I am an infectious diseases physician and basic scientist interested in the immunopathogenesis of HIV and hepatitis B virus. My work focuses on HIV viral reservoirs and immune reconstitution and the adaptive immune response to hepatitis B virus.
Systematically Exploring The Contribution Of Immunoproteasome To Immunodominance And T Cell Function
Funder
National Health and Medical Research Council
Funding Amount
$499,860.00
Summary
Vaccine will help us to fight both infectious diseases and malignancy. However, there are few successful vaccines for infectious agents and there is simply no vaccine to cure any tumor at the moment. So, it is essential for us to learn the basics related to vaccine development. Killer T cells eliminate tumour cells or virally infected host cells by recognising fragments (epitopes) derived from tumour- or virus-derived proteins displayed on a host molecule called MHC. Normally multiple epitopes a ....Vaccine will help us to fight both infectious diseases and malignancy. However, there are few successful vaccines for infectious agents and there is simply no vaccine to cure any tumor at the moment. So, it is essential for us to learn the basics related to vaccine development. Killer T cells eliminate tumour cells or virally infected host cells by recognising fragments (epitopes) derived from tumour- or virus-derived proteins displayed on a host molecule called MHC. Normally multiple epitopes are generated as part of the protein recycling program referred as proteine degradation which is mainly conducted by bundled enzyme complex, called proteasome. Two major forms of proteasomes are expressed by most cells. One called house-keeping proteasome and the other, which replaces the house-keeping one during viral infections is called immunoproteasome. The role that the immunoproteasome plays during anti-viral and anti-tumoral immune responses is not fully understood. In addition, the immunoproteasome is also expressed by a few cell types that do not suppose to need it if its function is entirely to generate better epitopes for MHC to display. In this project, we will sytematically explore the contribution of the immunoproteasome to overall anti-viral and anti-tumoral immune responses in three mouse model systems. The shared feature of these systems is that multiple killer T cell epitopes have been defined, which could potentially provide us with very sensitive assessments. The three systems are anti-influenza, anti-vaccinia virus and anti-tumor antigen (NY-ESO-1) mouse models.Read moreRead less
Investigation Of The Roles Of TNFa-related Apoptosis-inducing Ligand, TRAIL, In The Immune System.
Funder
National Health and Medical Research Council
Funding Amount
$436,980.00
Summary
TRAIL, is a newly described member of the tumour necrosis factor (TNF)-family of cytokines, which can kill a wide range of tumour cells, and virus infected cells, but not most normal cells. TRAIL has proven to be safe when administered to normal, tumour bearing, and virally-infected mice, and causes no detectable side-effects in these animals. As such it holds huge potential and is being widely investigated for use as a new anti-cancer therapy. Despite these findings, little is known about the t ....TRAIL, is a newly described member of the tumour necrosis factor (TNF)-family of cytokines, which can kill a wide range of tumour cells, and virus infected cells, but not most normal cells. TRAIL has proven to be safe when administered to normal, tumour bearing, and virally-infected mice, and causes no detectable side-effects in these animals. As such it holds huge potential and is being widely investigated for use as a new anti-cancer therapy. Despite these findings, little is known about the true physiological role of TRAIL in vivo. To define the normal roles of TRAIL, CIA has been characterising TRAIL gene knock-out mice. These studies have confirmed that TRAIL contributes to control of tumours in vivo, and in early events during anti-viral responses. However, these studies have also revealed novel roles for TRAIL in T cell biology, and B cell memory. Understanding how TRAIL contributes to these processes, will shed significant light on the potential of TRAIL to be used as a therapeutic agent for humans with lymphoproliferative disease, for illiciting better long-lived antibody responses such as after vaccination, and as an anti-viral reagent in immunocompromised individuals during virus infection.Read moreRead less
Viral infections of the gut are one of the most debilitating infections one can suffer from. Noroviruses are the most common causative agents of viral-associated gastroenteritis but unfortunately little is known regarding their biology and pathogenesis. Our study aims to investigate the replication and pathogenesis of a mouse norovirus to shed light on similar aspects relating to human norovirus infection. We aim to understand how virus infection in cells leads to disease symptoms.
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
Plasminogen activator inhibitor type 2 (PAI-2) or SerpinB2 is a protein that has been extensively studied in the field of cancer prognosis and inflammation. Although it is widely believed that this protein exists outside the cell and inhibits enzymes involved in blood clotting and cell migration, it is becoming increasingly clear that this may not be its primary function. We have identified two important new functions for this protein that are related to activities within the cell. These activit ....Plasminogen activator inhibitor type 2 (PAI-2) or SerpinB2 is a protein that has been extensively studied in the field of cancer prognosis and inflammation. Although it is widely believed that this protein exists outside the cell and inhibits enzymes involved in blood clotting and cell migration, it is becoming increasingly clear that this may not be its primary function. We have identified two important new functions for this protein that are related to activities within the cell. These activities involve regulation of cellular growth and resistence to viral infections. This grant seeks to characterise these different activities and determine how they affect cell behaviour and thereby determine the real role of this protein. Understanding what this protein actually does will have implications for understanding cancer prognosis and antiviral resistance.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