21187438

pubmed:Citation

3

Rotavirus is a dsRNA virus that infects epithelial cells that line the surface of the small intestine. It causes severe diarrheal illness in children and ?500,000 deaths per year worldwide. We studied the mechanisms by which intestinal epithelial cells (IECs) sense rotavirus infection and signal IFN-? production, and investigated the importance of IFN-? production by IECs for controlling rotavirus production by intestinal epithelium and virus excretion in the feces. In contrast with most RNA viruses, which interact with either retinoic acid-inducible gene I (RIG-I) or melanoma differentiation-associated gene 5 (MDA5) inside cells, rotavirus was sensed by both RIG-I and MDA5, alone and in combination. Rotavirus did not signal IFN-? through either of the dsRNA sensors TLR3 or dsRNA-activated protein kinase (PKR). Silencing RIG-I or MDA5, or their common adaptor protein mitochondrial antiviral signaling protein (MAVS), significantly decreased IFN-? production and increased rotavirus titers in infected IECs. Overexpression of laboratory of genetics and physiology 2, a RIG-I-like receptor that interacts with viral RNA but lacks the caspase activation and recruitment domains required for signaling through MAVS, significantly decreased IFN-? production and increased rotavirus titers in infected IECs. Rotavirus-infected mice lacking MAVS, but not those lacking TLR3, TRIF, or PKR, produced significantly less IFN-? and increased amounts of virus in the intestinal epithelium, and shed increased quantities of virus in the feces. We conclude that RIG-I or MDA5 signaling through MAVS is required for the activation of IFN-? production by rotavirus-infected IECs and has a functionally important role in determining the magnitude of rotavirus replication in the intestinal epithelium.

eng

AIM

MEDLINE

1550-6606

Electronic

186

Y

pubmed-meshheading:21187438-Adaptor Proteins, Signal Transducing, pubmed-meshheading:21187438-Animals, pubmed-meshheading:21187438-Cell Line, pubmed-meshheading:21187438-Cercopithecus aethiops, pubmed-meshheading:21187438-DEAD-box RNA Helicases, pubmed-meshheading:21187438-HT29 Cells, pubmed-meshheading:21187438-Humans, pubmed-meshheading:21187438-Interferon-beta, pubmed-meshheading:21187438-Intestinal Mucosa, pubmed-meshheading:21187438-Membrane Proteins, pubmed-meshheading:21187438-Mice, pubmed-meshheading:21187438-Mice, 129 Strain, pubmed-meshheading:21187438-Mice, Inbred C57BL, pubmed-meshheading:21187438-Mice, Knockout, pubmed-meshheading:21187438-Nerve Tissue Proteins, pubmed-meshheading:21187438-RNA, Viral, pubmed-meshheading:21187438-RNA Helicases, pubmed-meshheading:21187438-Response Elements, pubmed-meshheading:21187438-Rotavirus, pubmed-meshheading:21187438-Signal Transduction, pubmed-meshheading:21187438-Virus Replication

RIG-I/MDA5/MAVS are required to signal a protective IFN response in rotavirus-infected intestinal epithelium.

Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural