Abstract
BackgroundJapanese encephalitis virus (JEV) and West Nile virus (WNV) are neurotropic flaviviruses that can cause acute encephalitis with a high fatality rate. Currently there is no effective treatment for these infections.Methods and FindingsWe tested RNA interference (RNAi)-based intervention to suppress lethal JE and WN encephalitis in mice. To induce RNAi, we used either lentivirally expressed short hairpin RNA (shRNA) or synthetic short interfering RNA (siRNA). As target, we selected the cd loop-coding sequence in domain II of the viral Envelope protein, which is highly conserved among all flaviviruses because of its essential role in membrane fusion. Using as a target a species-specific sequence in the cd loop that is conserved only among the different strains of either JEV or WNV, we could achieve specific protection against the corresponding virus. However, by targeting a cross-species conserved sequence within the cd loop, we were able to protect mice against encephalitis induced by both viruses. A single intracranial administration of lentivirally delivered shRNA or lipid-complexed siRNA before viral challenge or siRNA treatment after viral challenge was sufficient for protection against lethal encephalitis.ConclusionsRNAi-based intervention affords near complete protection from both JEV- and WNV- induced encephalitis in mice. Our results show, to our knowledge for the first time, that siRNA can be used as a broad-spectrum antiviral agent for treating encephalitis caused by multiple related viruses.
Highlights
Flaviviruses are small (40–60 nm) enveloped viruses with a single-stranded positive–sense RNA genome that is approximately 11 kb long
To our knowledge for the first time, that short interfering RNA (siRNA) can be used as a broad-spectrum antiviral agent for treating encephalitis caused by multiple related viruses
Since the siRNA effect diminishes over time in cell lines because of dilution with cell division, to follow the kinetics of protection we cloned the sequence as a U6 promoter driven template for short hairpin RNA in the lentiviral vector pLL3.7 [23]
Summary
Flaviviruses are small (40–60 nm) enveloped viruses with a single-stranded positive–sense RNA genome that is approximately 11 kb long. The mosquito-borne flaviviruses such as the Japanese encephalitis virus (JEV) and West Nile virus (WNV) are among the most important examples of emerging and resurging pathogens. Japanese encephalitis virus (JEV) and West Nile virus (WNV) are neurotropic flaviviruses that can cause acute encephalitis with a high fatality rate. There are number of viruses that can cause encephalitis (inflammation of the brain) Two such viruses are West Nile virus and Japanese encephalitis virus, part of a family of viruses called flaviviruses, which are transmitted by mosquitoes and ticks. West Nile virus originated in Africa and the Middle East, but is in the Americas. Encephalitis caused by these viruses is often very severe and can be fatal. There are no specific treatments for the encephalitis caused by these viruses
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