Defining The Requirement For The Inhibition Of Bak To The Pathogenesis Of Cytomegalovirus Infection
Funder
National Health and Medical Research Council
Funding Amount
$592,661.00
Summary
Apoptosis, or programmed cell death is a powerful defence mechanism against viral infection. Thus, to replicate efficiently viruses have evolved means to inhibit apoptosis. The central aim of this work is to understand how cytomegalovirus prevents cell death protein during infection. The proposed studies will improve our understanding of the mechanisms that regulate viral replication and will contribute insights into the normal processes that control cell survival.
Dengue Host-cell Signalling Interactions: Novel Insights And Interventions
Funder
National Health and Medical Research Council
Funding Amount
$124,676.00
Summary
Dengue is a virus transmitted by mosquitoes that occurs in many tropical and subtropical regions. Approximately 40% of the world's population is at risk of this infection. Sometimes it can be mild but it can lead to severe illness and death especially with second infections. The body produces a response that over-reacts to the virus in these severe infections. The project aims to understand why the body does this and what parts of the immune system are affected using a model in mice.
Viral Interference With Apoptosis: Defining The Mechanisms And Effects On Viral Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$551,328.00
Summary
Apoptosis, or programmed cell death, is an orderly process whereby unwanted or damaged cells are removed from an organism. Deregulation of apoptosis has been implicated in the development of diseases such as cancer and autoimmunity. Therefore, a precise understanding of the mechanisms controlling the initiation of apoptosis has important clinical implications. In addition to removing unwanted cells, apoptosis functions as a defence mechanism to inhibit viral replication. Hence, in order to repli ....Apoptosis, or programmed cell death, is an orderly process whereby unwanted or damaged cells are removed from an organism. Deregulation of apoptosis has been implicated in the development of diseases such as cancer and autoimmunity. Therefore, a precise understanding of the mechanisms controlling the initiation of apoptosis has important clinical implications. In addition to removing unwanted cells, apoptosis functions as a defence mechanism to inhibit viral replication. Hence, in order to replicate efficiently viruses have evolved means to inhibit or interfere with apoptosis. The central aim of this work is to understand how two genes encoded by murine cytomegalovirus (MCMV) inhibit apoptosis and contribute to viral replication. MCMV is used as a model for human CMV (HCMV) infection. The majority of the human population is infected with HCMV which poses no risk to healthy individuals. However, reactivation of HCMV in people who are immunosuppressed such as transplant recipients or AIDS patiens is a significant cause of mortality. The MCMV infection model has provided important insights as to how the immune system controls infection and the mechanisms utilized by viruses to circumvent these processes. The proposed studies will improve our understanding of the processes that regulate viral replication. Understanding how viruses subvert host defence mechanisms will allow us to better understand their role in causing human disease, and thus, will provide key information for the design of improved anti-viral strategies. Importantly, the type of analyses proposed here will also contribute critical insights into the normal processes that control cell survival.Read moreRead less
The balance between cellular survival and death must be tightly regulated. Cells respond to viral infection by self-destructing, thus limiting viral spread to other cells. Viruses have evolved ways to subvert this defensive cell suicide. This project will define and characterise viral factors that maintain host cell survival during infection. These may be targets for the development of new anti-viral therapies and vaccines.
The Role Of Apoptotic Caspases In Regulating Type I Interferon Production
Funder
National Health and Medical Research Council
Funding Amount
$791,746.00
Summary
Type I interferons (IFNs) are potent anti-viral cytokines. Dysregulated type I IFN responses result in major pathologies, e.g., embryonic lethality and defects in tissue homeostasis. We have identified a novel molecular mechanism regulating IFN production that relies on the host’s own apoptotic caspases. We hypothesize that apoptotic caspases critically regulate IFN responses during the process of cell death, with implications for tissue homeostasis and host responses to infection.
Cytoplasmic DNA As A Danger Signal For Mammalian Cells
Funder
National Health and Medical Research Council
Funding Amount
$592,661.00
Summary
DNA in mammalian cells is contained within a structure known as the nucleus. The presence of DNA outside the nucleus in the cytoplasm of the cell is a sure sign that something is wrong, and may indicate the presence of a viral invader. In this case, the cell initiates anti-viral responses, including production of anti-viral proteins and death of the infected cell to stop replication of the virus. Lack of proper control of these responses may contibute to the autoimmune disease lupus.
The Mechanism Of Cell Death In Response To Cytoplasmic DNA, And Its Role In Tumour Suppression
Funder
National Health and Medical Research Council
Funding Amount
$517,897.00
Summary
DNA in mammalian cells is in a structure known as the nucleus. Retroviruses such as HIV generate DNA outside the nucleus in the cytoplasm, and detection of DNA in the cytoplasm can lead to cell death, as a defence. All cells carry the remnants of ancient retroviruses in their nuclear DNA. These are normally inactive but may contribute to cancer when activated. This project investigates how normal cells die with cytoplasmic DNA, and whether a defect in this process promotes development of cancer.
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
Cellular Activation And Apoptosis In Response To Foreign Cytoplasmic DNA
Funder
National Health and Medical Research Council
Funding Amount
$496,446.00
Summary
Viruses are simple organisms. They grow within cells, needing host cell proteins for their replication. Viruses have only a few proteins of their own, and evolve rapidly to change these. It is therefore challenging for the immune system to identify viral infections. Recently it has been recognised that the genetic material of viruses (DNA or RNA) is detected by the immune system. A novel pathway for recognition of viral double stranded DNA is emerging. The genetic material of mammalian cells (DN ....Viruses are simple organisms. They grow within cells, needing host cell proteins for their replication. Viruses have only a few proteins of their own, and evolve rapidly to change these. It is therefore challenging for the immune system to identify viral infections. Recently it has been recognised that the genetic material of viruses (DNA or RNA) is detected by the immune system. A novel pathway for recognition of viral double stranded DNA is emerging. The genetic material of mammalian cells (DNA) is found within the membrane-bound nucleus of the cell. The presence of DNA outside the nucleus in the cytoplasm is abnormal, and is detected as an indication of viral infection. This causes either death of the cell, or activation to produce anti-viral molecules. We have identified a protein from the cytoplasm of cells which binds specifically to DNA. This protein, X is found in association with foreign DNA within 5 minutes of it being introduced into the cell. In this project we propose to confirm that X recognises foreign DNA and initiates cellular activation or death. Other molecules to which X binds during this process will be identified. This project is relevant to a number of problems in health and disease as well as biotechnology. In both gene therapy and biotechnology, DNA is introduced into cells in order to allow those cells to make specific proteins. The cell sees the introduced DNA as a potential viral infection, and it responds in ways which limit the production of the desired proteins. Lupus is an autoimmune disease with high levels of DNA in circulation. X is proposed as a protein involved lupus in mouse models. We suggest that DNA taken up by cells is recognised by X and this contributes to the disease. Understanding the means by which DNA is recognised in the cytoplasm may allow the development of much more efficient processes for gene therapy and protein production in biotechnology, and more effective lupus and antiviral therapies.Read moreRead less
Herpesviruses infect most Australians and cause recurrent ulcers, birth defects and cancer. Infection lasts lifelong, and spreads to close contacts without obvious clinical signs. Thus disease is hard to prevent. However we can learn much from related animal infections. We have shown that both mouse and human herpesviruses enter mice via cells in the nose. Thus human infections might follow the same route. We will define what body defences work here and whether vaccines can prevent infection.