id/eprint/1191/.
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The nematode Caenorhabditis elegans has been a powerful experimental organism for almost half a century. Over the past ten years, researchers have begun to exploit the power of C. elegans to investigate the biology of a number of human pathogens. This work continues to uncover mechanisms of host immunity and pathogen virulence that are either analogous to those involved during pathogenesis in alternative animal hosts or mechanisms which are, thus far, unique to the worm. In this thesis, we present data that describes an immunological balance in C. elegans, whereby heightened tolerance to one pathogen, the enteric bacteria Salmonella Typhimurium, comes at the cost of increased susceptibility to another, the fatal fungal human pathogen Cryptococcus neoformans. We find that this susceptibility trade-off is mediated by the reciprocal activity of two immune genes: the lysozyme lys-7 and the tyrosine kinase abl-1. We suggest that ABL-1 controls two different DAF-16-dependent pathways to regulate this balance. Both pathways are necessary for wild type resistance to C. neoformans, whilst the activity of only one pathway is a requirement for the tolerance phenotype to S. Typhimurium. We infer from sequence data that LYS-7 has an atypical mode of action in C. elegans, which we hypothesise to be detrimental to the worm during S. Typhimurium pathogenesis and thus a contributing factor to the tolerance phenotype. Furthermore, we find that this tolerance has a Salmonella-dependency which we propose to be under the control of the alternative sigma factor, RpoS. Taken together, we describe an immunological balance in C. elegans for the first time, one that is mediated by both host and pathogen factors. We therefore suggest that the innate immune response of C. elegans has a higher level of immune complexity than previously believed, and that such trade-offs are evolutionarily ancient mechanisms.
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Barker, Emily Mary. "Virus-host interactions in the innate immune response to high-risk human papillomavirus." Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610618.
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Nicholls, Philip Keith. "The viral life cycle and host immune response during canine oral papillomavirus infection." Thesis, University of Cambridge, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.624413.
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Surendran, Naveen. "Unraveling the host innate immune response to a respiratory model of Brucella abortus." Diss., Virginia Tech, 2010. http://hdl.handle.net/10919/77100.
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Brucella are Gram-negative intracellular bacteria that cause abortion and infertility in livestock and chronic disease in humans. The Centers for Disease Control and Prevention (CDC) categorizes them as class B pathogens due to their zoonotic potential. Currently, there are no efficacious Brucella vaccines for humans available. Very few studies have focused on identifying protective vaccines against respiratory exposure. Protection by B. abortus rough vaccine strains RB51 and RB51SOD is through strong CD4⁺ Th₁ and CD8⁺ Tc₁ adaptive immunity. However, limited information is available on how they stimulate innate immunity. This knowledge is critical for improving these vaccines for their potential use in humans.
Dendritic cells (DCs) play a crucial role bridging innate and adaptive immunity. Therefore, enhancing the ability of rough vaccine strains to induce DC maturation and function could be critical for upregulating protective T-cell responses. Herein, we demonstrated that live vaccine strain RB51 induced significantly better (p≤0.05) DC maturation and function in vitro and upon intranasal inoculation in vivo compared to strain RB51SOD or strain 2308. Due to safety concerns of live vaccines, irradiated and heat killed vaccines were also tested; only live strain RB51 infected DCs induced significant (p≤0.05) DC function based on TNF-α and IL-12 secretion.
DC activation occurs through Toll-like receptors (TLRs) 2, 4 and 9. Our study reported that strain RB51 induced significant (p≤0.05) DC activation compared to strain 2308, which was not dependent on a specific TLR. However, strain RB51 induced TNF – α production was TLR2 and TLR9 dependent and IL-12 production was TLR2 and TLR4 dependent. TLR4 KO mice had significantly (p≤0.05) higher number of strain RB51 colonies present at day 14 post infection.
