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

Murapa, Patience, Ward, Martin R., Gandhapudi, Siva K., Woodward, Jerold G., D'Orazio, Sarah E.F.
Infection and immunity 2011 v.79 no.1 pp. 177-184
Listeria monocytogenes, T-lymphocytes, bacteria, blood serum, death, fever, genes, heat stress, interferon-gamma, mice, neutralization, pathogens, septic shock, transcription factors, tumor necrosis factor-alpha
Heat shock factor 1 (HSF1) is a stress-induced transcription factor that promotes expression of genes that protect mammalian cells from the lethal effects of severely elevated temperatures (>42°C). However, we recently showed that HSF1 is activated at a lower temperature (39.5°C) in T cells, suggesting that HSF1 may be important for preserving T cell function during pathogen-induced fever responses. To test this, we examined the role of HSF1 in clearance of Listeria monocytogenes, an intracellular bacterial pathogen that elicits a strong CD8⁺ T cell response in mice. Using temperature transponder microchips, we showed that the core body temperature increased approximately 2°C in L. monocytogenes-infected mice and that the fever response was maintained for at least 24 h. HSF1-deficient mice cleared a low-dose infection with slightly slower kinetics than did HSF1⁺/⁺ littermate controls but were significantly more susceptible to challenges with higher doses of bacteria. Surprisingly, HSF1-deficient mice did not show a defect in CD8⁺ T cell responses following sublethal infection. However, when HSF1-deficient mice were challenged with high doses of L. monocytogenes, increased levels of serum tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ) compared to those of littermate control mice were observed, and rapid death of the animals occurred within 48 to 60 h of infection. Neutralization of TNF-α enhanced the survival of HSF1-deficient mice. These results suggest that HSF1 is needed to prevent the overproduction of proinflammatory cytokines and subsequent death due to septic shock that can result following high-dose challenge with bacterial pathogens.