Fever enhances host bacterial defense while limiting mitochondrial damage

The fever response is triggered during infection and inflammation, but the importance of this response for the function of antimicrobial peptides (AMPs) remains unknown. We discovered that the activity of the human AMP LL-37 is temperature-dependent and were curious as to why. Its temperature-dependent activity is not an enzymatic accident, as AMPs from other animals with different body temperatures have distinct temperature sensitivities. We find that in general, AMP temperature sensitivities are tuned to animals’ body temperatures, and that for animals that can induce fever or raise their body temperature, this is used to increase the AMP’s antibacterial efficacy. This effect reflects a careful balance between optimizing antibacterial killing while minimizing mitochondrial damage. In contrast, cold-blooded animals that are unable to raise their body temperature use a different strategy to avoid mitochondrial damage. Together, this study suggests that fever is beneficial for antimicrobial defence by raising AMP activity towards bacteria while reducing mitochondrial damage when pathogens are absent.