By unraveling the innate immune responses to Brucella, the ultimate goal of these studies is to develop a protective vaccine for animals and people against respiratory challenge. As such, we tested several vaccination strategies. Despite enhanced DC activation and function achieved by vaccine strains, they failed to protect mice against intranasal challenge with strain 2308. Future experiments will address host-pathogen interaction at the lung microenvironment and elucidate immune mechanisms that will enhance protection against aerosol exposure.Ph. D.
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THULLEN, TIMOTHY DAVID. "ANALYZING THE HOST IMMUNE RESPONSE TO PNEUMOCYSTIS UTILIZING TWO RAT MODELS." University of Cincinnati / OhioLINK, 2003. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1066676759.
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Park, Myeongseon. "Dissecting the impact of macrophage migration inhibitory factor (MIF) on host immune response." Diss., Virginia Tech, 2018. http://hdl.handle.net/10919/97565.
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Macrophage migration inhibitory factor (MIF) has been implicated in mediating both innate and adaptive immune responses in inflammatory and infectious diseases. The sequence and structure of MIF is highly conserved across the avian phylogeny, which underlies high sequence homology and functional similarities between turkey and chicken MIFs. Turkey MIF (TkMIF) inhibited cell migration and promoted cell proliferation with production of inflammatory mediators, comparable to the biological properties of chicken MIF (ChMIF), thus indicating the biological cross-reactivity between turkey and chicken MIFs. This study identified the cell surface receptor(s) that could bind ChMIF and the biological roles triggered by such interactions. In addition to CD74, a previously identified receptor, CXCR4 also interacts with ChMIF. Moreover, the formation of receptor complexes was shown between CXCR4 and CD74. MIF signaling through CXCR4 and CD74 led to cell chemotaxis and proliferation activity as well as intracellular calcium influx. Intriguingly, Eimeria MIF (EMIF), a homologue secreted following parasitic infection, also interacted with CD74 leading to comparable biological functions to those of ChMIF. Given such observations, we hypothesized that CXCR4 and CD74 are receptors for ChMIF leading to the functional consequences similarly manifested by EMIF interaction with the corresponding receptors. EMIF, predominantly secreted from the invasive merozoite stage, may help the parasite exploit the host immune response by interacting with common ChMIF receptors. This may lead to functional mimicry thus provoking the question of whether EMIF would modulate the biological functions of ChMIF to manipulate the host defense that allows more efficient invasion of the host. To evaluate this concept, a transgenic E. tenella lacking MIF was generated by in vivo passage of E. tenella transfected with a CRISPR plasmid targeting EMIF. Although not fully disrupted, reduction of EMIF expression was observed in the transgenic E. tenella itself as well as in inoculated cells, which resulted in enhanced survival of host cells. Herein, we achieved a better characterization of the functional roles of both avian and parasite MIFs underlying the interaction with common host receptors, along with the essential role of parasite MIF promoting host cell death during parasitic infection.PHD
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Almond, Mark. "The effect of obesity on the host innate immune response to influenza infection." Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/47967.
