The immune system employs a variety of strategies to combat parasites including viruses. One of them is cytolytic lymphocytes, cells that can recognize and destroy virus-infected target cells. These cells use, besides other molecules, enzymes called granzymes to kill target cells by inducing suicide in them. We intend to investigate if those granzymes can protect cytolytic lymphocytes themselves from being infected by viruses and turned into viral factories. We are going to use a model of a natu ....The immune system employs a variety of strategies to combat parasites including viruses. One of them is cytolytic lymphocytes, cells that can recognize and destroy virus-infected target cells. These cells use, besides other molecules, enzymes called granzymes to kill target cells by inducing suicide in them. We intend to investigate if those granzymes can protect cytolytic lymphocytes themselves from being infected by viruses and turned into viral factories. We are going to use a model of a natural infection, ectromelia, mouse pox. Mouse pox is fatal in resistant strains of mice if the genes for the two dominant granzymes are deleted. This indicates that granzymes are essential for fighting this viral disease. We will explore in which cells of the immune system granzymes are expressed and whether virus entry into a cell can actually trigger their expression. Furthermore, we will investigate how the granzymes inhibit virus infection within the infected cell to determine whether the mechanisms involved resemble those used by cytolytic lymphocytes in killing of target cells (i.e. degradation of DNA and mitochondrial damage), or whether they represent entirely new facets of granzyme function. Finally, using viruses from a number of different families, we will establish whether these functions of granzymes also contribute to protection from other viral infections. An understanding of the role of these granzymes in the innate immune response, i.e. before antigen specific T cell and antibody responses are fully activated, is of great significance as it may allow us to manipulate this particular anti-viral response and thus enhance survival and reduce morbidity in viral infections.Read moreRead less
Defining The Molecular Effectors And Regulators Of Anti-viral Immune Responses
Funder
National Health and Medical Research Council
Funding Amount
$447,750.00
Summary
In humans, cytomegalovirus infection can cause severe disease and may even be fatal in individuals with immature or compromised immune systems, such as newborns, AIDS patients, transplant recipients and people treated with chemotherapeutic drugs. The majority of healthy individuals however can clear the infection with minimal disease. The ability of cytomegalovirus to cause disease is increased in the absence of effective immune responses which would normally clear the virus before illness occur ....In humans, cytomegalovirus infection can cause severe disease and may even be fatal in individuals with immature or compromised immune systems, such as newborns, AIDS patients, transplant recipients and people treated with chemotherapeutic drugs. The majority of healthy individuals however can clear the infection with minimal disease. The ability of cytomegalovirus to cause disease is increased in the absence of effective immune responses which would normally clear the virus before illness occurs. Understanding the role of specific mediators of anti-viral immune responses is therefore of paramount importance in establishing the guidelines for the design of more effective anti-viral therapies. The mouse model of cytomegalovirus infection provides a unique system to dissect the roles of specific components of the immune response during the course of viral infection. Our previous studies have shown that anti-viral immune responses are complex and involve a multitude of players. The central aim of the work in the current proposal is to establish the precise contribution of specific molecular effectors and regulators of anti-viral immune responses and define their relevance during the different stages of viral infection. Hence, the results of these studies will be relevant to understanding the pathogenesis of cytomegalovirus infection in humans and more importantly will provide critical insights into the rational design of improved antiviral drugs and vaccines. Since the molecules and cells under investigation are also known to play a crucial role in immune responses that control tumour growth and transplant survival, the proposed studies will provide valuable insight towards the development of new therapies for pathologies associated not only with cytomegalovirus infection, but also with the conditions named above.Read moreRead less
This research is directed by a team of medical and basic scientists with expertise in mechanisms of inflammation relevant to human disease. The program will investigate the molecular and cellular events that are responsible for inflammation in the kidneys, joints and blood vessels which lead to diseases such as glomerulonephritis, arthritis and atherosclerosis. The aim of the research is to find new therapeutic targets which may be specific to certain organs or disease processes, in order to dev ....This research is directed by a team of medical and basic scientists with expertise in mechanisms of inflammation relevant to human disease. The program will investigate the molecular and cellular events that are responsible for inflammation in the kidneys, joints and blood vessels which lead to diseases such as glomerulonephritis, arthritis and atherosclerosis. The aim of the research is to find new therapeutic targets which may be specific to certain organs or disease processes, in order to develop more effective and selective treatments ofchronic inflammatory disease in humans.Read moreRead less
Structural Basis Of Influenza A Virus-specific CD8+ T Cell Receptor Diversity
Funder
National Health and Medical Research Council
Funding Amount
$469,500.00
Summary
Viral infection results in the activation and proliferation of virus-specific T cells that mediate clearance of virally infected cells. Recognition of virally infected cells is meditated by presentation of peptide fragments complexed to Major histocompatibility complex (MHC) class I glycoproteins. Virus-specific T cells recognise these viral protein fragments via a specific receptor expressed at the T cell surface. This proposal plans to examine the structural factors that determine influenza-sp ....Viral infection results in the activation and proliferation of virus-specific T cells that mediate clearance of virally infected cells. Recognition of virally infected cells is meditated by presentation of peptide fragments complexed to Major histocompatibility complex (MHC) class I glycoproteins. Virus-specific T cells recognise these viral protein fragments via a specific receptor expressed at the T cell surface. This proposal plans to examine the structural factors that determine influenza-specific T cell receptor recognition. From these studies, we plan to determine how these structural factors can influence the diversity of virus-specific T cells that are generated after viral infection. The conclusions from these studies will enable us to determine why some virus-specific T cell responses are not diverse and what are the consequences for virus-specific T cell immunity. This has implications for the development of novel vaccine strategies designed to induce immunity against both viral and tumour challenge.Read moreRead less
Preclinical Development Of A Humanised Antibody To C5aR.
