Host genes controlling Flavivirus infection: new insights and application for developing highly effective Kunjin replicon-based Ebola vaccine (2016–2018)
Flaviviruses are a group of medically important arboviruses causing large outbreaks around the world with ~100 million cases p.a. Major flavivirus pathogens include dengue virus (DENV), Japanese encephalitis virus (JEV), and West Nile virus (WNV). In 1999 highly pathogenic NY99 strain of WNV emerged in US and to date has caused about 41,000 clinical infections and 1,700 deaths. In Australia, a relatively benign Kunjin (KUN) strain of WNV has been endemic since 1960. In 2011, however, a first unprecedented outbreak of severe encephalitis in horses caused by the new KUN strain NSW2011 was recorded in NSW and SA with more than 1000 infections and 10-15% mortality rate, raising a concern about potential outbreak of WNV pathogenic for humans in Australia in the future. This applications aims at identifying host factors controlling infection with NSW2011 virus using cutting edge in vivo RNAi screening approach with virus libraries encoding artificial microRNA (amiRs) that when processed in infected animals result in depletion of targeted host genes. Depleting host genes that restrict virus replication confer advantage to the viruses encoding corresponding amiRs and allow enrichment and subsequent amplification of these viruses in infected animals. Using this powerful in vivo virus selection approach we will identify novel and establish hierarchy between already known host genes in controlling WNV replication. We will then validate the role of identified host genes in controlling replication of other medically important flavivirues DENV and JEV. Finally, we will apply the obtained findings by incorporating amiRs targeting identified host genes restricting WNV replication into our proprietary KUN replicon-based Ebola vaccine candidate and cancer therapy vector. This should allow significantly reducing a dose and eliminating a need for repeated injections to achieve highly effective protection and/or tumour elimination.