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Background: We live in an ‘obesogenic environment’ in which overconsumption of affordable, energy-dense, processed foods has resulted in the prevalence of obesity more than doubling since 1980, such that it is now the commonest nutritional disorder worldwide. In March 2009, a novel strain of influenza A virus (pH1N1/09) emerged in Mexico, rapidly spreading around the world to cause the first influenza pandemic of the 21st century. For the first time during an influenza pandemic, obesity was convincingly identified as a novel, independent risk factor for multiple markers of disease severity, including hospitalisation, intensive care unit admission and death following infection. The aim of this project was to investigate the mechanisms underlying this increased susceptibility to severe outcomes following pH1N1/09 infection in morbidly obese individuals using primary human tissues. We hypothesised that obesity-associated hyper-leptinaemia would increase constitutive expression of the negative regulator, suppressor of cytokine signalling 3 (SOCS3), in key pulmonary structural and immune cells and that this, in turn, would attenuate interferon (IFN) expression and signal transduction, thus reducing induction of IFN stimulated genes (ISGs), the main antiviral effectors. Methodology: A case-control study design was adopted in which bronchial epithelial cells (hBECs), bronchoalveolar lavage (BAL) cells, peripheral blood mononuclear cells (PBMCs) and peripheral blood dendritic cells (DCs) were isolated from 15 morbidly obese individuals (body mass index (BMI) ≥ 35 kg/m2) and 15 age, gender and ethnicity-matched healthy weight (‘lean’) controls (BMI 20-25 kg/m2) by bronchoscopy and venesection to allow comparison of the type I and III IFN and pro- inflammatory cytokine responses following pandemic and seasonal influenza infection. Viral replication, ISG and SOCS expression profiles were also quantified in the primary cells and the constitution of the inflammatory environment in which the cells reside was evaluated through measurement of adipokines, cytokines, acute phase proteins and chemokines. Results: BAL cells from morbidly obese individuals exhibited deficient type I and III IFN responses to both pandemic and seasonal influenza virus infection. This IFN- deficiency was BAL cell specific and therefore not observed following infection of primary hBECs, PBMCs or DCs. Although unlikely, it is possible that the observed IFN deficiency may have been due to the confounding effects of the general anaesthesia that the obese subjects underwent during their bronchoscopy. Elevated leptin levels were observed in the lung and serum of the obese subjects; however, baseline constitutive SOCS3 mRNA expression was not increased in the obese subjects and we were unable to demonstrate leptin-induced upregulation of SOCS3. For the first time, we report relatively high expression of the lesser-studied adipokines resistin, visfatin and adipsin in the lung and nose. Additionally, we report that the acute phase protein, C-reactive protein (CRP), a biomarker of inflammation, was significantly elevated in the BAL fluid of the obese subjects. Conclusion: Obesity-associated BAL cell IFN deficiency may contribute to the increased susceptibility to severe outcomes seen in the obese population following influenza infection.
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Akinlotan, Morenikeji D. "Within-host dynamics of Chlamydia trachomatis infection: Repeat infections and the immune response." Thesis, Queensland University of Technology, 2018. https://eprints.qut.edu.au/119362/1/Morenikeji%20Akinlotan%20Thesis.pdf.
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Chlamydia trachomatis is the most common bacterial sexually transmitted infection worldwide. The control of its incidence is a major public health challenge. It is one of the major preventable causes of disability and mortality. Genital Chlamydia infection is asymptomatic and thus commonly undiagnosed and untreated. In this study, we use ordinary differential equation models to provide qualitative insights into the within-host dynamics of Chlamydia infections, the associated host immune response, and the in vivo control or treatment of the infection. The thesis examines optimal control treatment strategies for acute and chronic genital chlamydial infections, including an investigation of efficacious anti-Chlamydia vaccination strategies. Qualitative results of the presented models provide frameworks for the design of new and improved treatment strategies for genital chlamydial infections.
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Corrado, Alessia <1984>. "Staphylococcus aureus bones and joints infections: in vivo studies and host immune response." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amsdottorato.unibo.it/6570/1/Corrado_Alessia_Ph.D_thesis.pdf.
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Abstract
The aim of this work was the development of a murine model of septic arthrosynovitis and osteomyelitis caused by Staphylococcus aureus, which could mimic the natural disease occurring in humans and which could be suitable for testing preventive and therapeutic interventions. This model could be particularly useful since S. aureus-mediated joints and bones infections are relevant in humans, both in terms of frequency and severity.
Our attention focused in tracking bacterial infiltration in joints and bones over time using different microbiological and hystopathological tools, which allowed us to have a complete overview of the situation and to evaluate the immunological actions undertaken by the host to contain or eradicate the bacterial infection.
