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Mechanisms Of Virally-induced Immunosuppression: Effects On DC-NK Networks
Funder
National Health and Medical Research Council
Funding Amount
$566,308.00
Summary
Cytomegalovirus (CMV) infection induces immunosuppression that often results in adverse clinical outcomes. Our previous work established that dendritic cells (DC), cells involved in the initiation of immune responses, are a principle target for CMV. This proposal will test the hypothesis that CMV-induced immunosuppression is mediated by viral interference with DC. Understanding the mechanisms involved in the induction of immunosuppression is a crucial step towards developing better therapies.
Improving Adaptive Anti-viral Responses: A Key To Eliminating Persistent Viral Infection
Funder
National Health and Medical Research Council
Funding Amount
$402,391.00
Summary
Cytomegalovirus (CMV) can cause a persistent infection that can result in adverse clinical outcomes. Our previous work established that suboptimal adaptive immunity is responsible for viral persistence. This proposal will define the defect in adaptive immunity, its causes and how to improve it. The understanding gained from the proposed studies will provide crucial information for the development of improved anti-viral therapies and vaccines.
The Role Of Novel G-Protein Coupled Receptors In Immunity And Inflammatory Diseases
Funder
National Health and Medical Research Council
Funding Amount
$69,684.00
Summary
Recent advances in molecular biology techniques have resulted in the identification of many novel GPCRs. Novel GPCRs expressed selectively on immune cells display a potential target for novel therapies for inflammatory diseases such as Asthma and Rheumatoid arthritis. This project aims to define the activity and significance of a novel group of GPCRs, the GPR40 family. Outcomes of this project will be further understanding of immune cell development and inflammatory disease development.
The Effect Of Innate Immune Responses On The Induction Of Protective Immunity In Murine Typhoid Fever
Funder
National Health and Medical Research Council
Funding Amount
$136,500.00
Summary
Salmonella are important pathogens of humans causing diseases ranging from gastroenteritis, typhoid fever to arthritis. Like most if not all infections, the early interaction between the host and the bacterium is characterised by very non-specific symptoms. These non-specific symptoms arise because the so-called innate immune system is activated by the infection. The purpose of this grant is to establish whether these non-specific symptoms, caused by the release of immunological homrones called ....Salmonella are important pathogens of humans causing diseases ranging from gastroenteritis, typhoid fever to arthritis. Like most if not all infections, the early interaction between the host and the bacterium is characterised by very non-specific symptoms. These non-specific symptoms arise because the so-called innate immune system is activated by the infection. The purpose of this grant is to establish whether these non-specific symptoms, caused by the release of immunological homrones called cytokines, are essential to the development of an effective immune response which can protect against subsequent re-infection. This study has important implications for vaccines, of our understanding of how bacteria cause disease, and the role-capacity of the innate immune system in the development of immunity.Read moreRead less
Fc Alpha RI: Ligand Interaction And Membrane Organisation.
Funder
National Health and Medical Research Council
Funding Amount
$497,640.00
Summary
Antibodies tag invading viruses or bacteria thus marking them as foreign and targeting them for destruction by the immune system. In man the most prevelant antibody is IgA and this antibody provides protection from infecton in the blood and in the fluids at the surface of the lungs, gut and urinogenital tract. Once tagged by antibody the invading bacteria or antigen can be recogniseed white blood cells. These workhorses of the immune system use special molecules called Fc receptors on their surf ....Antibodies tag invading viruses or bacteria thus marking them as foreign and targeting them for destruction by the immune system. In man the most prevelant antibody is IgA and this antibody provides protection from infecton in the blood and in the fluids at the surface of the lungs, gut and urinogenital tract. Once tagged by antibody the invading bacteria or antigen can be recogniseed white blood cells. These workhorses of the immune system use special molecules called Fc receptors on their surface to recognise antibody tags. The receptor for IgA tags is called the Fc alpha receptor. This receptor is essential for the normal IgA-mediated protection against infection. However in a common kidney disease IgA tags accumulate in the glomerulus of the kidney stimulating white blood cells to attack and damage the kidney. This study will explain how the Fc alpha receptor recognises IgA antibody tags. It will investigate how the presentation of different forms of the receptor and different types of IgA antibody tags contributes to immunity to infection. For example one form of the receptor has a fat molecule joined to its end. We believe this may affect where the Fc alpha recptor goes to in the white blood cell membrane and whether it can activate the white blood cell to fight the invading microorganism.Read moreRead less
