Heat Shock Factor 1 Protects Mice from Rapid Death during Listeria monocytogenes Infection by Regulating Expression of Tumor Necrosis Factor Alpha during Fever

Heat shock factor 1 (HSF1) is a highly conserved transcriptional regulator that controls the expression of a variety of different gene products during heat shock and other environmental stresses (24, 33). Previous studies examining either the resistance of Caenorhabditis elegans to bacterial infection or the ability of mice to produce IgG have suggested that HSF1 may be important for generating protective immune responses (18, 38). In most cell types, the heat shock response that leads to trimerization and nuclear translocation of HSF1 occurs only during severe thermal stress, at temperatures at or above 42°C (32). However, in T cells, HSF1 can be activated at 39.5°C, a temperature that is within the range of a typical fever response (11). Fever is induced during infection by Toll-like receptor (TLR) ligands that trigger the release of proinflammatory cytokines such as interleukin 1β (IL-1β), IL-6, and tumor necrosis factor alpha (TNF-α) and prostaglandin E2, which acts on the hypothalamus to temporarily increase the thermoregulatory set point of the body (7). In mice, fever has been characterized as an elevation of 1.3 to 2.1°C above the basal core body temperature (13). Although raising the body temperature to produce a fever is an energy-costly process, the evolutionary conservation of febrile responses suggests that fever is beneficial for the host and that the immune mechanisms designed to clear infections must be well adapted to functioning at elevated temperatures (15). Since HSF1 is activated at much lower temperatures in T cells than in other cell types, we hypothesized that it might be needed to protect T cell function during infections that induce a fever response. In a previous in vitro study, we showed that T cells isolated from HSF1-deficient mice were unable to proliferate efficiently at physiologic fever temperature (39.5°C) (26). To further address this question in vivo, we chose to study the role of HSF1 during Listeria monocytogenes infection, since clearance of this intracellular bacterial pathogen is strictly dependent on protective T cell responses. Early resistance to listeriosis is mediated primarily by gamma interferon (IFN-γ) and TNF-α, and mice that lack either of these cytokines are highly susceptible to infection (3, 16, 28, 30). However, the activation and proliferation of CD8+ T cells that can lyse infected cells and release the bacteria from their protective intracellular niche are required for sterilizing immunity against L. monocytogenes. Although fever is a commonly described symptom associated with human listeriosis (22, 40), the ability of L. monocytogenes to induce fever in small animal models has not been well characterized. One early study showed that the rectal temperature of rabbits increased by 2°C following injection with a partially purified toxin derived from L. monocytogenes and that this response peaked at 24 h postinjection (35). However, there are no reports in the literature describing the fever response in mice following L. monocytogenes infection. In this paper, we monitored the core body temperature of mice infected with L. monocytogenes and found that both HSF1-deficient and wild-type mice maintain a fever response during the first 2 to 3 days postinfection. Surprisingly, we showed that CD8+ T cell responses were not impaired in HSF1-deficient mice during L. monocytogenes infection. However, HSF1−/− mice infected with at least 1 × 104 CFU of L. monocytogenes displayed increased lethality that appeared to be caused by misregulated production of proinflammatory cytokines such as TNF-α.