title: Antiviral effects of small interfering RNA simultaneously inducing RNA interference and type 1 interferon in coxsackievirus myocarditis.
abstract: Antiviral therapeutics are currently unavailable for treatment of coxsackievirus B3, which can cause life-threatening myocarditis. A modified small interfering RNA (siRNA) containing 5'-triphosphate, 3p-siRNA, was shown to induce RNA interference and interferon activation. We aimed to develop a potent antiviral treatment using CVB3-specific 3p-siRNA and to understand its underlying mechanisms. Virus-specific 3p-siRNA was superior to both conventional virus-specific siRNA with an empty hydroxyl group at the 5' end (OH-siRNA) and nonspecific 3p-siRNA in decreasing viral replication and subsequent cytotoxicity. A single administration of 3p-siRNA dramatically attenuated virus-associated pathological symptoms in mice with no signs of toxicity, and their body weights eventually reached the normal range. Myocardial inflammation and fibrosis were rare, and virus production was greatly reduced. A nonspecific 3p-siRNA showed relatively less protective effect under identical conditions, and a virus-specific OH-siRNA showed no protective effects. We confirmed that virus-specific 3p-siRNA simultaneously activated target-specific gene silencing and type I interferon signaling. We provide a clear proof of concept that coxsackievirus B3-specific 3p-siRNA has 2 distinct modes of action, which significantly enhance antiviral activities with minimal organ damage. This is the first direct demonstration of improved antiviral effects with an immunostimulatory virus-specific siRNA in coxsackievirus myocarditis, and this method could be applied to many virus-related diseases.
authors.affiliation: Department of Microbiology, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Jeonghyun
authors.initials: J
authors.lastname: Ahn
authors.forename: Ara
authors.initials: A
authors.lastname: Ko
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Jun
authors.forename: Minah
authors.initials: M
authors.lastname: Won
authors.forename: Yoo Kyum
authors.initials: YK
authors.lastname: Kim
authors.forename: Eun-Seon
authors.initials: ES
authors.lastname: Ju
authors.forename: Eun Seok
authors.initials: ES
authors.lastname: Jeon
authors.forename: Heuiran
authors.initials: H
authors.lastname: Lee
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D003384:Coxsackievirus Infections / Q000188:drug therapy*; D006367:HeLa Cells; D006801:Humans; D007370:Interferon Type I / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D009205:Myocarditis / Q000188:drug therapy* / Q000821:virology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014709:Vero Cells
chemical_list: D007370:Interferon Type I; D034741:RNA, Small Interfering