Viral Factors Involved In Flavivirus Replication And Virus-host Interactions
Funder
National Health and Medical Research Council
Funding Amount
$743,696.00
Summary
With our increased understanding of virus-host interactions it has become apparent that small, non-structural proteins and small RNAs of most viruses are vital for numerous, often multiple, functions in the viral life cycle. In the proposed project, we seek to gain a detailed understanding of the functions of small nonstructural protein NS2A and small abundant viral RNAs of medicaly important encephalitic flaviviruses, which have remained so far elusive and are at the cutting-edge in the researc ....With our increased understanding of virus-host interactions it has become apparent that small, non-structural proteins and small RNAs of most viruses are vital for numerous, often multiple, functions in the viral life cycle. In the proposed project, we seek to gain a detailed understanding of the functions of small nonstructural protein NS2A and small abundant viral RNAs of medicaly important encephalitic flaviviruses, which have remained so far elusive and are at the cutting-edge in the research field. We anticipate that with a better understanding of the roles of these factors in flaviviral replication and pathogenesis, novel targets for antiviral therapies and-or molecular determinants for inclusion in candidate vaccines will be identified.Read moreRead less
SERPINB2 IS AN INDUCIBLE HOST FACTOR INVOLVED IN ENHANCING HIV-1 TRANSCRIPTION AND REPLICATION
Funder
National Health and Medical Research Council
Funding Amount
$496,446.00
Summary
SerpinB2 is one of the most abundant proteins made at sites of inflammation. We have shown that HIV-1 infection also induces SerpinB2 and that SerpinB2 then helps the virus to replicate. In this grant we seek to understand how the virus causes this protein to be made and how this protein then increases virus replication. In the human population there are different forms of SerpinB2 and this grant seeks to determine whether these different forms affect HIV-1 replications differently. It may for i ....SerpinB2 is one of the most abundant proteins made at sites of inflammation. We have shown that HIV-1 infection also induces SerpinB2 and that SerpinB2 then helps the virus to replicate. In this grant we seek to understand how the virus causes this protein to be made and how this protein then increases virus replication. In the human population there are different forms of SerpinB2 and this grant seeks to determine whether these different forms affect HIV-1 replications differently. It may for instance be possible that an individual who has a certain form of SerpinB2 may be less susceptable to AIDS following HIV-1 infection.Read moreRead less
Immunopathogenesis Of West Nile Virus Encephalitis - Requirement For Interferon-gamma-dependent Soluble Mediators
Funder
National Health and Medical Research Council
Funding Amount
$250,500.00
Summary
Flaviviruses transmitted by arthropods cause considerable illness and death world-wide by their propensity to cause encephalitis. In August 1999, an outbreak of West Nile virus (WNV) encephalitis occurred in New York for the first time, indicating that these viruses are spreading beyond endemic areas. However, the mechanisms by which these viruses kill people are not at all clear. How the immune system deals with them is controlled by a complex network of interactions involving cells and soluble ....Flaviviruses transmitted by arthropods cause considerable illness and death world-wide by their propensity to cause encephalitis. In August 1999, an outbreak of West Nile virus (WNV) encephalitis occurred in New York for the first time, indicating that these viruses are spreading beyond endemic areas. However, the mechanisms by which these viruses kill people are not at all clear. How the immune system deals with them is controlled by a complex network of interactions involving cells and soluble mediators such as cytokines, chemokines, and nitric oxide, many induced or modulated by the cytokine, inteferon-gamma. Evidence suggests that these agents together influence both the types of cells that are mobilised to eradicate virus and also disease outcomes. Our hypothesis is that the host's own immune system is inadvertently responsible for encephalitis through an over-vigorous attempt to destroy the infecting virus, resulting in damage to the brain. To study WNV encephalitis, we are using a mouse model developed in this laboratory that reproduces the features of human disease. Another strain of these mice has the gene for interferon-gamma (IFN) inactivated or 'knocked out', so they cannot respond in the conventional way to virus infection. This mouse survives WNV infection significantly better than normal mice and becomes immune. Therefore we will compare cellular and soluble mediator responses of these mice during WNV infection to those of normal mice. We will also delete specific cell types making interferon-gamma in normal mice, as well as transfering such cells into knockout mice. Experiments will indicate which cell types are responsible and when particular components cause most damage. Thus, we will better understand how interferon-gamma recruits cells that mediate immune brain damage in this model. By understanding the events that lead to death in encephalitis, it may be possible to prevent or ameliorate them by means of immune intervention.Read moreRead less
Statistical Methods For Identifying Structural Variation In Tumour Genomes Using Next Generation Sequencing
Funder
National Health and Medical Research Council
Funding Amount
$243,458.00
Summary
New DNA sequencing technology can sequence a tumour genome affordably in 2 weeks. This re-sequencing data can be used to find small mutations and large-scale chromosomal rearrangements that together are the drivers of cancer. These may one day be used to guide cancer therapy. This project will develop new algorithms for finding mutations and apply these to discover the genetic basis of drug resistance in a model lymphoma system.
