I am a Clinical Immunologist, Immunopathologist, clinical researcher and laboratory scientist exploring the interactions between T cell and viral infections. My area of particular interest is the mechanisms by which HIV infection subverts effective T cel
The Genetics Governing The Specificity Of T Cell Receptors For Peptide-MHC
Funder
National Health and Medical Research Council
Funding Amount
$303,828.00
Summary
T lymphocytes play a pivotal role in the immune system by recognising virus-infected tissue through the use of highly specific cell surface receptors. These T cell receptors (TCR) recognise viral peptides (p) presented by MHC molecules on the surface of virus-infected cells. For a TCR to be successfully triggered, it must lock onto an exact 3-dimentional pMHC match. In this way, any given TCR must simultaneously recognise both the viral peptide and the MHC presenting it. Such recognition must be ....T lymphocytes play a pivotal role in the immune system by recognising virus-infected tissue through the use of highly specific cell surface receptors. These T cell receptors (TCR) recognise viral peptides (p) presented by MHC molecules on the surface of virus-infected cells. For a TCR to be successfully triggered, it must lock onto an exact 3-dimentional pMHC match. In this way, any given TCR must simultaneously recognise both the viral peptide and the MHC presenting it. Such recognition must be sensitive and precise since a false positive could result in destruction of healthy tissue. There are a huge variety of TCRs and pMHCs, but there are only a few examples where the precise molecular interactions within the TCR-pMHC complex are known. Surprisingly, these studies have shown very limited consistency in the way the TCRs bind the pMHCs and therefore, the structural rules that underlie why TCRs consistently bind MHC remains a mystery of critical importance to this fundamental feature of the immune system. In this proposal, we will attempt to elucidate the rules of TCR-pMHC engagement. Another question to be addressed in this proposal is: During a viral infection, why are certain TCRs chosen above others that also have the capacity to recognise the same viral peptide? By investigating exactly which feature-s of these receptors predisposes their supremacy, we may be better able to predict the outcome of a pathogen attack and to even one day build our own super receptors. Finally, this proposal will also investigate how natural mutations in TCR genes across the human population affect our individual responses to viruses. Overall, advances in each of these core areas of medical research will aid in the development of new intelligent vaccines and individualised drugs for the treatment of cancer and infectious disease.Read moreRead less
Investigations Into The Biology And Functionality Of The Human T Cell Receptor
Funder
National Health and Medical Research Council
Funding Amount
$424,262.00
Summary
T lymphocytes play a pivotal role in the immune system by recognising virus-infected tissue and tumour cells through the use of specific cell surface receptors called T cell receptors (TCR). This project will study why partcular TCRs are used by the immune system, and will also examine the specificity of T cell recognition by determine the range of molecules an individual T cell can recognise. The work will aid in the development of new intelligent vaccines for cancer and infectious disease.
Interactions Between Adaptable Pathogens, Drugs And The Human Host
Funder
National Health and Medical Research Council
Funding Amount
$5,727,327.00
Summary
The Centre for Clinical Immunology and Biomedical Statistics (CCIBS) represents a collaboration between Royal Perth Hospital and Murdoch University that has brought together internationally recognised expertise in clinical immunology, experimental biology and innovation in biostatistics and computing. These resources have been applied to a broad range of research issues within the broad framework of HIV and hepatitis C disease and treatment. CCIBS has become a leading centre of research excellen ....The Centre for Clinical Immunology and Biomedical Statistics (CCIBS) represents a collaboration between Royal Perth Hospital and Murdoch University that has brought together internationally recognised expertise in clinical immunology, experimental biology and innovation in biostatistics and computing. These resources have been applied to a broad range of research issues within the broad framework of HIV and hepatitis C disease and treatment. CCIBS has become a leading centre of research excellence internationally, establishing a reputation for innovative approaches to host-viral interactions that are built on a long tradition of research into the population genetics of both human and viral genomes, combined with a willingness to negotiate complex computation and statistical challenges in order to faithfully reflect dynamic biological processes at a population level. An early recognition that large and integrated repositories of genetic and clinical data are fundamental to the research success in the genomic era has also led to the creation of the single most comprehensive repository of HIV genetic sequencing data in the world. The contributions that CCIBS has made to several distinct areas of research, including understanding viral adaptation to host immune responses, the development of genetic testing to predict drug hypersensitivity reactions, and causes of antiretroviral drug-associated toxicities, have been published in prestigious journals including Science, Nature, Nature Immunology, The Lancet, Proceedings of National Academy of Sciences, and The American Journal of Human Genetics, and have also resulted in numerous international collaborations that recognise the unique attributes that CCIBS has been able to bring to the global research effort aimed at understanding fundamental aspects of HIV and hepatitis C biology and treatment.Read moreRead less
