Microbiology & Immunology - Theses
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ItemAntibody-mediated passive immunity against Helicobacter pylori(University of Melbourne, 2008)
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ItemThe role of T cells in the immunopathology of Helicobacter pylori infections in mice(University of Melbourne, 2007)
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ItemThe role of dendritic cells in CD8+T cell priming after epidermal HSV-1 infection(University of Melbourne, 2006)
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ItemInduction of immune responses by lipopeptide vaccines(University of Melbourne, 2006)
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ItemThe effect of hydrogen on soil bacterial communities( 2007)Most legume-nodulating rhizobia release hydrogen into the surrounding soil. The effect of hydrogen on soil bacterial communities in microcosms and surrounding legume roots was investigated by generating Terminal Restriction Fragment Length Polymorphism (T-RFLP) profiles of bacterial 16S rRNA genes. (For complete abstract open document).
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ItemUtility of envelope T cells in preventing AIDS: HIV-1 and SIV envelope-specific T cells: controlling HIV-1 and SIV infection in pigtail macaques and their utility as a T cell immunogen( 2008)HIV/AIDS annually kills millions of people worldwide. Those claimed by the disease are quickly replaced by those newly infected. Three times as many new infections occur globally, as patients who are likely to have access to antiretroviral therapy. We need a HIV vaccine. However, the better HIV protein to target for this vaccine in unknown. Structural proteins such as Group specific antigen (Gag) and Envelope (Env) were thought likely candidates due to viral structural proteins usually being highly conserved and constrained in their ability to mutate to escape T cell attack. To establish if Env-specific T cells could control viraemia, 2 large vaccine trials were conducted with 66 pigtail macaques participating. Also, 2 reversion trials involving 4 pigtail macaques were undertaken. Env-specific T cell epitopes were mapped in both SHIV (simian/human immunodeficiency virus) and SIV (simian immunodeficiency virus)-infected macaques using IFNγ intracellular cytokine staining and flow cytometry.
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ItemEnvelope protein domains of duck hepatitis B virus: role in assembly and infectivity( 2005-12)Hepatitis B virus (HBV) is a global public health problem with an estimated number of 350 million carriers world wide who are at risk of development of severe liver disease and hepatocellular carcinoma. Despite currently available nucleoside analogue therapies no general therapeutic breakthrough, which completely clears infection has been achieved after more then two decades of research. Therefore there is a continuing need to identify new antiviral targets that may be translated into useful therapies. Hepatitis B fusion represents a possible novel antiviral target. However, its mechanism and the envelope proteins involved remain unknown, due to the lack of an efficient infection system to study the early stages of virus infection. On the other hand, the study of the related duck hepatitis B virus (DHBV) and the ability to carry out an in vitro infection of primary duck hepatocytes has provided some insight into the hepadnaviral mechanism of entry and the role of envelope proteins domains in this process. ( For complete abstract open document)
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ItemSmall animal models of Gal-mediated and xenograft rejection( 2004-11)Xenotransplantation is the final frontier of using vascularised organs or cellular grafts to treat end-organ disease and offers a potential solution to the worldwide shortage of human tissue available for transplantation. The main immunological barrier to xenografting from pig-to-primate is the antigen, Galactose-α1,3-Galactose (Gal) which is found in all species except humans and other higher primates. Even with the major advancement of deleting Gal from the potential pig donor species with the aid of cloning technology, complete elimination may be elusive as alternative genes yet to be fully characterised, may still produce Gal at low levels. Thus, the human immune response against Gal may continue to be a barrier to successful xenotransplantation. The aim of this project was to develop small animal models of the important components of xenograft rejection that largely relate to the anti-Gal immune response. These include models of hyperacute, acute vascular and chronic xenograft-like rejection that in turn, provide new insights in the immune mechanisms of the rejection processes. The role of antibody and both innate and cognate cellular immunity are explored. Both vascularised heart grafts and non-vascularised skin graft models are examined as rejection of solid organs may differ from cellular transplantation. The project also provides a platform for future studies in testing genetic and pharmacotherapeutic strategies to overcome the rejection processes uncovered.