Antibodies and cytokines profiles, as well as recruitment of host immune cells at joints of immunized and infected mice were therefore monitored for a time period that allowed us to study both the acute and the chronic phases of the disease in situ. Finally the Novartis vaccine formulation proposed against S. aureus infections was tested for its capacity to protect immunized mice from joints infections, and the preventive immunization was compared to a standard antibiotic prophylaxis.
The availability of powerful tools to study specific bacterial-mediated diseases is nowadays an important requirement for the scientific community to shed light on the complex interactions between host and pathogens and to test treatments for preventing or contrasting infections. We believe that our work significantly contributes to the overall knowledge in the field of S. aureus-dependent pathologies, opening the possibility for further investigations in several fields of study.
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Corrado, Alessia <1984>. "Staphylococcus aureus bones and joints infections: in vivo studies and host immune response." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amsdottorato.unibo.it/6570/.
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Abstract
The aim of this work was the development of a murine model of septic arthrosynovitis and osteomyelitis caused by Staphylococcus aureus, which could mimic the natural disease occurring in humans and which could be suitable for testing preventive and therapeutic interventions. This model could be particularly useful since S. aureus-mediated joints and bones infections are relevant in humans, both in terms of frequency and severity.
Our attention focused in tracking bacterial infiltration in joints and bones over time using different microbiological and hystopathological tools, which allowed us to have a complete overview of the situation and to evaluate the immunological actions undertaken by the host to contain or eradicate the bacterial infection.
Antibodies and cytokines profiles, as well as recruitment of host immune cells at joints of immunized and infected mice were therefore monitored for a time period that allowed us to study both the acute and the chronic phases of the disease in situ. Finally the Novartis vaccine formulation proposed against S. aureus infections was tested for its capacity to protect immunized mice from joints infections, and the preventive immunization was compared to a standard antibiotic prophylaxis.
The availability of powerful tools to study specific bacterial-mediated diseases is nowadays an important requirement for the scientific community to shed light on the complex interactions between host and pathogens and to test treatments for preventing or contrasting infections. We believe that our work significantly contributes to the overall knowledge in the field of S. aureus-dependent pathologies, opening the possibility for further investigations in several fields of study.
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Lee, Jinhwa. "Effects of PB1-F2 and PA-X on the pathogenicity of H1N1 influenza virus." Diss., Kansas State University, 2016. http://hdl.handle.net/2097/34617.
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Doctor of PhilosophyDepartment of Diagnostic Medicine/Pathobiology
Wenjun Ma
Influenza A virus (IAV) is a negative sense, single-stranded, segmented RNA virus with eight gene segments. It is an important respiratory pathogen which causes annual epidemics and occasional pandemics worldwide in humans and leads to considerable economic problems for the livestock industry. To control and prevent this significant disease, understanding the pathogenesis of IAVs is critical. Although some molecular mechanisms regarding virulence have been determined, IAV pathogenesis is not completely understood and is difficult to predict. The eight viral gene segments of IAV were thought to encode for 10 viral proteins. Since 2001, eight additional viral proteins have been identified, including PB1-F2, PB1-N40, PA-X, NS3, PA-N155, PA-N182, M42, and PB2-S1. However, the functions of these novel proteins in influenza virus replication as well as pathogenesis have not been fully elucidated. Although PB1-F2 protein is an important virulence factor of IAV, the effects of this protein on viral pathogenicity of swine influenza virus (SIV) remain unclear. In Chapter 2, we investigated the contribution of the PB1-F2 protein to viral pathogenicity of a virulent triple-reassortant (TR) H1N1 SIV in different hosts, pigs and mice. Our data indicate that PB1-F2 expression in virulent TR H1N1 SIV modulates virus replication and pathogenicity in the natural host, pigs, but not in mice. In addition, single amino acid (aa) substitution at position 66 (N/S) in the PB1-F2 has a critical role in virulence in mice but no effect was found in pigs. A novel IAV protein, PA-X consists of the N-terminal 191aa of PA protein and a unique C-terminal 41 (truncated form) or 61 (full-length form) aa residues encoded by +1 ribosomal frameshifting. Although several studies have demonstrated the PA-X protein as an important immune modulator and virulence factor, the impact of different expressions of PA-X protein including full-length, truncated or PA-X deficient forms on viral pathogenicity and host response remains unclear. In Chapter 3, we showed that expression of either truncated or full-length PA-X protein in 2009 human pandemic H1N1 (pH1N1) viruses suppresses host antiviral response by host shutoff activity which promotes viral growth and virulence in mice when compared to loss of PA-X expression. Furthermore, full-length PA-X expression displayed stronger impact on viral pathogenicity and host immune response compared to truncated PA-X expression. Taken together, our results provide new insights into the impact of PB1-F2 and PA-X proteins on virus replication, pathogenicity and modulation of host immune responses. This knowledge is important for better understanding of IAV pathogenesis.
