NHMRC Research Fellowship (SRFB): Pathogenic flaviviruses: molecular mechanisms of disease, host response and vaccines (2014–2019)
Prof Khromykh¿s group focuses on in-depth analysis of viral and host factors determining outcome of infection with encephalitic West Nile virus (WNV) with a goal of applying obtained knowledge to highly comprehensive design of
vaccines, anti-viral drugs and viral vectors for cancer therapy. The proposed research has four objectives: 1.Identify WNV virulence determinants and their role in evasion of IFNá/â response.
The research will employ our recently developed rapid method for generation of infectious flavivirus cDNA to create a suit of chimeric viruses between pathogenic and attenuated WNV strains and analyse their virulence in wild type mice and mice defective in various factors of IFNá/â
response. The results will identify which combinations of viral and host factors determine outcome of WNV infection
2.Determine mechanisms of regulation of host response by the subgenomic flavivirus RNA. We were the first to discover mechanism of generation, essential role in WNV pathogenicity, and function of subgenomic flavivirus RNA
(sfRNA) in evasion of IFNá/â response. We will determine the exact mechanisms by which sfRNA exerts this and other functions in inhibiting cell mRNA decay and RNA interference pathways, and identify cellular factors/pathway providing a link between different processes inhibited by sfRNA 3.Identify WNV-encoded miRNAs and their functions in virus-host interactions.
We have recently discovered WNV-encoded micro RNA, the first micro RNA produced by cytoplasmic RNA viruses. The research will focus
on identifying targets of this and other WNV-encoded miRNAs in insect and mammalian cells and their role in viral replication and pathogenesis 4.Develop arbovirus diagnostic reagents, vaccine candidates and vectors for cancer therapy. This applied research will develop new diagnostic reagents for detecting arboviruses, extend Kunjin replicon-based approach for generating
effective flavivirus DNA vaccine candidates and cancer therapy vectors