Increased core temperature during febrile disease modulates cytokine expression, enhances host defense, and improves survival in bacterial infection

Abstract

Bacterial infections are a common cause of illness. Septic shock is a severe, often life-threatening consequence of Gram-negative bacterial infection which occurs in 500,000 to 750,000 patients per year in the United States. Host defense strategies during infection balance containment and elimination of infection against collateral tissue injury, either of which can be lethal. Fever is a complex, but remarkably consistent response to infection. It constitutes a major feature of the systemic acute phase response, and typically begins very early and persists for several days during infections. Clinical and experimental evidence suggest that the increase in core temperature which occurs during infections is protective, in part by enhancing host defenses. While it is not surprising that a response as consistent and phylogenetically conserved as fever has been integrated into the regulation of host defenses, the mechanisms responsible for these effects are poorly understood. Our work has focused on how febrile range temperatures modify expression of cytokines. Using a mouse model in which core temperature is externally controlled, we showed that changes in core temperature within the normal mouse/human basal to febrile ranges profoundly altered the early cytokine expression pattern in response to the nonreplicating agonist, bacterial endotoxin (LPS). Specifically, the early TNFalpha secretion rate is enhanced, but the duration of maximal TNFalpha production is shortened, generating an enhanced early, self-limited TNFalpha pulse. We identified the Kupffer cell as the predominant source of the excess TNFalpha production in the warmer animals. Plasma IL-6 levels increased 2.7-fold and IL-1beta expression was delayed in the warmer animals. While TNFalpha levels were increased predominantly in livers of the warmer mice, IL-1beta levels were higher in lung, and IL-6 levels were widely increased in multiple organs in the warmer animals. This demonstrates that the thermal component of fever may directly contribute to shaping the host response by regulating the timing, magnitude, and tissue distribution of cytokine generation during the acute phase response. We have extended these studies in LPS-challenged mice by comparing survival, cytokine expression, and bacterial clearance in mice maintained with 36.5° or 39.5°C core temperature during peritonitis with a clinically relevant and lethal pathogen, Klebsiella pneumoniae. The early pulse in plasma TNFalpha expression associated with the increase in core temperature to febrile levels was qualitatively similar to the early, self-limited peak in TNFalpha expression reported in the LPS-challenged mice with 39.5°C core temperature. The 3°C increase in core temperature increased survival of mice infected with K. pneumoniae 5055-Caroli strain reduced mortality from 100% to 50%. This change in survival was associated with a 100,000-fold reduction in peritoneal bacterial load and a 500 to 5000 fold decrease in bacterial load in the blood and distal organs. Interestingly, the febrile mice died with 6-40 fold lower bacterial loads, suggesting different mechanisms of death in the two groups of animals. When K. pneumoniae was cultured in vitro, it grew at nearly identical rates at 37° and 39.5°C, indicating the protective effects of the core temperature increase in vivo was mediated by modulation of host:pathogen interactions rather than through direct effects on the bacteria. The possible mechanisms of these effects are currently being studied in our laboratory.