Prevention and cure of rotavirus infection via TLR5/NLRC4-mediated production of IL-22 and IL-18

• Type of Material: Article
• Authors: Benyue Zhang, Georgia State University; Benoit Chassaing, Georgia State University; Zhenda Shi, Georgia State University; Robin Uchiyama, Georgia State University; Zhan Zhang, Georgia State University; Timothy Denning, Emory University; Sue E. Crawford, Baylor College of Medicine; Andrea J. Pruijssers, Vanderbilt University; Jason A. Iskarpatyoti, Vanderbilt University; Mary K. Estes, Baylor College of Medicine; Terence S. Dermody, Vanderbilt University; Wenjun Ouyang, Genentech; Ifor Williams, Emory University; Matam Vijay-Kumar, Pennsylvania State University; Andrew Gewirtz, Emory University
• Language: English
• Date: 2014-11-14
• Publisher: American Association for the Advancement of Science
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 by the American Association for the Advancement of Science; all rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1126/science.1256999
• Title of Journal or Parent Work: Science
• ISSN: 0036-8075
• Volume: 346
• Issue: 6211
• Start Page: 861
• End Page: 865
• Grant/Funding Information: B.C. is supported by a fellowship from the Crohn’s and Colitis Foundation of America.; This work was supported by NIH grants DK061417—and an accompanying award from the American Reinvestment and Recovery Act—AI107943, DK064730, DK56338, AI038296, and AI080656.; T.S.D. is supported by Elizabeth B. Lamb Center for Pediatric Research.
• Keywords: MUCOSAL; Science & Technology - Other Topics; BACTERIAL FLAGELLIN; SALMONELLA; IMMUNITY; NLRC4; DIARRHEA; Multidisciplinary Sciences; CD8(+) T-CELLS; PROTECTS; DEFENSE; Science & Technology; DENDRITIC CELLS
• Research Categories: Biology, Virology; Health Sciences, Immunology; Health Sciences, Pathology

Abstract

Activators of innate immunity may have the potential to combat a broad range of infectious agents. We report that treatment with bacterial flagellin prevented rotavirus (RV) infection in mice and cured chronically RV-infected mice. Protection was independent of adaptive immunity and interferon (IFN, type I and II) and required flagellin receptors Toll-like receptor 5 (TLR5) and NOD-like receptor C4 (NLRC4). Flagellin-induced activation of TLR5 on dendritic cells elicited production of the cytokine interleukin-22 (IL-22), which induced a protective gene expression program in intestinal epithelial cells. Flagellin also induced NLRC4-dependent production of IL-18 and immediate elimination of RV-infected cells. Administration of IL-22 and IL-18 to mice fully recapitulated the capacity of flagellin to prevent or eliminate RV infection and thus holds promise as a broad-spectrum antiviral agent.