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
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
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.
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.
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
Several members of the Flaviviridae family are major pathogens of humans including dengue (DEN), yellow fever (YF), tick-borne encephalitis (TBE), Murray valley encephalitis (MVE), Japanese encephalitis (JE), and hepatitis C virus (HCV). An Australian flavivirus Kunjin (KUN), however, appears to be naturally attenuated and does not cause an overt disease in humans. In contrast, genetically and antigenically closely related to KUN, New York strain of West Nile virus (NY WN) has already caused ~50 ....Several members of the Flaviviridae family are major pathogens of humans including dengue (DEN), yellow fever (YF), tick-borne encephalitis (TBE), Murray valley encephalitis (MVE), Japanese encephalitis (JE), and hepatitis C virus (HCV). An Australian flavivirus Kunjin (KUN), however, appears to be naturally attenuated and does not cause an overt disease in humans. In contrast, genetically and antigenically closely related to KUN, New York strain of West Nile virus (NY WN) has already caused ~500 deaths and over 20,000 registered infections since its emergence in North America in 1999, including 223 deaths and 9122 infections in 2003 alone. Recent studies with DEN indicated that flaviviruses may interfere with early steps of IFN-signalling pathway. The type I Interferon (IFN) response is the first line of defence against viral infections and many viruses have developed different strategies to counteract this response in order to ensure their survival in the infected host. In this grant we seek to exploit our extensive understanding of the molecular biology of KUN virus and the contrasting behaviour of KUN and NY WN viruses to gain an understanding of the role of flavivirus-mediated suppression of host anti-viral IFN response in virus-host relationships and its importance in determining virus virulence.Read moreRead less
Coordinated Cleavages In The Flavivirus Structural Polyprotein: Role In Virus Assembly And Host-pathogen Interaction
Funder
National Health and Medical Research Council
Funding Amount
$285,000.00
Summary
Flaviviruses are important human pathogens responsible for epidemics of hemorrhagic fever or encephalitis, world-wide. This project aims to investigate unique aspects in the biology of the flaviviruses with wider cell biological and immunological implications. First, we propose to test a mechanism important for the efficient assembly of virus particles. An understanding of this stage of the virus life-cycle will benefit research applying recombinant DNA technology in order to produce replication ....Flaviviruses are important human pathogens responsible for epidemics of hemorrhagic fever or encephalitis, world-wide. This project aims to investigate unique aspects in the biology of the flaviviruses with wider cell biological and immunological implications. First, we propose to test a mechanism important for the efficient assembly of virus particles. An understanding of this stage of the virus life-cycle will benefit research applying recombinant DNA technology in order to produce replication-incompetent viruses for use in vaccination and gene delivery. Second, we have recently discovered a mechanism for immune-modulation, so far unique to the flaviviruses, which interferes with the immune response important in the destruction of virus-infected cells. This project aims to identify the viral gene products responsible for this phenomenon.Read moreRead less
Regulation Of Subcellular Localisation Of Respiratory Syncytial Virus M Protein: Implications For Pathology
Funder
National Health and Medical Research Council
Funding Amount
$580,195.00
Summary
Respiratory syncytial virus (RSV) is the major cause of viral pneumonia in infants and the elderly, causing more deaths in winter than influenza. We have observed RSV M protein in the nucleus of infected host cells where it inhibits host cell transcription. We propose to investigate the regulation of nuclear localisation of M by phosphorylation and binding to cellular factors and its importance to RSV pathogenesis. The results will relate strongly to future drug and vaccine development.
Cellular Microenvironments Facilitating The Replication And Propagation Of Flaviviruses
Funder
National Health and Medical Research Council
Funding Amount
$505,279.00
Summary
Flaviviruses are the agents of many mosquito-transmitted infections and many deaths globally each year. The emerging virus West Nile virus (strain New York) is a member of this virus family and shares 99% amino acid homology with the endemic Australian virus Kunjin virus. During virus growth in cells, cellular membrane structures are induced or rearranged by these viruses for their own purpose. That being the production of more virus particles for reinfection of other cells. Using Kunjin virus a ....Flaviviruses are the agents of many mosquito-transmitted infections and many deaths globally each year. The emerging virus West Nile virus (strain New York) is a member of this virus family and shares 99% amino acid homology with the endemic Australian virus Kunjin virus. During virus growth in cells, cellular membrane structures are induced or rearranged by these viruses for their own purpose. That being the production of more virus particles for reinfection of other cells. Using Kunjin virus as a model, and advanced techniques in biochemistry and electron microscopy, we have identified for the first time these membrane structures as the apparent sites of replication of the viral RNA or genetic material, and of the viral proteins involved. We have also observed how new virus particles are able to get out of infected cells and shown how some drugs can prevent this occurring thus limiting their transmission. This research will focus on how the membrane structures are formed in infected cells. The research will determine what cellular components are required by the virus to help it propagate. In particular specific cellular proteins and membrane components that are captured by the virus and moved to different sites in the infected cells. These apparent requirements could possibly lead us to a greater understanding of the complex interactions that occur between the invading virus and the host cells. We aim to directly visualize the process of infection within living cells using new and innovative microscopic techniques. Another of our objectives is to determine the effects of infection on normal cells. The question being whether flavivirus infection disrupts normalcell fuctions like secretion etc. An understanding of these processes, and how the viral RNA is copied into new RNA for more virus particles, will assist in the development of antiviral drugs for treatment of this pathogenic group of viruses.Read moreRead less