title: Silencing early viral replication in macrophages and dendritic cells effectively suppresses flavivirus encephalitis.
abstract: West Nile (WN) and St. Louis encephalitis (SLE) viruses can cause fatal neurological infection and currently there is neither a specific treatment nor an approved vaccine for these infections. In our earlier studies, we have reported that siRNAs can be developed as broad-spectrum antivirals for the treatment of infection caused by related viruses and that a small peptide called RVG-9R can deliver siRNA to neuronal cells as well as macrophages. To increase the repertoire of broad-spectrum antiflaviviral siRNAs, we screened 25 siRNAs targeting conserved regions in the viral genome. Five siRNAs were found to inhibit both WNV and SLE replication in vitro reflecting broad-spectrum antiviral activity and one of these was also validated in vivo. In addition, we also show that RVG-9R delivers siRNA to macrophages and dendritic cells, resulting in effective suppression of virus replication. Mice were challenged intraperitoneally (i.p.) with West Nile virus (WNV) and treated i.v. with siRNA/peptide complex. The peritoneal macrophages isolated on day 3 post infection were isolated and transferred to new hosts. Mice receiving macrophages from the anti-viral siRNA treated mice failed to develop any disease while the control mice transferred with irrelevant siRNA treated mice all died of encephalitis. These studies suggest that early suppression of viral replication in macrophages and dendritic cells by RVG-9R-mediated siRNA delivery is key to preventing the development of a fatal neurological disease.
authors.affiliation: Paul L. Foster School of Medicine, Center of Excellence in Infectious Diseases, Texas Tech University Health Sciences Center, El Paso, Texas, United States of America.
authors.forename: Chunting
authors.initials: C
authors.lastname: Ye
authors.forename: Sojan
authors.initials: S
authors.lastname: Abraham
authors.forename: Haoquan
authors.initials: H
authors.lastname: Wu
authors.forename: Premlata
authors.initials: P
authors.lastname: Shankar
authors.forename: N
authors.initials: N
authors.lastname: Manjunath
mesh_terms: D000818:Animals; D002460:Cell Line; D017124:Conserved Sequence / Q000235:genetics; D003713:Dendritic Cells / Q000187:drug effects / Q000473:pathology / Q000821:virology*; D004660:Encephalitis / Q000517:prevention & control* / Q000821:virology; D004665:Encephalitis Virus, St. Louis / Q000187:drug effects / Q000502:physiology; D005416:Flavivirus / Q000187:drug effects / Q000502:physiology*; D018177:Flavivirus Infections / Q000517:prevention & control / Q000821:virology*; D020868:Gene Silencing / Q000187:drug effects; D007275:Injections, Intravenous; D008264:Macrophages / Q000187:drug effects / Q000473:pathology / Q000821:virology*; D051379:Mice; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology*; D014902:West Nile virus / Q000187:drug effects / Q000502:physiology
chemical_list: D034741:RNA, Small Interfering