Molecular Biology of Orthoreoviruses

• Oncolytic viral therapy using reovirus

  Mammalian orthoreoviruses (reoviruses) are members of the family Reoviridae and contain a genome consisting of 10 segments of double-stranded (ds)RNA. Reoviruses are highly tractable experimental models for studies of dsRNA virus replication and pathogenesis. In the last decade, the potential of reoviruses as oncolytic agents against various tumors, including head and neck, colon, breast and pancreatic cancers, has been investigated in animal models and humans. The putative oncolytic potential of reoviruses is based on the observation that reoviruses induce cell death and apoptosis in tumor cells with an activated Ras signaling pathway. However, while wild-type reovirus-based oncolytic therapies have been safe, the efficacy so far is limited. We are thus using genetic modification to develop safer and more effective reovirus-based cancer therapeutics.

• Highly pathogenic bat reovirus

  Bats are a natural reservoir for many important zoonotic viruses, including Hendra virus, Nipah virus and potentially SARS coronavirus and Ebola virus. In 1968, the Pteropine orthorevirus (PR) was isolated from flying fox. While it was not associated with and human disease, Melaka virus which is genetically similar to PRVB was recently isolated from a human patient in Malaysia with acute respiratory tract infection (RTI). Subsequently, other related strains of bat-associated orthreoviruses have been isolated in Malyasia, Indonesia and China. We also isolated and characterized another new PRV, Miyazaki-Bali/2007 virus from a patient with acute RTI after returning to Japan from Indonesia in 2007. These isolates have given rise to increasing concern about bat-transmitted orthoreovirus infection in humans. We are investigating how PRV replicates and causes disease by using a combination of genetic biochemical and biophysical approaches. Our aim is ultimately to develop vaccines, diagnostics and therapeutics for bat reovirus-related diseases.

• Selected Publications:
• Reverse Genetics for Fusogenic Bat-Borne Orthoreovirus Associated with Acute Respiratory Tract Infections in Humans: Role of Outer Capsid Protein σC in Viral Replication and Pathogenesis.
  Kawagishi T, Kanai Y, Tani H, Shimojima M, Saijo M, Matsuura Y, Kobayashi T.
  PLoS Pathog. 2016 Feb 22;12(2):e1005455.
  
• Imported case of acute respiratory tract infection associated with a member of species nelson bay orthoreovirus.
  Yamanaka A, Iwakiri A, Yoshikawa T, Sakai K, Singh H, Himeji D, Kikuchi I, Ueda A, Yamamoto S, Miura M, Shioyama Y, Kawano K, Nagaishi T, Saito M, Minomo M, Iwamoto N, Hidaka Y, Sohma H, Kobayashi T, Kanai Y, Kawagishi T, Nagata N, Fukushi S, Mizutani T, Tani H, Taniguchi S, Fukuma A, Shimojima M, Kurane I, Kageyama T, Odagiri T, Saijo M, Morikawa S.
  PLoS One. 2014 Mar 25;9(3):e92777. doi: 10.1371/journal.pone.0092777. eCollection 2014.
• A plasmid-based reverse genetics system for animal double-stranded RNA viruses.
  Kobayashi T, Antar AA, Boehme KW, Danthi P, Eby EA, Guglielmi KM, Holm GH, Johnson EM, Maginnis MS, Naik S, Skelton WB, Wetzel JD, Wilson GJ, Chappell JD, Dermody TS.
  Cell Host Microbe. 2007 Apr 19;1(2):147-57. Erratum in: Cell Host Microbe. 2007 Aug 16;2(2):139.