OVEREXPRESSION OF THE T-CELL RECEPTOR V-BETA-3 IN TRANSGENIC MICE INCREASES MORTALITY DURING INFECTION BY ENTEROTOXIN A-PRODUCING STAPHYLOCOCCUS-AUREUS

We have previously demonstrated that staphylococcal enterotoxins contr ibute to arthritis and mortality during staphylococcal infection. To f urther explore the mechanism by which bacterial superantigens contribu te to the pathogenesis of Staphylococcus aureus septicemia, T-cell rec eptor V beta 3 transgenic (TGV beta 3) mice and nontransgenic (non-TG) littermates were inoculated intravenously with S. aureus AB-1, which produces large amounts of staphylococcal enterotoxin A, which specific ally reacts with T-cell receptor V beta 3. Within 9 days after inocula tion, 85% of the TGV beta 3 mice died, compared with 31% of their non- TG littermates (P < 0.01). The high mortality of TGV beta 3 mice was a ccompanied by elevated bacterial burdens in the blood, spleen, and kid neys. The in vivo kinetics of cytokine mRNA expression was studied by an in situ hybridization technique. Staphylococcal infection gave rise to increased expression of interleukin 1 beta (IL-1 beta) mRNA and sp arsely expressed tumor necrosis factor alpha (TNF-alpha), IL-4, and IL -10 mRNAs in both groups. Gamma interferon mRNA expression increased o n day 3 and was maintained at a detectable level in the late phase of infection in TGV beta 3 mice, in contrast to non-TG mice. Impressively , significantly higher expression of TNF-beta mRNA in TGV beta 3 mice was noted throughout the course of infection than in non-TG littermate s. These findings suggest that overproduction of TNF-beta and gamma in terferon, the Th1 cytokines, may play a crucial role in the pathogenes is of septicemia caused by enterotoxin-secreting staphylococci.