PACAP is a pathogen-inducible resident antimicrobial neuropeptide affording rapid and contextual molecular host defense of the brain

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Significance Neuropeptides of the central nervous system regulate neurodevelopment, metabolism, emotion, and stress responses. However, despite previously established recognition of antimicrobial activity in vitro, their precise role(s) in host defense of the brain and other contexts in vivo have been poorly understood. Here, we discovered that the neuropeptide PACAP is an evolutionarily conserved antimicrobial peptide induced in the brain in response to bacterial and fungal infection. Tissue-specific PACAP induction coincided with minimal immune cell infiltration or neuroinflammation. These findings support an emerging paradigm wherein coevolution of the immune and nervous systems is linked through ancient, multifunctional peptides having neurological and immunomodulatory functions that protect the brain. We predict that PACAP is a prototypical example of a general class of endogenous, infection-inducible host-defense neuropeptides and serves as a model template to design next-generation antiinfectives with neurohomeostatic and immunomodulatory capabilities.