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Coon, Courtney A. c. "Host-Parasite Interactions in an Invasive Songbird." Scholar Commons, 2014. https://scholarcommons.usf.edu/etd/5004.
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Introduced species are the greatest threat to biodiversity after habitat loss. Understanding the processes that permit organisms to become successful invaders may provide opportunities to prevent or limit their dispersal and establishment and thereby alleviate some of their harmful effects. The goal of my dissertation research has been to investigate whether invasive species have distinctive interactions with parasites, and some of the mechanisms that may underlie that variation. I used one of the world's most successful vertebrate invaders as a case study: the house sparrow (Passer domesticus; Introduction).
Previous research in the house sparrow suggested that loss of parasite diversity may contribute to invasion success. However, my work demonstrates that infection with common avian malaria parasites is primarily a function of environmental heterogeneity and is not a predictor of time since introduction for house sparrows that are currently expanding their range in Kenya (Chapter 1). Interestingly, in spite of a large proportion of the population being infected with avian malaria, a state that should reduce competitive ability of house sparrow populations, this species is still able to establish themselves among native competitors. Though there are a number of potential mechanisms that could explain this pattern, one of the most convincing explanations is that house sparrows, and perhaps other introduced species, have adaptive differences in immunity.
As such, the findings of Chapter 1 inspired two studies in which my collaborators and I showed that house sparrows from two non-native populations seem capable of maintaining normal health, performance and behavior during immune challenge, a response often referred to as parasite tolerance. Specifically, in Chapter 2, we found that when Floridian house sparrows, established since ~1870, were challenged with synthetic pathogens that mimicked infection with a fungi, an RNA virus or Gram-negative bacteria, only individuals challenged by the synthetic bacteria showed measurable sickness behaviors and secretion of an inflammatory protein. In Chapter 3, we compared parasite tolerance in Kenyan house sparrows (introduced in ~2000) and a native congener, the grey-headed sparrow (P. griseus) to a common intestinal parasite of songbirds. We found that both species were tolerant in that they were able to maintain fat reserves, protein reserves and vertical flight ability during infection. However, house sparrows maintained burdens that were, on average, more than 10x those of grey-headed sparrows. Moreover, when examining nutrient allocation in the two species, house sparrows appeared to assimilate nutrients more efficiently than grey-headed sparrows and did not change how nutrients were allocated among immune and reproductive organs during experimental infection. Grey-headed sparrows, however, did shift nutrient allocation among immune and reproductive organs during experimental infection. Together, the larger nutrient pool and maintenance of nutrient allocation patterns in challenged house sparrows suggests that no physiological trade-offs occurred and that house sparrows experienced a lower cost of parasite exposure.
In the fourth Chapter, I explored why house sparrows had such high coccidia burdens in comparison to their congeners. We suspected burden was a function of the frequency of exposure to coccidia. Consequently, we explored heterogeneity in foraging preferences and other behaviors in Floridian house sparrows and their role in coccidia burden. As expected, we found that house sparrows did not avoid contaminated food. In fact, they ate contaminated and uncontaminated foods indiscriminately. What was surprising was a lack of correlation between burden and consumption of contaminated foods and all of the behaviors we monitored (i.e., aggression, activity, feeding rates and defecation frequency). Overall, these data suggest that house sparrows do not benefit from typical parasite-avoidance behaviors.
