Regulation Of Metabolic Dysfunction And Exhaustion Of Virus-specific T Cells During Chronic Infection
Funder
National Health and Medical Research Council
Funding Amount
$749,152.00
Summary
T cells control infections and cancer cells. During chronic infection or tumor development, however, loss of function of T cells prevents efficient clearing of pathogens or cancer cells, a phenomenon termed T cell ‘exhaustion’. We have found that the regulator protein IRF4 controls cellular nutrient usage, growth and function of T cells and that very amounts of IRF4 occur in T cells during chronic infection. We propose to examine the precise role of IRF4 in chronically stimulated T cells.
Role Of PLZF In Regulating The Interferon Response
Funder
National Health and Medical Research Council
Funding Amount
$531,696.00
Summary
The Interferon (IFN) pathway is essential for immune defense against pathogens in vertebrates. IFNs both protect and alert cells about viral, bacterial, and other immune assaults and promote a cellular antiviral state, reduce proliferation, or induce apoptosis depending on the cell type and environment. Based on these properties, IFNs have been used clinically against a variety of diseases including viral infections, immunomodulatory disorders and hematologic and solid tumors including renal cel ....The Interferon (IFN) pathway is essential for immune defense against pathogens in vertebrates. IFNs both protect and alert cells about viral, bacterial, and other immune assaults and promote a cellular antiviral state, reduce proliferation, or induce apoptosis depending on the cell type and environment. Based on these properties, IFNs have been used clinically against a variety of diseases including viral infections, immunomodulatory disorders and hematologic and solid tumors including renal cell carcinoma. However, the factors determining outcome of IFN treatment, remain to be determined. We have identified a subset of interferon stimulated genes whose sustained expression was found to correlate with heightened antiviral sensitivity of renal cell carcinoma cell lines to IFN. Many of these genes were found to have binding sites for the transcriptional repressor promyleocytic zinc finger protein (PLZF). PLZF was first identified in a subset of Acute Promyelocytic Leukemia patients and is involved in maintenance of erythroid lineage stem cells and spermatogonial stem cells in male mice. PLZF has not previously been implicated in the IFN response. Accordingly, we investigated the expression of interferon stimulated genes and showed that increased expression of immune related genes depends on PLZF expression. PLZF was also found to directly associate with binding sites in promoters of interferon stimulated genes and that this requires histone deacetylation. Thus, we uncovered a novel function for PLZF in enhancement of IFN associated gene expression. We propose to test the hypothesis that PLZF is an essential component of the IFN response. As a corollary, we will also test whether PLZF expression can be linked to IFN responsiveness in renal cell carcinoma. These studies will establish the role of PLZF in the IFN response and define its utility in predicting IFN responsiveness in therapeutic applications.Read moreRead less
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.
Human Dendritic Cell Subsets And Their Application For Immunotherapy
Funder
National Health and Medical Research Council
Funding Amount
$443,946.00
Summary
Immunotherapy is a promising non-toxic strategy for the treatment of many cancers, viruses and other diseases. It works by teaching the patient's own immune system to recognize and destroy the cancer. Specialized blood cells called dendritic cells are essential to this process but they are poorly understood in humans. I aim to investigate the function these cells and use this information to develop new treatments for cancer and viruses.
Characterising And Visualising Cross-presenting Dendritic Cells Following Cutaneous Vaccinia Infection
Funder
National Health and Medical Research Council
Funding Amount
$415,682.00
Summary
Live imaging of cells within lymphoid organs provides a valuable tool allowing insight into how immune responses are initiated. Utilising novel reagents we will visualise and define these events following cutaneous infection with vaccinia virus.
Defining The Roles Of The Chemotactic Receptor EBI2 For The Regulation Of Leukocyte Migration And The Generation Of Immunity
Funder
National Health and Medical Research Council
Funding Amount
$421,747.00
Summary
The proposed study aims at improving our understanding of the role of the immune cell receptor Epstein-Barr virus-induced gene 2 (EBI2) in guiding the movement of white blood cells during immune responses. The project will investigate the function of EBI2 in the control of infectious diseases and its regulation on human immune cells. These insights have the potential to create new therapeutic approaches to treat human autoimmune and inflammatory diseases and improve vaccine design.
Vaccines that deposit memory T cells within the lung, gut and genital tract hold enormous therapeutic potential, as these mucosal surfaces are major portals of entry into the body for many viruses. However, the accumulation of large numbers of T cells within the mucosal tissue may increase the number of target cells for T cell trophic viruses (eg HIV) to infect. We will explore factors that result in the generation of mucosal memory T cells that are resistant to virus infection.
Long Lived, Virus Resistant Resident Memory T Cells
Funder
National Health and Medical Research Council
Funding Amount
$415,218.00
Summary
Vaccines that deposit memory T cells within the lung, gut and genital tract hold enormous therapeutic potential, as these mucosal surfaces are major portals of entry into the body for many viruses. However, the accumulation of large numbers of T cells within the mucosal tissue may increase the number of target cells for T cell trophic viruses (eg HIV) to infect. We will explore factors that are important in the generation of mucosal memory T cells that are also resistant to virus infection.