Synergism of Pseudomonas aeruginosa exotoxin A with endotoxin, superantigen, or TNF results in TNFR1- and TNFR2-dependent liver toxicity in mice.

Pseudomonas aeruginosa is a potentially dangerous Gram-negative nosocomial pathogen, causing bacteremia in debilitated patients, and a prominent cause of bacterial cholangitis. Opportunistic infections with other nosocomial pathogens, e.g. Staphylococcus aureus, are common. Hence, multi-intoxication with P. aeruginosa exotoxin A (PEA) and other bacterial toxins, including endotoxin (LPS) and the superantigen S. aureus enterotoxin B (SEB), is very likely. Here we show that PEA synergistically interacted with LPS, SEB, or recombinant murine tumor necrosis factor alpha (rmuTNF) in mice, resulting in severe liver injury. Enhanced and prolonged circulation of cytokines, including TNF, which depended on the presence of T cells, was a remarkable feature of synergistic PEA/LPS- or PEA/SEB-induced hepatotoxicity. PEA/LPS-, PEA/SEB- or PEA/rmuTNF-induced liver injury was mediated by both TNF receptors (TNFRs), i.e. TNFR1 and TNFR2. In view of the fact that TNFR1, but not TNFR2, signaling is unequivocally required for host defense, our results suggest that anti-TNFR2 strategies might be beneficial to protect the liver from inflammatory damage caused by synergistic interactions of PEA with other TNF-inducing bacterial toxins.