A single vertebrate DNA virus protein disarms invertebrate immunity to RNA virus infection
Don B Gammon,
Sophie Duraffour,
Daniel K Rozelle,
Heidi Hehnly,
Rita Sharma,
Michael E Sparks,
Cara C West,
Ying Chen,
James J Moresco,
Graciela Andrei,
John H Connor,
Darryl Conte Jr.,
Dawn E Gundersen-Rindal,
William L Marshall,
John R Yates,
Neal Silverman,
Craig C Mello
Affiliations
Don B Gammon
RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, United States
Sophie Duraffour
Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
Daniel K Rozelle
Department of Microbiology, Boston University, Boston, United States
Heidi Hehnly
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
Rita Sharma
RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, United States; Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, United States
Michael E Sparks
Agricultural Research Service, United States Department of Agriculture, Beltsville, United States
Cara C West
Department of Medicine, University of Massachusetts Medical School, Worcester, United States
Ying Chen
RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, United States
James J Moresco
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, United States
Graciela Andrei
Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
John H Connor
Department of Microbiology, Boston University, Boston, United States
Darryl Conte Jr.
RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, United States
Dawn E Gundersen-Rindal
Agricultural Research Service, United States Department of Agriculture, Beltsville, United States
William L Marshall
Department of Medicine, University of Massachusetts Medical School, Worcester, United States
John R Yates
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, United States
Neal Silverman
Department of Medicine, University of Massachusetts Medical School, Worcester, United States
Craig C Mello
RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, United States; Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, United States
Virus-host interactions drive a remarkable diversity of immune responses and countermeasures. We found that two RNA viruses with broad host ranges, vesicular stomatitis virus (VSV) and Sindbis virus (SINV), are completely restricted in their replication after entry into Lepidopteran cells. This restriction is overcome when cells are co-infected with vaccinia virus (VACV), a vertebrate DNA virus. Using RNAi screening, we show that Lepidopteran RNAi, Nuclear Factor-κB, and ubiquitin-proteasome pathways restrict RNA virus infection. Surprisingly, a highly conserved, uncharacterized VACV protein, A51R, can partially overcome this virus restriction. We show that A51R is also critical for VACV replication in vertebrate cells and for pathogenesis in mice. Interestingly, A51R colocalizes with, and stabilizes, host microtubules and also associates with ubiquitin. We show that A51R promotes viral protein stability, possibly by preventing ubiquitin-dependent targeting of viral proteins for destruction. Importantly, our studies reveal exciting new opportunities to study virus-host interactions in experimentally-tractable Lepidopteran systems.
