A role for IFN-αβ in virus infection-induced sensitization to endotoxin

Underlying viral infections can heighten sensitivity and worsen cytokine-mediated disease following secondary inflammatory challenges, Mechanisms for this are poorly understood. The impact of the innate response to lymphocytic choriomeningitis virus (LCMV) infection on sensitivity to endotoxin (LPS) was investigated, Compared with uninfected mice, infection with LCMV for 2-days-sensitized mice to LPS by similar to2-fold for lethality and by 2- to 6-fold for serum TNF-alpha levels. Priming for LPS-induced TNF-alpha was also seen with splenic and peritoneal leukocytes isolated from infected mice and challenged with LPS ex vivo, The effect on TNF-alpha production was present in the absence of IFN-gamma, its major producers NK and T cells, and the major pathways for its induction through IL-12 and the signal transducer and activator of transcription 4 (STAT4), and therefore was IFN-gamma independent. ;Early LCMV infection induces high concentrations of the type 1 IFNs, IFN-alpha beta. Administration of recombinant IFN-alpha alone heightened the TNF-alpha response to LPS, Innate IFN-alpha beta and IFN-gamma responses to LCMV exist in a delicate balance. To reduce priming for LPS-induced TNF-alpha during LCMV, deficiencies in both the IFN-alpha beta and IFN-gamma receptors or STATI, a transcription factor downstream to bath IFNs, were required. These data demonstrate that early viral infection can enhance sensitivity to bacterial products, and that this sensitization can occur in part as a result of endogenously expressed IFN-alpha beta. This work also raises issues about potential complications associated with IFN-alpha beta therapies.