A single siRNA suppresses fatal encephalitis induced by two different flaviviruses.
BACKGROUND
Japanese 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.


RESULTS
We 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.


CONCLUSIONS
RNAi-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.
Kumar
Priti
P
The CBR Institute for Biomedical Research and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
Lee
Sang Kyung
SK
Shankar
Premlata
P
Manjunath
N
N
D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D004664:Encephalitis Virus, Japanese / Q000472:pathogenicity*; D004672:Encephalitis, Japanese / Q000628:therapy* / Q000821:virology; D004797:Enzyme-Linked Immunosorbent Assay; D007372:Interferons / Q000502:physiology; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D034622:RNA Interference; D034741:RNA, Small Interfering; D012367:RNA, Viral / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014901:West Nile Fever / Q000628:therapy* / Q000821:virology; D014902:West Nile virus / Q000472:pathogenicity*
D034741:RNA, Small Interfering; D012367:RNA, Viral; D007372:Interferons