A novel link between metabolism and host defence. This project aims to delineate how a protein modification that consists of the addition of a small sugar to cellular proteins, known as O-GlcNAcylation, provides a link between metabolism and complex cell functions. The model for these studies is a cell type of the immune system known as dendritic cells. Upon encountering pathogens these cells undergo metabolic changes that increase the rate of O-GlcNAcylation of proteins involved in immune respo ....A novel link between metabolism and host defence. This project aims to delineate how a protein modification that consists of the addition of a small sugar to cellular proteins, known as O-GlcNAcylation, provides a link between metabolism and complex cell functions. The model for these studies is a cell type of the immune system known as dendritic cells. Upon encountering pathogens these cells undergo metabolic changes that increase the rate of O-GlcNAcylation of proteins involved in immune responses, altering their function. This project will study how O-GlcNAcylation works and is regulated. The project expects to develop new technology and provide high-level training, increasing the competitiveness of the strategic biotechnology sector in AustraliaRead moreRead less
Imaging the generation and recall of protective antiviral immune responses in vivo. Our understanding of the in vivo dynamics of cellular immune responses to infectious diseases is poor. This project will utilise advanced intravital imaging combined with novel tools to dissect the cellular events involved in the generation and recall of T cell responses to localised virus infection, combined with a detailed functional analysis of the lymphoid organ stroma. Such fundamental information will contr ....Imaging the generation and recall of protective antiviral immune responses in vivo. Our understanding of the in vivo dynamics of cellular immune responses to infectious diseases is poor. This project will utilise advanced intravital imaging combined with novel tools to dissect the cellular events involved in the generation and recall of T cell responses to localised virus infection, combined with a detailed functional analysis of the lymphoid organ stroma. Such fundamental information will contribute to the development of new generation vaccines and therapies to protect against tissue-specific infectious diseases, cancers and autoimmune diseases.Read moreRead less
Regulation Of T Follicular Helper Cell Development And Effector Function In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$419,197.00
Summary
Immune cells mature into distinct populations with specialized functions. One subsets are T follicular helper (TFH) cells which are important for instructing B cells to produce antibodies following infection or vaccination. The means by which TFH cells are generated are unknown. We will determine mechanisms whereby TFH cells are produced and how they function. We hope to design approaches that will modulate the function of TFH cells in cases of immunodeficiencies, autoimmunity or vaccination.
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE110100092
Funder
Australian Research Council
Funding Amount
$300,000.00
Summary
Fluorescence microscopy with optical tweezers: imaging cellular responses. Life relies on the ability of our cells to receive and respond to signals with pinpoint accuracy, involving both chemical and mechanical signals. This equipment will allow scientists to expose cells to both types of signals and measure the response at an unprecedented level of accuracy for the first time.
A study into post-translational modifications on adaptive immunity. Using proteomics, structural biology and cellular immunology, this project aims to provide a greater understanding of the impact of PTMs on the immune system. The immune system combats pathogens by mounting T-cell responses against foreign antigens present in infected cells. However, T-cells activated by self-antigens that are inadvertently presented by healthy cells can cause aberrant T-cell reactivity and disease. Post-transla ....A study into post-translational modifications on adaptive immunity. Using proteomics, structural biology and cellular immunology, this project aims to provide a greater understanding of the impact of PTMs on the immune system. The immune system combats pathogens by mounting T-cell responses against foreign antigens present in infected cells. However, T-cells activated by self-antigens that are inadvertently presented by healthy cells can cause aberrant T-cell reactivity and disease. Post-translational modifications (PTMs) are common in the host's proteins, but surprisingly little is known about their effect on T-cell immunity.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE140100166
Funder
Australian Research Council
Funding Amount
$370,000.00
Summary
Imaging Cell and Tissue Architecture using Confocal and Super-Resolution Microscopy. Imaging cell and tissue architecture using confocal and super-resolution microscopy: This project aims to understand how the architecture of cells and tissues is controlled. This is because the organisation of biological space underpins the function of cells, tissues and organisms. This project will test the role of identified parts of cell architecture in regulating specific animal functions/pathologies. It wil ....Imaging Cell and Tissue Architecture using Confocal and Super-Resolution Microscopy. Imaging cell and tissue architecture using confocal and super-resolution microscopy: This project aims to understand how the architecture of cells and tissues is controlled. This is because the organisation of biological space underpins the function of cells, tissues and organisms. This project will test the role of identified parts of cell architecture in regulating specific animal functions/pathologies. It will do this by using new microscope technologies which are at the frontier of visualising cell structure in isolation and in the context of tissue including application to the living animal. The dynamic organisation of structures in cells will be imaged in living tissue. Novel insights into structure/function relationships in the body will impact the health industry and generate opportunities for new diagnostics and therapeutics. Read moreRead less