In sum, this dissertation research implies that house sparrows respond to parasite infection differently than many other known vertebrates, most likely in an effort to maximize efficient use of resources and, in so doing, augment competitive ability and invasion success.
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Yin, Han. "MOLECULAR ANALYSIS OF HTLV-2 APH-2 IN VIRAL TRANSFORMATION, PERSISTENCE AND HOST IMMUNE RESPONSE." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1322156034.
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Caller, Laura Grace. "An investigation into BK Polyomavirus and host-virus interactions." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/288073.
Full textAbstract:
The potentially oncogenic human pathogen BK Polyomavirus (BKPyV) was first identified in 1971 and has since been associated with a number of diseases primarily in immunosuppressed patients. Infection is established in early life and by adulthood up to 90% of populations show seroconversion for the major capsid protein VP1. Despite this infections are rarely cleared, maintaining a silent asymptomatic persistence punctuated with periods of viral shedding in the urine. The virus is non-enveloped and comprises a simple ~5.2 Kb dsDNA genome which expresses just seven known proteins, necessitating a heavy reliance on, and interactions with, host mechanisms in order to efficiently replicate and disseminate within a population. The poorly understood lifelong persistence and failure to clear infection highlights our lack of understanding of the viral life cycle and viral interactions with host processes and responses to infection. Indeed, non-enveloped viruses are thought to spread solely through infected cell lysis but such large-scale lysis should trigger an acute inflammatory response, which is rarely seen in healthy immunocompetent individuals. The research conducted for this thesis first investigates the egress of BKPyV in a non-lytic manner, presenting evidence for an active non-lytic method of viral egress that is dependent on cellular anion homeostasis. Moreover, data generated for this thesis suggests that virions egress via an unconventional secretion pathway which traffics directly from the endoplasmic reticulum (ER) to the plasma membrane in single-membraned vesicles. Further research undertook a whole cell quantitative temporal viromic (QTV) approach, post-experimentally tagging whole cell lysate peptides with isobaric labels (Tandem Mass Tagging, TMT) to provide a greater understanding of host cell proteomic changes throughout BKPyV infection in two primary human cell types over 72 hours of infection. Such an approach identified ~9000 cellular proteins, of which a surprisingly small number changed significantly in abundance in response to BKPyV infection. Of those that were changed in abundance a large proportion were related to cell cycle, revealing that BKPyV infection induces a pseudo-G2 arrest, similar to the G2/M checkpoint. Validation of TMT results in both cell types provided confidence in this robust data set, and further studies highlighted the importance of not only cell cycle status, but the activity of CDK1 for efficient viral infection and replication. Additionally, TMT generated data emphasised the lack of innate immune induction in response to BKPyV infection, suggesting BKPyV exhibits a sophisticated evasion of pathogen recognition.
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Welschinger, Robert. "Role of host response to hepadnavirus sAg in immunity and recovery." Thesis, The University of Sydney, 2004. https://hdl.handle.net/2123/27987.
Full textAbstract:
Human Hepatitis B Virus (HBV) is a major global health problem affecting many
millions of people. Individuals infected by perinatal transmission, become life long
chronic carriers. They constitute a reservoir for the dissemination of infection, and
many develop major health problems, such as cirrhosis, and hepatocellular
carcinoma (HCC), later in life. Although new transmission can be limited by the use
of a protein-based vaccine, the number of carriers continue to rise because the
vaccine remains unavailable in many high prevalence, low-income areas. Treatment
with nucleoside analogues and interferon is prolonged, expensive, and out of reach
for most carriers. An inexpensive therapeutic vaccine which might be effective in
established human carriers would have an immediate impact on a major global
problem.