Defining The Mechanisms That Regulate Effective Long-term Anti-viral Immunity
Funder
National Health and Medical Research Council
Funding Amount
$547,315.00
Summary
Human cytomegalovirus (HCMV) is a common human pathogen which normally causes a mild or even asymptomatic infection. However, in immunocompromised individuals, HCMV causes severe disease whose manifestations include chorioretinitis, interstitial pneumonia and hepatitis. Similarly, in neonates lacking a fully mature immune system, HCMV causes severe morbidity. Vaccines that protect against HCMV induced cytomegalic inclusion disease have been designated Level I (most favourable) due to the predict ....Human cytomegalovirus (HCMV) is a common human pathogen which normally causes a mild or even asymptomatic infection. However, in immunocompromised individuals, HCMV causes severe disease whose manifestations include chorioretinitis, interstitial pneumonia and hepatitis. Similarly, in neonates lacking a fully mature immune system, HCMV causes severe morbidity. Vaccines that protect against HCMV induced cytomegalic inclusion disease have been designated Level I (most favourable) due to the prediction that they could save lives and prevent life-long disability. Similarly, therapies that prevent and-or reduce HCMV reactivation will significantly improve the prognosis of transplant and AIDS patients. The murine CMV (MCMV) infection model has provided important insights as to how the immune system controls infection, and the mechanisms utilized by the virus to circumvent these processes. The design of effective therapies and vaccines requires a thorough understanding of the mechanisms required to generate and maintain long-lasting anti-viral responses. The studies outlined in this proposal aim to define the impact of specific components of the immune system n the generation, maintenance and effectiveness of anti-viral immunity. The well characterized MCMV model will be used to address these issues.Read moreRead less
The Role Of Fractalkine In Leukocyte Recruitment In The Periphery
Funder
National Health and Medical Research Council
Funding Amount
$215,196.00
Summary
This research will determine whether a new type of gene plays an important role in inflammation in tissues in the periphery. If it does, we will design strategies to inhibit its function, thereby controlling its effects in inflammation. Such treatment may be useful for diseases such as rheumatoid arthritis, diabetes as well as allergies.
Crystallographic Studies Of Non-canonical Peptides Binding To MHC Class I Molecules.
Funder
National Health and Medical Research Council
Funding Amount
$489,750.00
Summary
Virus infected cells and cancer cells are recognised and eliminated from our body by specialised cells called T-cell lymphocytes. This recognition process is the key step in the immune response and some fundamental questions in immunology are centred on the nature of this process. At the molecular level, the recognition is mediated by the specific interaction between proteins on the surface of the cells. On the T-cell lymphocyte, the T-cell receptor (TCR) binds specifically to a protein called t ....Virus infected cells and cancer cells are recognised and eliminated from our body by specialised cells called T-cell lymphocytes. This recognition process is the key step in the immune response and some fundamental questions in immunology are centred on the nature of this process. At the molecular level, the recognition is mediated by the specific interaction between proteins on the surface of the cells. On the T-cell lymphocyte, the T-cell receptor (TCR) binds specifically to a protein called the MHC on the surface of the target cell. The target cell can be a cancer cell, or an infected antigen presenting cell (specialised cells in the body which present protein fragments (peptides) on their surface via MHC). The structure of a TCR and TCR-MHC have been solved in terms of the shape of the molecules at atomic resolution, bringing detailed information on how these two proteins interact with each other. In this proposal the structural basis of antigen presentation and recognition in cell-mediated immunity will be determined by three-dimensional structures of different peptides on MHC by x-ray crystallography. Cell surface antigen presentation by MHC molecules is crucial for initiating the cellular immune response against invading pathogens and cancer. This proposal encompasses a combined biochemical, immunological, and biophysical approach to understand the range of ligands which can bind to MHC which are subsequently recognised by the TCR. To understand the antigenic properties of modified peptides at the structure level, the x-ray structure of MHC with modified bound synthetic peptides will be determined.Read moreRead less
In Vivo Responses To Pathogen-derived Mediators Of Acute Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$94,250.00
Summary
Sepsis causes large numbers of deaths worldwide. It is not known why some patients tolerate an infection and fully recover, while other patients with an equivalent infection are highly vulnerable to severe illness and death from sepsis. Heart failure is a common underlying condition in sepsis. This research will focus on how an infection can cause sudden cardiac death. It will have implications for care of patients with severe infection and also sudden infant death syndrome.