Human Respiratory Syncytial Virus Nucleoprotein and Inclusion Bodies Antagonize the Innate Immune Response Mediated by MDA5 and MAVS

• Type of Material: Article
• Authors: Aaron W. Lifland, Georgia Institute of Technology; Jeenah Jung, Georgia Institute of Technology; Eric Alonas, Georgia Institute of Technology; Chiara Zurla, Georgia Institute of Technology; James E. Crowe, Vanderbilt University; Philip Santangelo, Emory University
• Language: English
• Date: 2012-08
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2012, American Society for Microbiology. All Rights Reserved.
• Final Published Version (URL): http://dx.doi.org/10.1128/JVI.00215-12
• Title of Journal or Parent Work: Journal of Virology
• ISSN: 0022-538X
• Volume: 86
• Issue: 15
• Start Page: 8245
• End Page: 8258
• Grant/Funding Information: This work was supported by NIH grant R01GM094198 (P.J.S.) and the March of Dimes (J.E.C.).
• Keywords: NF-KAPPA-B; IDENTIFICATION; RIG-I; CYTOPLASMIC INCLUSIONS; PROXIMITY LIGATION; RECOGNITION; INFECTED-CELLS; MATRIX PROTEIN; Science & Technology; Virology; Life Sciences & Biomedicine; RNA; VIROLOGY; NONSTRUCTURAL PROTEINS
• Research Categories: Biology, Microbiology; Health Sciences, Immunology; Biology, Virology

Abstract

Currently, the spatial distribution of human respiratory syncytial virus (hRSV) proteins and RNAs in infected cells is still under investigation, with many unanswered questions regarding the interaction of virus-induced structures and the innate immune system. Very few studies of hRSV have used subcellular imaging as a means to explore the changes in localization of retinoicacid-inducible gene-I (RIG-I)-like receptors or the mitochondrial antiviral signaling (MAVS) protein, in response to the infection and formation of viral structures. In this investigation, we found that both RIG-I and melanoma differentiation-associated gene 5 (MDA5) colocalized with viral genomic RNA and the nucleoprotein (N) as early as 6 h postinfection (hpi). By 12 hpi, MDA5 and MAVS were observed within large viral inclusion bodies (IB). We used a proximity ligation assay (PLA) and determined that the N protein was in close proximity to MDA5 and MAVS in IBs throughout the course of the infection. Similar results were found with the transient coexpression of N and the phosphoprotein (P). Additionally, we demonstrated that the localization of MDA5 and MAVS in IBs inhibited the expression of interferon β mRNA 27-fold following Newcastle disease virus infection. From these data, we concluded that the N likely interacts with MDA5, is in close proximity to MAVS, and localizes these molecules within IBs in order to attenuate the interferon response. To our knowledge, this is the first report of a specific function for hRSV IBs and of the hRSV N protein as a modulator of the innate immune response.