Viral infection causes rapid sensitization to lipopolysaccharide:: Central role of IFN-αβ

LPS is the major active agent in the pathogenesis of Gram-negative septic shock. in this report we have studied the influence of concurrent viral infection on the outcome of LPS-induced shock. We find that infection with vesicular stomatitis virus sensitizes mice to LPS at an early time point following infection. Treatment of mice with the chemical IFN inducer, polyinosinic: polycytidylic acid, has a similar effect. This hypersensitivity to LPS correlated with hyperproduction of TNF-alpha in vivo. The cellular and molecular mechanisms underlying this phenomenon were investigated using Ab-depleted and gene-targeted mice. Our results revealed that while NK cell depletion and elimination of IFN-gamma partially protected against the sensitizing effects of vesicular stomatitis virus and polyinosinic:polycytidylic acid, the most striking effect was observed in IFN-alpha betaR-deficient mice. Thus hyperproduction of TNF-alpha was completely abrogated in IFN-alpha betaR-deficient mice, indicating that the principal mechanism underlying rapid virus-induced sensitization to LPS is an IFN-alpha beta -mediated priming of mice for an augmented production of TNF-alpha in response to LPS. This conclusion was further supported by the finding that pretreatment of mice with rIFN-alpha beta mimicked the effect of viral infection. In conclusion, our results reveal a previously unrecognized proinflammatory effect of IFN-alpha beta and point to a new pathway through which viral infection may influence the outcome of concurrent bacterial infection.