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

Underlying viral infections can heighten sensitivity and worsen cytokine-me diated disease following secondary inflammatory challenges, Mechanisms for this are poorly understood. The impact of the innate response to lymphocyti c 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 a lso seen with splenic and peritoneal leukocytes isolated from infected mice and challenged with LPS ex vivo, The effect on TNF-alpha production was pr esent 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 transduce r and activator of transcription 4 (STAT4), and therefore was IFN-gamma ind ependent. ;Early LCMV infection induces high concentrations of the type 1 I FNs, IFN-alpha beta. Administration of recombinant IFN-alpha alone heighten ed the TNF-alpha response to LPS, Innate IFN-alpha beta and IFN-gamma respo nses 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-gam ma receptors or STATI, a transcription factor downstream to bath IFNs, were required. These data demonstrate that early viral infection can enhance se nsitivity to bacterial products, and that this sensitization can occur in p art as a result of endogenously expressed IFN-alpha beta. This work also ra ises issues about potential complications associated with IFN-alpha beta th erapies.