The first part of this study was undertaken to identify critical virus and host factors
responsible for recovery from DHBV infection. The DHBV model has been pivotal
in understanding the immunopathogenesis of hepadnaviral infections, and recent
advances have opened the way to investigation of immunopathology.
Initially, the effect of age and dose on the kinetics, and outcome of infection was
investigated, to define conditions where viral clearance could be studied. A biphasic
pattern of infection was discovered, in which an initial peak of viraemia was cleared,
only to be followed by rebound, and subsequent persistence. A mutation near the
start of the surface open reading frame was identified in these cases, associated with
attempted clearance of the infection. Transmission studies determined that the
replication competency of the mutant genome was less than that of the wild type
genome.
Because of earlier reports that immune response to DHBs predicted viral clearance,
theoretical modelling of the surface gene was performed to determine the effect of
the mutation on the genome, and associated polymerase protein. Irnmunogenic
predictions for the S gene sequence were also undertaken and tested experimentally.
A lymphocyte proliferation assay was used to determine the CMI response of na'1've,
carrier, and protein vaccinated ducks to peptides spanning the surface protein. A
DNA vaccine, was produced based on a polytope incorporating 7 peptides to which
immune ducks selectively respond. This vaccine stimulated production of
neutralising antibodies in naive ducks, and also induced a 90% reduction in the
average level of Viraemia in chronically infected ducks. Such evidence suggests that
co-operation of B- and T-cells occurs when these epitopes interact with the immune
response.
A feature of the duck'model system is that the cellular and humoral arms of the
immune system can be modulated by surgical removal of the thymus, or bursa of
Fabricius. The effect of reducing the total number of B- or T-cells on the outcome of
DHBV infection was examined. Contrary to expectation, bursectomised ducks
cleared the infection less efficiently than thymectomised ducks. While this indicates
that antibodies play an essential role in clearance, such selective depletion of
suppressor T-cells by thymectomy, may also promote removal of the virus.
The findings encourage further work into DNA vaccines with the expectation that
incorporating a broader repertoire of peptides, in combination with cytokine
sequences, will increase efficacy, to a level greater than current antiviral therapy.
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Anderson, Sarah M. "The Fatty Acid Oleate in the C. elegans Innate Immune Response." eScholarship@UMMS, 2021. https://escholarship.umassmed.edu/gsbs_diss/1133.
Full textAbstract:
Host metabolism is profoundly altered during bacterial infection, both as a consequence of immune activation and secondary to virulence strategies of invading pathogens. As a result, the metabolic pathways that regulate nutrient acquisition, energy storage, and resource allocation in host cells must adapt to pathogen stress in order to meet the physiological demands of the host during infection. In this work, we uncover that the synthesis of the monounsaturated fatty acid (MUFA) oleate is necessary for the pathogen-mediated induction of immune defense genes. Accordingly, C. elegans deficient in oleate production are hypersusceptible to infection with diverse human pathogens, which can be rescued by the addition of exogenous oleate. However, oleate is not sufficient to drive protective immune activation.
Oleate is also important for proper lipid storage and abundance. We found that exposure to pathogenic bacteria drives rapid somatic depletion of lipid stores in C. elegans. Activating the p38/MAPK immune signaling pathway in the absence of pathogens was also sufficient to drive loss of somatic fat. In addition, we found that transcriptional suppression of MUFA synthesis occurs during P. aeruginosa infection, in a manner dependent on pathogen virulence. Finally, we showed that the host compensates for the pathogen-induced depletion of fatty acids by promoting the redistribution of oleate from non-intestinal tissues to support immune function in the intestine. Together, these data add to the known health-promoting effects of MUFAs, and suggest an ancient link between nutrient stores, metabolism, and host responses to bacterial infection.
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Hendry, Julie. "The host immune and inflammatory response to Burkholderia cepacia in adults with cystic fibrosis." Thesis, University of Newcastle Upon Tyne, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.285320.
