Fever enhances host bacterial defence while limiting mitochondrial damage

Abstract Infection triggers the fever response, but the response’s effect on antimicrobial peptide (AMP) function remains unknown. We discovered that human AMP LL-37 antibacterial activity is temperature-dependent and were curious as to why. Its temperature dependence is not an accident, as AMPs from other animals with different body temperatures have distinct temperature sensitivities. We find that AMP temperature sensitivities are tuned to animals’ body temperatures, and that for animals able to raise their body temperature, this is used to increase the AMP’s antibacterial efficacy. This effect reflects a 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 defense by raising AMP activity towards bacteria while reducing mitochondrial damage when pathogens are absent.