Regulation Of Viral Latency In Gamma-herpesvirus Infection
Funder
National Health and Medical Research Council
Funding Amount
$258,000.00
Summary
The cost to public health from herpesvirus infection is enormous. The gamma-herpesviruses chronically infect more than 95% of the world's population. This group of viruses induce a state of immunosuppression that cause down-regulation of immune responses. This allows the virus the opportunity to evade the immune system and thus survive within the host. The gamma-herpesviruses do not generally cause serious disease in normal individuals but reactivation of gamma-herpesviruses can cause severe dis ....The cost to public health from herpesvirus infection is enormous. The gamma-herpesviruses chronically infect more than 95% of the world's population. This group of viruses induce a state of immunosuppression that cause down-regulation of immune responses. This allows the virus the opportunity to evade the immune system and thus survive within the host. The gamma-herpesviruses do not generally cause serious disease in normal individuals but reactivation of gamma-herpesviruses can cause severe disease, even mortality, in individuals with an immature or a compromised immune system. Viral reactivation is a major complication of immunosuppressive diseases such as HIV (which currently affects more than 45 million people) and in transplant recipients. The virally-induced changes in the host cells can result in the development of secondary infections, post-transplantation lymphoproliferative disease and even the development of tumours. The central aim of the studies described in this proposal is to understand the cellular and viral mechanisms regulating how the virus is maintained in the host. These studies will improve our understanding of how antigen presenting cells and CD8+ T lymphocytes ensure an immune response is maintained and may identify critical targets to facilitate the rational design of antiviral drugs and vaccines.Read moreRead less
The Role Of T Cell Receptor Avidity In Determining T Cell Repertoires And Responses
Funder
National Health and Medical Research Council
Funding Amount
$472,500.00
Summary
T cells are an essential component of the immune system. CD8 T cells, in particular, play a vital role in the immune response to viruses and tumors, predominantly via killing of virally infected cells and tumor cells, as well as the release of inflammatory mediators. T cells must be activated before they can mediate such anti-viral or anti-tumor effects and this activation occurs through the binding of pathogen or tumor fragments (peptides) by a receptor on the surface of T cells (T cell recepto ....T cells are an essential component of the immune system. CD8 T cells, in particular, play a vital role in the immune response to viruses and tumors, predominantly via killing of virally infected cells and tumor cells, as well as the release of inflammatory mediators. T cells must be activated before they can mediate such anti-viral or anti-tumor effects and this activation occurs through the binding of pathogen or tumor fragments (peptides) by a receptor on the surface of T cells (T cell receptor). Each individual has an entire repertoire of T cells with unique T cell receptors which interact with peptides with varying binding strengths. After stimulation of T cells by e.g. viral infection, a subset of the T cell repertoire will become expanded and dominate the anti-viral immune response. This study aims to investigate how, during a viral infection, the strength (or 'avidity') of the interaction between the T cell receptor and the peptide influences (i) whether or not a T cell clone is recruited into the immune response and, if so, its dominance over other clones within that response, and (ii) how efficiently a T cell is activated. It is anticipated that particular virus peptide-specific T cell populations with an overall high avidity will be better able to produce inflammatory mediators and kill infected cells compared to lower avidity T cell populations specific for a different virus peptide. It is also expected that the higher avidity populations will exhibit greater diversity of TCRs. Further, within peptide-specific populations, it is anticipated that the relatively high avidity T cell clones will dominate the specific response. This study will contribute to a greater understanding of factors contributing to T cell recruitment and activation. Armed with this knowledge we will be better able to design vaccines to elicit optimal T cell responses to viral infection.Read moreRead less
Effective Immunotherapy For HPV Associated Cervical Cancer Precursor Lesions
Funder
National Health and Medical Research Council
Funding Amount
$482,640.00
Summary
Vaccines to prevent cervical cancer are currently being developed. These will be used to prevent infection with the causal virus, papillomavirus. However, there are very many people world wide who already have papillomavirus infection, which could turn into cancer at any point over the next 30 years. Therefore, there is a need for a vaccine that could be given along with the preventative vaccine, which would treat existing infections. This study addresses the characteristics of the immune respon ....Vaccines to prevent cervical cancer are currently being developed. These will be used to prevent infection with the causal virus, papillomavirus. However, there are very many people world wide who already have papillomavirus infection, which could turn into cancer at any point over the next 30 years. Therefore, there is a need for a vaccine that could be given along with the preventative vaccine, which would treat existing infections. This study addresses the characteristics of the immune response required to treat existing papillomavirus infections, since this is not currently known.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
