Febrile core temperature is essential for optimal host defense in bacterial peritonitis

Abstract

Fever, a nonspecific acute-phase response, has been associated with improved survival and shortened disease duration in infections, but the mechanisms of these beneficial responses are poorly understood. We previously reported that increasing core temperature of bacterial endotoxin (LPS)-challenged mice to the normal febrile range modified expression of tumor necrosis factor alpha (TNF-alpha), interleukin 1beta (IL-1beta), and IL-6, three cytokines critical to mounting an initial defense against microbial pathogens, but survival was not improved in the warmer animals. We speculated that our inability to show a survival benefit of optimized cytokine expression in the warmer animals reflected our use of LPS, a nonreplicating agonist, rather than an infection with viable pathogens. The objective of this study was to determine if increasing murine core temperature altered cytokine expression and improved survival in an experimental bacterial peritonitis model. We showed that housing mice at 35.5 degrees C rather than 23 degrees C increased core temperature from 36.5 to 37.5 degrees C to 39.2 to 39.7 degrees C, suppressed plasma TNF-alpha expression for the initial 48 h, delayed gamma interferon expression, improved survival, and reduced the bacterial load in mice infected with Klebsiella pneumoniae peritonitis. We showed that the reduced bacterial load was not caused by a direct effect on bacterial proliferation and probably reflected enhanced host defense. These data suggest that the increase in core temperature that occurs during bacterial infections is essential for optimal antimicrobial host defense.

FIG. 1

Effect of ambient temperature on core temperature in mice after inoculation with K. pneumoniae. Mice were inoculated i.p. with 100 CFU of K. pneumoniae strain 5055 and then placed in 23 or 35.5°C ambient temperature; core temperature was sequentially measured using a rectal thermistor probe. Mean ± SE; n = 4; ∗, P < 0.05 compared with mice at 23°C ambient temperature.

FIG. 2

Influence of core temperature on survival after inoculation with K. pneumoniae. Mice were inoculated i.p. with 100 CFU of the Caroli strain of K. pneumoniae and then placed in 23°C (No fever) or 35.5°C (Fever) ambient temperature; survival was followed over 12 days.

FIG. 3

Influence of core temperature on bacterial clearance after inoculation with K. pneumoniae. Mice were inoculated i.p. with 100 CFU of K. pneumoniae strain 5055 and then placed in 23°C (No Fever) or 35.5°C (Fever) ambient temperature. Six mice in each group were sacrificed at the indicated times, and the bacterial CFU in blood, peritoneal lavage fluid, and organ homogenates was determined by plating on MacConkey agar. Mean ± SE; n = 6; ∗, P < 0.05 compared with the “no fever” mice.

FIG. 4

Direct influence of temperature on bacterial proliferation in vitro. One hundred milliliters of LB medium was inoculated with 10 CFU of K. pneumoniae strain 5055 and cultured at 37 or 39.5°C in a shaking incubator; the OD₆₅₀ was sequentially measured as a measure of bacterial proliferation.

FIG. 5

Influence of core temperature on cytokine expression after inoculation with K. pneumoniae. Mice were inoculated i.p. with 100 CFU of K. pneumoniae strain 5055 and then placed in 23°C (No fever) or 35.5°C (Fever) ambient temperature. Six mice in each group were sacrificed at the indicated times. Heparinized blood was collected from the left ventricle, and the peritoneum was lavaged with 5 ml of Hanks basal salt solution. The concentrations of the indicated cytokines in plasma (A) and peritoneal lavage fluid (B) were measured by enzyme-linked immunosorbent assay and quantified using a recombinant standard curve. Cytokine concentrations are expressed per milliliter of plasma and peritoneal fluid. Mean ± SE; n = 6; ∗, P < 0.05 compared with the “no fever” mice.