Viral infection causes rapid sensitization to lipopolysaccharide: central role of IFN-alpha beta.
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-alphabetaR-deficient mice. Thus hyperproduction of TNF-alpha was completely abrogated in IFN-alphabetaR-deficient mice, indicating that the principal mechanism underlying rapid virus-induced sensitization to LPS is an IFN-alphabeta-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-alphabeta mimicked the effect of viral infection. In conclusion, our results reveal a previously unrecognized proinflammatory effect of IFN-alphabeta and point to a new pathway through which viral infection may influence the outcome of concurrent bacterial infection.
Nansen
A
A
Institute of Medical Microbiology and Immunology, University of Copenhagen, Copenhagen, Denmark.
Randrup Thomsen
A
A
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D004198:Disease Susceptibility; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D007369:Interferon Inducers / Q000008:administration & dosage; D007370:Interferon Type I / Q000008:administration & dosage / Q000502:physiology*; D007371:Interferon-gamma / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008216:Lymphocytic Choriomeningitis / Q000276:immunology / Q000382:microbiology / Q000401:mortality; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D011070:Poly I-C / Q000008:administration & dosage; D011994:Recombinant Proteins; D018353:Rhabdoviridae Infections / Q000276:immunology* / Q000382:microbiology / Q000401:mortality; D012772:Shock, Septic / Q000276:immunology* / Q000401:mortality / Q000821:virology; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology*
D007369:Interferon Inducers; D007370:Interferon Type I; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D011070:Poly I-C