Murine Responses to Endotoxin: Another Dirty Little Secret?

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For over a century, clinicians and investigators have injected bacterial endotoxins (lipopolysaccharides, LPS) into the veins of animals. Remarkably, some vertebrates (humans, horses, rabbits) are as much as 100,000-fold more likely to succumb to an intravenous dose of LPS than are others (baboons, mice, rats, chickens). With the recent triumph of the laboratory mouse as the major experimental animal model for infectious diseases in humans, the striking difference between human and murine sensitivity to LPS toxicity seems to have become a “dirty little secret” of innate immunology, just as Janeway’s clue to the importance of innate immunity--the potency of adjuvants—was long ignored by students of B and T cells (1). Like many other immunological differences between these species (2), the possibility that results of experiments in mice using LPS and other stimulatory microbial molecules might not apply to humans has been infrequently acknowledged. Now Warren and Cavaillon have called attention to this issue by studying it (3). Their conclusion – that the key factor(s) that account for the striking difference in sensitivity to endotoxin infusion are found in serum, not host cells – should help us think more clearly about many mouse models of human disease. Their results also raise the interesting possibility that these factors might be identified and harnessed to dampen human responses to bacterial diseases.