Funder
National Health and Medical Research Council
Funding Amount
$124,875.00
Summary
Complement factor C5a is one of the most potent inflammatory mediators in the body. We have developed a monoclonal antibody that blocks the C5a receptor in vitro, and completely shuts down disease in a mouse model of rheumatoid arthritis. We plan to develop this promising new antibody into a potent therapy to treat a range of chronic and acute inflammatory diseases. The antibody has been humanised and this will be tested in three models of inflammation (rheumatoid arthritis, sepsis and colitis) ....Complement factor C5a is one of the most potent inflammatory mediators in the body. We have developed a monoclonal antibody that blocks the C5a receptor in vitro, and completely shuts down disease in a mouse model of rheumatoid arthritis. We plan to develop this promising new antibody into a potent therapy to treat a range of chronic and acute inflammatory diseases. The antibody has been humanised and this will be tested in three models of inflammation (rheumatoid arthritis, sepsis and colitis) to determine the efficacy of the antibody, safety, the most effective dose, timing and route of administration. These studies are a necessary prelude to human clinical trials, which we hope to perform in approximately 24 months.Read moreRead less
Understanding and regulating autoimmune disease through the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) family transcription factor, v-rel reticuloendotheliosis viral oncogene homolog B (RelB). This program is well-aligned with the national research priority: Promoting and Maintaining Good Health. The disabling conditions rheumatoid arthritis and type 1 diabetes affect over 1% of Australia's population. They are incurable, so disability and the need for treatment p ....Understanding and regulating autoimmune disease through the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) family transcription factor, v-rel reticuloendotheliosis viral oncogene homolog B (RelB). This program is well-aligned with the national research priority: Promoting and Maintaining Good Health. The disabling conditions rheumatoid arthritis and type 1 diabetes affect over 1% of Australia's population. They are incurable, so disability and the need for treatment persist into old age and life expectancy is reduced. The program focuses on more effective and safer treatment, and future disease prevention, with immune therapy. This will have social and economic benefits to Australia. The research will advance Australia's intellectual leadership in Immunology, providing research training and career opportunities, and will lead to strong collaborations between basic scientists, clinicians and industry.Read moreRead less
Assessment Of Alpha-galactosylceramide As A Novel Adjuvant For Pandemic Influenza: A Virua Vaccine
Funder
National Health and Medical Research Council
Funding Amount
$220,042.00
Summary
The occurrence of human infections with pathogenic avian H5N1 Influenza A viruses was the first documentation of these viruses demonstrating an ability to directly transmit from birds to humans. The virulent nature of these infections, and the fact that there is no pre-existing immunity to these viruses in the human population has raised the concern that these viruses may emerge to cause the next influenza pandemic. Vaccination is our most effective way of protecting against influenza infection, ....The occurrence of human infections with pathogenic avian H5N1 Influenza A viruses was the first documentation of these viruses demonstrating an ability to directly transmit from birds to humans. The virulent nature of these infections, and the fact that there is no pre-existing immunity to these viruses in the human population has raised the concern that these viruses may emerge to cause the next influenza pandemic. Vaccination is our most effective way of protecting against influenza infection, however there are no commercially available avian influenza vaccines available. Moreover, recent evidence suggests current vaccines strategies may be less than effective. This proposal aims to evaluate the efficacy of a novel vaccine strategy that promotes immune protection against a potential pandemic influenza strain.Read moreRead less
The Role Of RasGRP4, A Mast Cell Specific Protein In Mast Cell Growth, Differentiation And Activation
Funder
National Health and Medical Research Council
Funding Amount
$580,433.00
Summary
Mast cells are cells found in the body which are strategically located at mucosal sites and skin where they form a very important barrier in the immune defence. Mast cells have been implicated in a range of inflammatory disorders such as asthma and more recently they have been shown to participate in immunity against bacteria, viruses and fungi. Although a lot of work has been performed to analyze how mast cells respond to different stimuli and what factors are important in their activation, the ....Mast cells are cells found in the body which are strategically located at mucosal sites and skin where they form a very important barrier in the immune defence. Mast cells have been implicated in a range of inflammatory disorders such as asthma and more recently they have been shown to participate in immunity against bacteria, viruses and fungi. Although a lot of work has been performed to analyze how mast cells respond to different stimuli and what factors are important in their activation, there is little work available concerning what in the mast cell controls it's ability to become a mast cell and not any other cell. We have identified a specific protein that has been designated RasGRP4 which is restricted to mast cells and has, we believe, an important role to play not only in guiding immature cells to become mast cells but also in controlling some of the important functions of mast cells. Understanding this molecule more extensively will give us a much better understanding of diseases that the mast cell is involved in such as asthma and other inflammatory disorders. In addition it may shed insights into how mast cells are involved in immunity against bacteria and viruses.Read moreRead less