The Genetics Governing The Specificity Of T Cell Receptors For Peptide-MHC
Funder
National Health and Medical Research Council
Funding Amount
$303,828.00
Summary
T lymphocytes play a pivotal role in the immune system by recognising virus-infected tissue through the use of highly specific cell surface receptors. These T cell receptors (TCR) recognise viral peptides (p) presented by MHC molecules on the surface of virus-infected cells. For a TCR to be successfully triggered, it must lock onto an exact 3-dimentional pMHC match. In this way, any given TCR must simultaneously recognise both the viral peptide and the MHC presenting it. Such recognition must be ....T lymphocytes play a pivotal role in the immune system by recognising virus-infected tissue through the use of highly specific cell surface receptors. These T cell receptors (TCR) recognise viral peptides (p) presented by MHC molecules on the surface of virus-infected cells. For a TCR to be successfully triggered, it must lock onto an exact 3-dimentional pMHC match. In this way, any given TCR must simultaneously recognise both the viral peptide and the MHC presenting it. Such recognition must be sensitive and precise since a false positive could result in destruction of healthy tissue. There are a huge variety of TCRs and pMHCs, but there are only a few examples where the precise molecular interactions within the TCR-pMHC complex are known. Surprisingly, these studies have shown very limited consistency in the way the TCRs bind the pMHCs and therefore, the structural rules that underlie why TCRs consistently bind MHC remains a mystery of critical importance to this fundamental feature of the immune system. In this proposal, we will attempt to elucidate the rules of TCR-pMHC engagement. Another question to be addressed in this proposal is: During a viral infection, why are certain TCRs chosen above others that also have the capacity to recognise the same viral peptide? By investigating exactly which feature-s of these receptors predisposes their supremacy, we may be better able to predict the outcome of a pathogen attack and to even one day build our own super receptors. Finally, this proposal will also investigate how natural mutations in TCR genes across the human population affect our individual responses to viruses. Overall, advances in each of these core areas of medical research will aid in the development of new intelligent vaccines and individualised drugs for the treatment of cancer and infectious disease.Read moreRead less
Investigations Into The Biology And Functionality Of The Human T Cell Receptor
Funder
National Health and Medical Research Council
Funding Amount
$424,262.00
Summary
T lymphocytes play a pivotal role in the immune system by recognising virus-infected tissue and tumour cells through the use of specific cell surface receptors called T cell receptors (TCR). This project will study why partcular TCRs are used by the immune system, and will also examine the specificity of T cell recognition by determine the range of molecules an individual T cell can recognise. The work will aid in the development of new intelligent vaccines for cancer and infectious disease.
Structure And Function Of The Hepatitis C Virus Glycoproteins E1 And E2.
