title: Rotavirus-induced IFN-β promotes anti-viral signaling and apoptosis that modulate viral replication in intestinal epithelial cells.
abstract: Rotavirus (RV), a leading cause of diarrhea, primarily infects intestinal epithelial cells (IEC). Rotavirus-infected IEC produce IFN-β and express hundreds of IFN-dependent genes. We thus hypothesized that type 1 IFN plays a key role in helping IEC limit RV replication and/or protect against cell death. To test this hypothesis, we examined IEC (HT29 cells) infected with RV (MOI 1) ± neutralizing antibodies to IFN-α/β via microscopy and SDS-PAGE immunoblotting. We hypothesized that neutralization of IFN would be clearly detrimental to RV-infected IEC. Rather, we observed that blockade of IFN function rescued IEC from the apoptotic cell death that otherwise would have occurred 24-48 h following exposure to RV. This resistance to cell death correlated with reduced levels of viral replication at early time points (< 8 h) following infection and eventuated in reduced production of virions. The reduction in RV replication that resulted from IFN neutralization correlated with, and could be recapitulated by, blockade of IFN-induced protein kinase R (PKR) activation, suggesting involvement of this kinase. Interestingly, pharmacologic blockade of caspase activity ablated RV-induced apoptosis and dramatically increased viral protein synthesis, suggesting that IFN-induced apoptosis helps to control RV infection. These results suggest non-mutually exclusive possibilities that IFN signaling is usurped by RV to promote early replication and induction of cell death may be a means by which IFN signaling possibly clears RV from the intestine.
authors: Department of Pathology, School of Medicine, Emory University, Atlanta, GA, USA.
authors: Amena H
authors: AH
authors: Frias
authors: Rheinallt M
authors: RM
authors: Jones
authors: Nimita H
authors: NH
authors: Fifadara
authors: Matam
authors: M
authors: Vijay-Kumar
authors: Andrew T
authors: AT
authors: Gewirtz
mesh_terms: D015075:2-Aminopurine / Q000494:pharmacology; D000914:Antibodies, Viral / Q000494:pharmacology; D000963:Antimetabolites / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D061945:Caspase Inhibitors; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology*; D019073:HT29 Cells; D006801:Humans; D020287:In Situ Nick-End Labeling; D016899:Interferon-beta / Q000096:biosynthesis* / Q000276:immunology / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000166:cytology / Q000821:virology; D007422:Intestines / Q000821:virology; D009842:Oligopeptides / Q000494:pharmacology; D012401:Rotavirus / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000914:Antibodies, Viral; D000963:Antimetabolites; D061945:Caspase Inhibitors; D009842:Oligopeptides; C517629:benzyloxycarbonyl-valyl-alanyl-aspartic acid; D015075:2-Aminopurine; D016899:Interferon-beta