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 Cross-reactive T Cells In Severe Lung Disease Following Viral Respiratory Infections
Funder
National Health and Medical Research Council
Funding Amount
$1,003,390.00
Summary
Why do some patients clinically deteriorate at a greater rate than others during acute respiratory viral infections despite similar or identical clinical management? One explanation is the reactivation immunity towards ubiquitous viruses that then go on to cross-react against the new respiratory pathogen leading to an overly aggressive and destructive response in the lung. We will examine this potential of existing anti-viral immune responses to exacerbate disease in lung transplantation, as suc
In Vivo Imaging Of Virus-specific T Cell Responses In The Skin
Funder
National Health and Medical Research Council
Funding Amount
$332,258.00
Summary
Effective vaccination against many viral infections such as Herpes Simplex Virus (HSV) may be achieved by directing the cells of the immune system to specific sites in the body where they can lie in wait against the disease. To direct the immune system in this way, we must first understand how immune cells orchestrate themselves in tissues. This project will utilise advanced imaging techniques to study immune cells in real time to understand how they protect against viral infections in the skin.
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
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.
Transcriptional Regulation Of T Lymphocyte And Dendritic Cell Development
Funder
National Health and Medical Research Council
Funding Amount
$605,096.00
Summary
Differentation of lymphocytes is a fundamental process in protection against disease . A small number of proteins critically regulate the decisions the cells make in becoming effective antigen presenting cells (that stimulate other immune cells), effector cells (that kill pathogen infected cells) or memory cells (that are essential for protection against secondary infections). Understanding this process and its regulation is critical to therapeutic treatment of autoimmune and infectious disease.
Identifying The Mechanism And Spectrum Of Activity Of The Antiviral Protein IFITM3
Funder
National Health and Medical Research Council
Funding Amount
$507,200.00
Summary
In response to an infection cells within the body are capable of expressing a range of molecules that help them resist infection, one such molecule is interferon induced transmembrane protein 3 (IFITM3). This recently identified but poorly studied potent antiviral protein dramatically influences the course of influenza infection in both mice and humans. We will explore the mechanisms of antiviral activity of IFITM3 and determine factors important in initiating and retaining expression.