Funder
National Health and Medical Research Council
Funding Amount
$533,828.00
Summary
Hepatitis C virus (HCV) infects approximately 3 % of the global human population with 150,000-200,000 HCV-infected individuals currently living in Australia. Chronic HCV infection is associated with recurrent, progressively worsening liver disease, liver cirrhosis and hepatocellular carcinoma. The current therapy (interferon-ribavirin) is effective in only 40 % of patients and is often associated with severe side-effects. The mechanisms that HCV uses to replicate in liver cells is poorly underst ....Hepatitis C virus (HCV) infects approximately 3 % of the global human population with 150,000-200,000 HCV-infected individuals currently living in Australia. Chronic HCV infection is associated with recurrent, progressively worsening liver disease, liver cirrhosis and hepatocellular carcinoma. The current therapy (interferon-ribavirin) is effective in only 40 % of patients and is often associated with severe side-effects. The mechanisms that HCV uses to replicate in liver cells is poorly understood. In this project we aim to better understand how the viral glycoproteins, E1 and E2, function in the initiation of infection. In particular, we will examine how these glycoproteins bind to liver cell receptors and then mediate virus-cell membrane fusion. These processes lead to the penetration of the HCV genetic material into the cell where it is replicated. These studies are essential for the discovery of new targets for antiviral agents and vaccines.Read moreRead less
Critical Role Of TNF In Host-virus Interactions And Outcome Of Infection: Involvement Of Reverse Signalling Through MTNF
Funder
National Health and Medical Research Council
Funding Amount
$496,500.00
Summary
Cytokines are molecules produced by cells that take part in the immune response. They coordinate the activities of leukocytes and are important in the host response to virus infections. For their part, viruses have evolved strategies to try and evade the host response. The analysis of these strategies in the context of a viral infection will lead to a better understanding of the immune system and host-virus interactions. Tumour necrosis factor is a cytokine made by specific leukocytes, in two st ....Cytokines are molecules produced by cells that take part in the immune response. They coordinate the activities of leukocytes and are important in the host response to virus infections. For their part, viruses have evolved strategies to try and evade the host response. The analysis of these strategies in the context of a viral infection will lead to a better understanding of the immune system and host-virus interactions. Tumour necrosis factor is a cytokine made by specific leukocytes, in two stages: First, the cytokine is exposed on the surface of the cell and then it is clipped off and released as a soluble form. In either form it can interact with specific receptors on other cells and, in this way, change the cells' activities. We have found that binding of tumour necrosis factor receptors to the cytokine, while it is in its membrane form, can also send a message backwards into the cell bearing the tumour necrosis factor. This process, known as reverse signalling, then changes the activity of this cell and constitutes a major new route through which information transfer can occur. In this project we will characterize the biological changes that result from reverse signalling in specific types of leukocytes. We will be looking at the role of membrane tumour necrosis factor in two separate models of viral disease. The first is influenza pneumonia that is responsible for a great deal of morbidity and mortality worldwide. The second is a model of poxvirus infection (mousepox) that mimics the disease smallpox in humans. Human poxvirus infections are on the rise (e.g. monkeypox) and there is an increased threat of smallpox as a weapon of bioterrorism. Mousepox is a good model for the study of generalized viral infections and is also an excellent example of a virus that encodes proteins specifically designed to interfere with host tumour necrosis factor. Our studies will focus on the role of this cytokine in host-virus interactions and the outcome of infection.Read moreRead less
Functions Of Viral Chemokine Receptor Homologues Important For Cytomegalovirus Pathogenesis And Latency
Funder
National Health and Medical Research Council
Funding Amount
$461,597.00
Summary
Cytomegalovirus (CMV) causes life-threatening disease in babies, transplant recipients and HIV-AIDS patients. We will focus on a CMV gene that has been 'hijacked' from the host cell and enables the virus to switch on signalling molecules within infected cells. We will determine how these signals enable CMV to infect sites of the body that are critical for virus transmission and contribute to long-term virus persistence. Our results will provide new strategies for drugs against CMV.
We seek to gain a detailed understanding of how interactions between the West Nile virus proteins and host factors involved in the IFN response determine the outcome of virus infection. Better understanding of the mechanisms employed by this highly pathogenic virus to disable the mammalian host's IFN response will have wider implications for our understanding of other human diseases such as cancer, autoimmunity and provide new avenues for design of efficient antiviral and anticancer therapies.