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Keeton, Roanne Shay. "The role of TNFRp55 and TNFRp75 in the host immune response to Mycobacterium tuberculosis." Doctoral thesis, University of Cape Town, 2009. http://hdl.handle.net/11427/11889.
Full textAbstract:
Includes abstract.Includes bibliographical references (leaves 85-97).
Tumor necrosis factor alpha (TNFα) is critical for host protective immunity against Mycobacterium tuberculosis infection. TNFRp55 and TNFRp75 can both bind TNFα and conduct signaling, however the respective roles, in particular that of TNFRp75 in an M. tuberculosis aerosol inhalation infection was poorly defined. In this study the role of signaling through TNFRp55 and TNFRp75 was investigated using TNFR deficient mice in an aerosol inhalation M. tuberculosis infection model.
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Thompson, Iain James. "Manipulation of antigen presenting cells to enhance host immune responses to bacterial infection." Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/40916.
Full textAbstract:
Vaccine development for intracellular pathogens, where a protective and long lasting T cell response is desirable, has proved to be a significant challenge. Dendritic cell (DC) vaccination has been used to both elucidate mechanisms important in providing protection against a range of pathogens and more recently as a vaccine strategy in its own right. Additionally, targeting of vaccine antigens via monoclonal antibodies specific to DCs has developed as a more clinically appropriate alternative. This thesis investigates whether DC manipulation can enhance survival and reduce bacterial load in murine models of anthrax and melioidosis. Prophylactic DC vaccination for B. anthracis required CpG ODN 1826 for the maturation of antigen-stimulated DCs in vitro. Following their adoptive transfer, DCs failed to induce an antigen-specific response. However, when combined with the rPA and alum anthrax vaccine, DC vaccination enhanced antigen-specific T cell responses. This approach increased murine survival and significantly reduced bacterial load. DC vaccination as a therapeutic strategy for B. pseudomallei again required CpG ODN 1826 for DC maturation and activation. Antigen stimulated DCs migrated to lymph nodes within 48 hours of adoptive transfer where they induced an antigen-specific T cell response with a mixed Th1/Th17 profile. DC vaccination failed to affect survival with increased splenic weight and bacterial load in two out of three murine efficacy studies. Targeting of the protective B. pseudomallei antigen LolC, conjugated to a monoclonal antibody specific for DEC205, an endocytic DC receptor, failed to induce either a specific immune response or impact survival or bacterial load. Overall, DC vaccination reduced B. anthracis bacterial load when used prophylactically in combination with rPA and alum. As a therapeutic strategy the results are suggestive of DC vaccination enhancing B. pseudomallei infection. Future studies should examine the potential for antigen specific immune responses generated by DC vaccination to be used as an adjunct to antibiotic therapy, when B. pseudomallei replication is controlled.
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Li, Huajing, and 李華菁. "Oral commensal/pathogenic bacteria-host cells crosstalk : immuno-inflammatory response, microenvironmental regulation and signaling mechanism." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/208543.
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Olive, Andrew James. "Immunity to Chlamydia trachomatis and Host-Pathogen Interactions During Infection." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:11263.
Full textAbstract:
Infections with the bacterial pathogen Chlamydia trachomatis are a critical public health problem. Chlamydia remains the number one cause of preventable blindness worldwide and the leading cause of bacterial sexually transmitted infections in the United States. In humans, repeat and persistent infections with Chlamydia result in severe inflammation. Inflammation in the conjunctiva can result in blindness, while inflammation in the genital tract can result in pelvic inflammatory disease, ectopic pregnancy or infertility. In order to curb the increasing incidence of Chlamydia infections worldwide it will be necessary to develop a protective vaccine that affords long-term protection and prevents pathologies. To better inform vaccine development we must understand the mechanisms that drive long-term immunity in the genital tract and elucidate critical interactions between Chlamydia and host cells to uncover potential mechanisms of immune evasion.