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ItemImmunological studies of a glycosylation-based mouse model of colitis( 2004-04)Immune dysfunction is a well-recognized factor in the pathogenesis of Inflammatory Bowel Disease (IBD). Numerous mouse models of colitis highlight how varied immunological defects, particularly of T-cells, can give rise to intestinal inflammation. It is increasingly recognized that glycosylation status has a major impact on the development and function of T-cells. In particular maturation in the thymus is regulated by a number of glycosylation-dependent mechanisms. Abnormal glycosylation has been identified in human IBD although this is almost entirely within the context of the mucosal barrier. Mice transgenic for a human glycosyltransferase (α1-2fucosyltransferase, hFUT1) were generated at our institution. These mice were subsequently observed to develop colitis and thus they provide an opportunity to examine the relative importance of glycosylation-induced defects in barrier function or immune function in the pathogenesis of colitis. The aim of this thesis was to further characterize this model, with a particular emphasis on identifying the pathological mechanism behind the intestinal inflammation. It was observed that hFUT1 mice have a profound and unexpected defect in T-cell development. A marked peripheral T-cell deficiency was evident, including a near total absence of CD4 CD25 regulatory T-cells. Examination of the thymus revealed a complete maturation block at the cortico-medullary transition point with profound disturbances in thymocyte glycosylation patterns. The glycosylation defects present were shown to be directly due to the transgene and to inhibit the normal glycosylation changes that mediate thymocyte maturation. Full immune reconstitution experiments confirmed that the abnormal thymocyte glycosylation is responsible for the maturation arrest, the peripheral T-cell deficiency and the observed colitis. A number of therapeutic studies were also undertaken, with prevention of colitis also observed with IL-12 blockade and with manipulation of the intestinal microflora.
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ItemA genetic analysis of the virulence determinants of Moraxella bovis( 2000)Limited information is available regarding the process by which Moraxella bovis induces the condition known as infectious bovine keratoconjunctivitis or IDK in cattle. Previous work has indicated that there are two proteins (type IV pili and a haemolysin) secreted by the bacterium that are essential for disease progression. Of these two proteins, the majority of work has been carried out on the type IV pili. Many of the genes required for type IV pili expression have been identified and characterised. To date the gene encoding the haemolysin secreted by M bovis has not been identified and therefore its role in IBK infection has not been fully investigated. In addition to these recognised virulence determinants, the bacterium secretes a number of other proteins that have the potential to play a role in the disease. This study describes the isolation and characterisation of a number of these known and putative virulence determinants produced by M bovis. Using a cosmid library generated using genomic DNA from the M. hovis strain Dalton 2d, an open reading frame (ORF) that encoded proteolytic activity was identified (mbp). The ORF was 3.4kb in size and had the capability of encoding a protein with a molecular weight of 120kDa. This protein was expressed using a Gram-positive expression system and this data, together with sequence analysis, suggested that Mbp belonged to the autotransporter secretion family. The generation of an isogenic protease mutant allowed for the preliminary analysis of the role Mbp may play in the pathogenesis of an M. hovis infection. This revealed that perhaps Mbp in some instances may have either a regulatory role for expression of the haemolysin and possibly type IV pili. A gene that encoded lipase activity (plb) was found to be an ORF of 1.8kb, encoding a protein of65.8kDa molecular weight. This protein was abundantly expressed in recombinant E coli. Further analysis of the enzymatic activity of PLB revealed that it had the specificity of a phospholipase B and this activity was found to be relatively heat stable. Partial sequence of an operon encoding the haemolytic activity observed for M. hovis was obtained and this suggested that the M bovis haemolysin belongs to the RTX toxin family. Complementation experiments using the a.-haemolysin from E. coli confirmed that the M. bovis haemolysin had RTX-like requirements for activation and secretion. The conservation of each of these possible virulence factors in all of the pathogenic M. bovis strains that were tested indicated that they may have the potential to be used in a vaccine preparation to protect against a heterologous M bovis infection.