Costimulatory Mechanisms For Enhancing CD8 T Cell Responses During An Acute Respiratory Infection
Funder
National Health and Medical Research Council
Funding Amount
$438,750.00
Summary
Following an infection, a person's immune system responds to fight the pathogen. One of the most important consequences of the immune response to an infectious disease is the establishment of memory to that particular disease so that a person is able to clear the same pathogen faster upon subsequent exposures. This memory is due to specific cells called memory lymphocytes. One subset of these cells are called CD8+ T cells and these are important for controlling and clearing viral infections. New ....Following an infection, a person's immune system responds to fight the pathogen. One of the most important consequences of the immune response to an infectious disease is the establishment of memory to that particular disease so that a person is able to clear the same pathogen faster upon subsequent exposures. This memory is due to specific cells called memory lymphocytes. One subset of these cells are called CD8+ T cells and these are important for controlling and clearing viral infections. New vaccine strategies are aimed at improving CD8 T cell responses so that they are more effective at fighting diseases such as HIV which causes AIDS and Hepatitis C virus. The mechanisms which lead to long lived memory CD8 T cells are not well understood. This research will characterise the function of genes involved in activating CD8 T cells and producing more memory CD8 T cells. The influenza model will be used as it is a well characterised model for studying anti-viral immunity. This project involved studying the mechansims of known genes involved in CD8 T cell responses to influenza. Also the discovery of new genes which are involved in CD8 T cell memory will be identified and characterised using new novel technologies, such as ENU mutagenesis, that only now are able to be utilised since the mouse genome (DNA) has been sequenced. This research will provide a basis for design of new and more effective vaccines.Read moreRead less
Transcriptional Regulation Of T Cell Memory Programming
Funder
National Health and Medical Research Council
Funding Amount
$549,092.00
Summary
Differentiation of T cells is required to protect against disease. A group of proteins, called transcription factors, critically regulate this fundamental process, during which T cells become effector cells (that can kill pathogen infected cells) or memory cells (that are essential for protection against secondary infections). To identify the functions and hierarchy of these regulators is critical to therapeutic treatment of autoimmune and infectious disease and is the aim of this application.
Mechanisms Regulating The Shutdown Of Cytotoxic T Cell Populations In Acute And Persistent Viral Infections
Funder
National Health and Medical Research Council
Funding Amount
$386,120.00
Summary
Apoptosis, or programmed cell death, is the form of cell death responsible for removal of unwanted or excess cells from the body. This is an essential mechanism to allow remodelling of tissues as an embryo grows and is a crucial way in which the body prevents the unwanted outgrowth of individual cell types. Control of cell growth in this way is a key checkpoint in preventing cancers. This regulatory mechanism is also important in determining the number and type of immune cells that are generated ....Apoptosis, or programmed cell death, is the form of cell death responsible for removal of unwanted or excess cells from the body. This is an essential mechanism to allow remodelling of tissues as an embryo grows and is a crucial way in which the body prevents the unwanted outgrowth of individual cell types. Control of cell growth in this way is a key checkpoint in preventing cancers. This regulatory mechanism is also important in determining the number and type of immune cells that are generated at steady state and following an immune response. Two families of proteins are essential in initiating this process of apoptosis. One is known as the BH-3-only family, while the other is the tumour-necrosis receptor (TNFR) family. These families are made up of several family members, each of which responds to different types of stimuli, and are expressed in different tissues in the body. So far only one BH-3-only family member, BIM, has been identified to regulate shut-down of an immune response. This action prevents the generation of large numbers of highly aggressive cells that are specific for a pathogen inadvertently causing damage to the body. This control checkpoint is a normal, but vital, part of the immune response. Other members of these families are also likely to play an important role in this process, but as yet their identity is unknown. This study will determine which members of the BH-3-only and TNFR family members play a role in (i) regulating the numbers of lymphocytes present at steady state, and (ii) in the shut-down process in different types of pathogen infection. This work will provide insight into how lymphocytes are regulated in the resting animal, and in disease.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
Molecular Basis Of T Cell Receptor Bias In Viral Immunity
Funder
National Health and Medical Research Council
Funding Amount
$540,075.00
Summary
Viral infection results in the activation and proliferation of T cells that eradicate infected cells. Recognition of infected cells is meditated by presentation and recognition of viral protein fragments via specific cell surface receptors. This proposal plans to examine the factors that determine the diversity of the immune response and the consequences of such diversity on anti-viral immunity. This has implications for the development of vaccines.