NHR-49/PPAR-α and HLH-30/TFEB cooperate for <i>C. elegans</i> host defense via a flavin-containing monooxygenase.

Abstract

The model organism <i>Caenorhabditis elegans</i> mounts transcriptional defense responses against intestinal bacterial infections that elicit overlapping starvation and infection responses, the regulation of which is not well understood. Direct comparison of <i>C. elegans</i> that were starved or infected with <i>Staphylococcus aureus</i> revealed a large infection-specific transcriptional signature, which was almost completely abrogated by deletion of transcription factor <i>hlh-30/TFEB</i>, except for six genes including a flavin-containing monooxygenase (FMO) gene, <i>fmo-2/FMO5</i>. Deletion of <i>fmo-2/FMO5</i> severely compromised infection survival, thus identifying the first FMO with innate immunity functions in animals. Moreover, <i>fmo-2/FMO5</i> induction required the nuclear hormone receptor, NHR-49/PPAR-α, which controlled host defense cell non-autonomously. These findings reveal an infection-specific host response to <i>S. aureus</i>, identify HLH-30/TFEB as its main regulator, reveal FMOs as important innate immunity effectors in animals, and identify the mechanism of FMO regulation through NHR-49/PPAR-α during <i>S. aureus</i> infection, with implications for host defense and inflammation in higher organisms.