Synergism for cytokine-mediated disease during concurrent endotoxin and viral challenges: Roles for NK and T cell IFN-gamma production

Viral infections in humans or mice can result in increased sensitivity to c hallenges with bacteria, bacterial products, or cytokine administration, Du ring lymphocytic choriomeningitis virus infections, mice are more sensitive to the lethal effects of bacterial endotoxin LPS, and in the experiments r eported here, were observed at up to 10-fold lower doses in infected than i n uninfected mice, The mechanisms responsible for heightened susceptibility under these conditions were evaluated, kinetic studies demonstrated that,v irus-infected mice had 3- to 50-fold increases over uninfected mice in peak serum TNF, IL-12, and LFN-gamma levels after LPS administration, All three cytokines contributed to lethality during dual challenge, because neutrali zation of any one of the factors protected from death, Production of TNF wa s not dependent on either NK or T cells, In contrast, these populations wer e the predominant sources of IFN-gamma, as determined by lack of detectable IFN-gamma production in NK and T cell-deficient mice and by intracellular cytokine expression in the cell subsets, Concordant with the demonstrations that both cell populations produced IFN-gamma and that this factor was cri tical for lethality, removal of either subset alone was not sufficient to p rotect mice from death resulting from dual challenges, Increased resistance required absence of both cell subsets, Taken together, the data show that during viral infections, the normally protective immune responses can profo undly modify reactions to secondary heterologous challenges, to result in d ysregulated cytokine expression and consequent heightened detrimental effec ts.