Molecular Pathogenesis Of Emerging West Nile Viruses
Funder
National Health and Medical Research Council
Funding Amount
$594,133.00
Summary
West Nile virus (WNV) is a mosquito-borne virus that causes potentially fatal encephalitis in humans and horses. This project will investigate the recent emergence of pathogenic for horses WNV in Australia and the potential of this new isolate to cause severe disease in humans. We will define the viral and host factors determining the outcome of WNV infection. This project will provide knowledge on the factors involved in the emergence of virulent WNV strains from attenuated isolates.
The Role Of Noncoding Subgenomic Flavivirus RNA In Virus-host Interactions
Funder
National Health and Medical Research Council
Funding Amount
$624,429.00
Summary
Flaviviruses such as Dengue, Japanese encephalitis , and West Nile are major human pathogens causing more than 50 million infections per year. Elements in viral genome responsible for pathogenesis of these viruses are not well defined. Recently we have identified a unique for these viruses noncoding subgenomic flavivirus RNA (sfRNA) and showed that it is contributing to viral pathogenesis. In this proposal we aim to determine mechanisms by which sfRNA facilitates viral pathogenesis.
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
Enterovirus 71 In The Asia-Pacific Region: Reverse Genetic Approaches To Virus Surveillance And Vaccine Development.
Funder
National Health and Medical Research Council
Funding Amount
$690,833.00
Summary
In this research the team will use advanced biotechnological techniques to study the distribution and virulence markers of an important emerging infectious disease, enterovirus 71 encephalitis, in the Asia-Pacific region. The knowledge and technical advances derived from this study will be shared with neighbouring countries in order to conduct sensitive surveillance for this infection throughout the region. The study's other major aim is to use cutting-edge biotechnological techniques to develop ....In this research the team will use advanced biotechnological techniques to study the distribution and virulence markers of an important emerging infectious disease, enterovirus 71 encephalitis, in the Asia-Pacific region. The knowledge and technical advances derived from this study will be shared with neighbouring countries in order to conduct sensitive surveillance for this infection throughout the region. The study's other major aim is to use cutting-edge biotechnological techniques to develop a genetically defined, live attenuated vaccine strain. Candidate vaccine strains will be tested for their effectiveness in both cell culture-based and animal models.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
Transport And Egress Of Herpes Simplex Virus In Neurones
Funder
National Health and Medical Research Council
Funding Amount
$592,023.00
Summary
Herpes simplex virus (HSV) enters the human body via the skin before entering the termini of nerve cell processes. It is transported along these processes to the body of the nerve cell. HSV lies dormant within these nerve cell bodies near the spinal cord in most people. Intermittently the virus reactivates and is transported back down the nerve cell processes to the skin where it causes blisters-ulcers or is shed without causing symptoms. The aim of this grant is to determine how HSV is transpor ....Herpes simplex virus (HSV) enters the human body via the skin before entering the termini of nerve cell processes. It is transported along these processes to the body of the nerve cell. HSV lies dormant within these nerve cell bodies near the spinal cord in most people. Intermittently the virus reactivates and is transported back down the nerve cell processes to the skin where it causes blisters-ulcers or is shed without causing symptoms. The aim of this grant is to determine how HSV is transported within nerve cells at the molecular level. Recent discoveries have shown how virus transport in nerve cells is dependent on interactions between specific viral proteins and cellular motor proteins and how the virus escapes from nerves to infect skin and cause disease. Such information on viral transport will allow development of inhibitors of this process which may be candidates for use as antivirals for control of recurrent herpes simplex. In addition, this information will allow the virus to be exploited for use in gene therapy to introduce DNA into human nerve cells to correct genetic abnormalities. Finally this data will assist in understanding similar mechanisms for other viruses transported in nerve cells such as those causing shingles and rabies.Read moreRead less
Immunopathological Role Of Monocyte-macrophages In Flavivirus Encephalitis.
Funder
National Health and Medical Research Council
Funding Amount
$445,011.00
Summary
Viral encephalitis is a life-threatening infection of the brain for which there are no reliable treatments. White cells called monocytes enter the brain from the blood and although important in the immune response that destroys the virus, can also damage the brain. Our work focuses on determining how monocytes migrate into the brain in viral infection, what functions they have once inside the brain, and how to exclude a certain types of monocytes that we have found to be particularly damaging.
Lipocalin 2 In Host Defence Of The Central Nervous System
Funder
National Health and Medical Research Council
Funding Amount
$575,014.00
Summary
Lipocalin 2 is a protein that is involved in protection of the host organism against bacterial infections. We have found that high levels of lipocalin 2 are produced by a variety of cells in the brain in response to not only bacterial products but also to infection with West Nile virus (WNV). WNV is a dangerous virus known to cause lethal encephalitis. This project will determine the role of lipocalin 2 in the defence of the host against WNV encephalitis.
I am a molecular virologist studying the events of virus replication and virus-host interactions with the ultimate goal to understand the mechanisms determining viral pathogenesis and develop safe and effective vaccines.
Transport, Assembly And Egress Of Herpes Simplex Virus In Neurones
Funder
National Health and Medical Research Council
Funding Amount
$639,661.00
Summary
Herpes simplex viruses 1 and 2 are important pathogens, causing encephalitis, blindness and severe neonatal infection but they also enhance the acquisition of HIV three-fold. The transport of the virus to and from the periphery to the spinal cord is a key component of their life cycle. Determination of the exact mechanism will assist in a general understanding of nerve function and the development of new strategies for antiviral drugs.