INSURMOUNTABLE HEAT: THE EVOLUTION AND PERSISTENCE OF DEFENSIVE HYPERTHERMIA.

Fever, the rise in body temperature set point in response to infection or injury, is a highly conserved trait among vertebrates, and documented in many arthropods. Fever is known to reduce illness duration and mortality. These observations present an evolutionary puzzle: why has fever continued to be an effective response to fast-evolving pathogenic microbes across diverse phyla, and probably over countless millions of years? Framing fever as part of a more general thermal manipulation strategy that we term defensive hyperthermia, we hypothesize that the solution lies in the independent contributions to pathogen fitness played by virulence and infectivity. A host organism deploying defensive hyperthermia alters the ecological environment of an invading pathogen. To the extent that the pathogen evolves to be able to function effectively at elevated temperatures, it disadvantages itself at infecting the next (thermonormative) host, becoming more likely to be thwarted by that host's immune system and outcompeted by wild ecotype conspecifics (a genetically distinct strain adapted to specific environmental conditions) that, although more vulnerable to elevated temperatures, operate more effectively at the host's normal temperature. We evaluate this hypothesis in light of existing evidence concerning pathogen thermal specialization, and discuss theoretical and translational implications of this model.