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
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
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
Human cytomegalovirus (HCMV) is a classic example of a group of herpes viruses, which is found universally throughout all geographic locations and socioeconomic groups, and infects 50% of adults in developed countries. HCMV infection is important to certain high-risk groups. Major areas of concern are: (1) the risk of infection to unborn baby during pregnancy, (2) the risk of infection to people who work with children, and (3) the risk of infection to immunocompromised persons (e.g. organ transp ....Human cytomegalovirus (HCMV) is a classic example of a group of herpes viruses, which is found universally throughout all geographic locations and socioeconomic groups, and infects 50% of adults in developed countries. HCMV infection is important to certain high-risk groups. Major areas of concern are: (1) the risk of infection to unborn baby during pregnancy, (2) the risk of infection to people who work with children, and (3) the risk of infection to immunocompromised persons (e.g. organ transplant patients and HIV-infected individuals). Epidemiological studies have shown that 80%-90% of developing unborn babies who acquire congenital HCMV infection displays a variable pattern of pathological sequelae within the first few years of life that may include hearing loss, vision impairment and mental retardation. There is an increasing argument that a reduction in HCMV load will have a significant effect on the sequelae associated with congenital HCMV infection. Indeed, vaccination provides the most practical modality of achieving such a reduction in HCMV load. To develop such a vaccine, formulation based on viral antigens that activate both protective cellular and humoral responses needs to be tested to assess its immunogenicity. No such vaccine is presently available for HCMV. In this application we have sought to develop a prophylactic vaccine and to test its efficacy in a immunocompetent transgenic mouse model and as well under conditions of immunosuppression (CD4 T cell deficient). The overall strategy is to use this prophylactic vaccine to stimulate the cellular (CD8+ and CD4+ T cells) and humoral responses against multiple HCMV antigens. This vaccine will be based on the novel chimeric polyepitope technology and exploits a novel replication deficient adenovirus expression system which has recently been approved for human use.Read moreRead less
I am a viral immunologist studying the requirements for an effective host response to viral infection. I am also investigating the potential for the development of efficacious vaccines to protect against infection and ways of intervening in the disease pr
The Early Inflammatory Response To Virulent And Avirulent Influenza Viruses
Funder
National Health and Medical Research Council
Funding Amount
$252,761.00
Summary
Innate immune mechanisms are vital components of host defences against pathogens. In this proposal I aim to investigate the particular mechanisms that operate in early defence against influenza virus infection and compare the ability of virulent and avirulent virus strains to (i) be recognized by components of the innate immune system, and (ii) to trigger an early inflammatory response to infection. It is anticipated that virulent virus strains have adapted to avoid recognition by innate cells s ....Innate immune mechanisms are vital components of host defences against pathogens. In this proposal I aim to investigate the particular mechanisms that operate in early defence against influenza virus infection and compare the ability of virulent and avirulent virus strains to (i) be recognized by components of the innate immune system, and (ii) to trigger an early inflammatory response to infection. It is anticipated that virulent virus strains have adapted to avoid recognition by innate cells such as macrophages. By avoiding this route of uptake and destruction, the virus is free to infect and replicate in other cells of the respiratory tract. Furthermore, by evading macrophage entry, the virus avoids triggering the release of early inflammatory mediators from these cells and this may affect both the speed and the magnitude of the subsequent inflammatory response. This study will contribute to a greater understanding of factors involved in initiating and regulating inflammation in the respiratory tract following viral infection. Furthermore, the findings may provide new insights into mechanisms of virulence of influenza and other enveloped viruses.Read moreRead less
Immunodominance In Vaccinia Virus And Recombinant Vaccinia Vaccines
Funder
National Health and Medical Research Council
Funding Amount
$388,455.00
Summary
When confronted with an invading microbe, the human immune system does not recognise its overall shape. Instead, the microbe is chopped up into tiny fragments, called peptides, and these can be recognised by special cells of the immune system called T cells which orchestrate a response. We have a good understanding of this chopping process and can predict many of these peptides, but this is only part of the story. Not all peptides will be recognized by a T cell. Further, through processes we do ....When confronted with an invading microbe, the human immune system does not recognise its overall shape. Instead, the microbe is chopped up into tiny fragments, called peptides, and these can be recognised by special cells of the immune system called T cells which orchestrate a response. We have a good understanding of this chopping process and can predict many of these peptides, but this is only part of the story. Not all peptides will be recognized by a T cell. Further, through processes we do not understand well, T cells that recognize only a few out of the many peptides will dominate an entire immune response. As a result, immune responses are focused in such a way that they recognize only a tiny portion of an invading microbe. Focusing of immune responses also occurs during immunization with vaccines. Some new, genetically engineered vaccines use a harmless microbe to carry small parts of more dangerous pathogens. The parts chosen will not cause any disease by themselves, so the whole vaccine is safe. Vaccines built in this way are in clinical trials for diseases such as AIDS and malaria, but do not work as well as was hoped. These new vaccines are largely made up of the carrier and the parts of the microbe we wish to immunize against (e.g. a part of the AIDS virus) will be only a small fraction of the whole vaccine. Ideally we would like the immune system to focus on this small part of our choosing, but the few studies done suggest that this is not the case. In this project we will study vaccines that use a carrier called vaccinia virus. We will test to what extent immune responses are focused inappropriately. We will then genetically alter the virus and use new immunisation strategies to try and shift the focus of the immune response so that it targets the right parts of the vaccine. The ultimate aim is to improve vaccines, but in the process we may learn more about how the immune system chooses its targets.Read moreRead less