Fever and the heat shock response: distinct, partially overlapping processes

The heat shock response is an ancient and highly conserved process that is essential for surviving environmental stresses, including extremes of tempe rature. Fever is a more recently evolved response, during which organisms t emporarily subject themselves to thermal stress in the face of infections. We review studies showing that fever is beneficial in the infected host. We show that core temperatures achieved during fever can activate the heat sh ock response and discuss some of the biochemical consequences of such an ef fect. We present data suggesting 4 possible mechanisms by which fever might confer protection: (1) directly killing or inhibiting growth of pathogens; (2) inducing cytoprotective heat shock proteins (Hsps) in host cells; (3) inducing expression of pathogen Hsps, an activator of host defenses; and (4 ) modifying and orchestrating host defenses. Two of these mechanisms direct ly involve the heat shock response. We describe how heat shock factor-1, th e predominant heat-induced transcriptional enhancer not only activates tran scription of Hsps but also regulates expression of pivotal cytokines and ea rly response genes. The relationship between fever and the heat shock respo nse is an illuminating example of how a more recently evolved response migh t exploit preexisting biochemical pathways for a new function.