Viral infection. Prevention and cure of rotavirus infection via TLR5/NLRC4-mediated production of IL-22 and IL-18.
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.
Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA.
Benyue
B
Zhang
Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA.
Benoit
B
Chassaing
Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA.
Zhenda
Z
Shi
Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA. Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA.
Robin
R
Uchiyama
Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA.
Zhan
Z
Zhang
Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA. Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA.
Timothy L
TL
Denning
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA.
Sue E
SE
Crawford
Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, TN, USA.
Andrea J
AJ
Pruijssers
Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, TN, USA.
Jason A
JA
Iskarpatyoti
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA.
Mary K
MK
Estes
Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, TN, USA. Departments of Pediatrics, Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA.
Terence S
TS
Dermody
Department of Immunology, Genentech, South San Francisco, CA, USA.
Wenjun
W
Ouyang
Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA.
Ifor R
IR
Williams
Department of Nutritional Sciences and Medicine, Pennsylvania State University, University Park, PA 16802, USA.
Matam
M
Vijay-Kumar
Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA. Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA. agewirtz@gsu.edu.
Andrew T
AT
Gewirtz
D000818:Animals; D003967:Diarrhea / Q000276:immunology / Q000628:therapy / Q000821:virology; D004195:Disease Models, Animal; D005243:Feces / Q000821:virology; D005408:Flagellin / Q000008:administration & dosage* / Q000276:immunology; D018398:Homeodomain Proteins / Q000235:genetics; D007113:Immunity, Innate; D020382:Interleukin-18 / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D007378:Interleukins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D012400:Rotavirus Infections / Q000276:immunology / Q000517:prevention & control* / Q000628:therapy; D051198:Toll-Like Receptor 5 / Q000235:genetics / Q000502:physiology*; D017201:Virus Shedding; D000097043:Interleukin-22
D005408:Flagellin; D018398:Homeodomain Proteins; D020382:Interleukin-18; D007378:Interleukins; D051198:Toll-Like Receptor 5; D000097043:Interleukin-22; C064658:RAG-1 protein