Understanding how Flaviviruses interact with the host immune system to cause disease
This laboratory is investigating the interaction of neurotropic Flaviviruses with the vertebrate host immune system to discover how it causes immune-mediated disease (immunopathology).
Flaviviruses are small RNA viruses transmitted by mosquitoes and ticks. They are a major cause of illness and death around the world. Yellow fever, dengue, Japanese encephalitis and Murray Valley encephalitis are well known, however, the flavivirus, West Nile virus (WNV), which causes encephalitis in humans and animals, has spread throughout USA, Mexico and Canada, after a novel outbreak in New York in 1999. WNV causes 10-15 % death in encephalitis and survivors may end up with permanent nervous system damage.
Importantly, the disease caused by these viruses is likely to be due to over-vigorous activity of the immune response, in common with influenza and SARS. Indeed, infection of cells with WNV, causes a massive increase in the cell surface molecules that normally help induce a successful immune responses. These molecules are the major targets recognized by T lymphocytes that control the virus infection by killing infected cells. Not surprisingly, such changes are associated with increased killing of infected cells by antiviral T cells.
So, why does a virus paradoxically encourage an immune response that will eradicate it? Flavivirus-mediated increases in the immune response may constitute a novel virus survival strategy. However, it may also be the cause of the excessive immune system-mediated damage (immunopathology) in disease caused by flaviviruses. How these dramatic interactions occur are unknown and investigation of the mechanisms of these is the main thrust of this laboratory, since if immune disease could be reduced, infected patients would likely survive without permanent damage. In recent experiments, we have successfully modified several elements of the immune response selectively to achieve effective immunity that both eradicates virus and saves lives.
Current possible projects for PhD students in the lab:
Reducing the immune response without helping the virus to become established.
1. Immigrating leukocytes into the brain in WNV encephalitis in vivo - their role in mortality or survival.
2. Changes in gene expression in neurons and microglia in WNV encephalitis in vivo to help or inhibit immunpathology.
How is the over-vigorous immune response established?
1. The role of mucosal dendritic cells in vivo in controlling or enhancing virus infection in the vaginal epithelium in sexually transmitted disease.
2. The role of skin dendritic cells in vivo in initiating over-vigorous WNV immune responses after the bite of an infected mosquito.
3. How are epithelial barriers maintained in cell defence against virus infection - the role of various anti-viral molecules, such as IDO in cell defence in vivo.
4. Why isn't the foreign embryo rejected by the mother - the use of in vivo virus infection models to test the limits of acceptance of the foetus as an immunological foreigner in its own mother.
5. Modelling the immune response to West Nile virus in vivo - can modeling tell us where the real experiments are?
How are flaviviruses spread around the body and paradoxically survive in the face of a self-induced massive immune response??
1. The role of microparticles in the immune response to WNV - does it help or hinder disease?
2. The role of NF-kB in gene changes mediated by WNV infection
We have significant NH&MRC and ARC funding for these projects. We use the following techniques: Cell culture, virological techniques, live cell microcapture, Fluorescence cell sorting and flow cytometry (Aria and ImageStream), laser capture microdissection, , RT-PCR, microarray assays, siRNA inhibition, protein histochemistry, immunohistochemistry, image analysis.
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Encephalitis, Infectious Disease, neurological damage, immune damage., Flaviviruses, Interferon, immunopathology, virus immune response, viral immunity, T cells, macrophages, microglia, Dendritic cells, IDO., Brain & nervous system disorders, Infectious diseases, Cell biology, Infection & immunity, Neuroscience & psychology
The opportunity ID for this research opportunity is: 133