Negative regulation of C. elegans innate immunity by orphan nuclear receptor NHR-42

Positive and negative regulators of innate immunity work together to maintain immune homeostasis. We previously discovered that HLH-30/TFEB is a critical transcription factor that positively regulates host defense genes upon S. aureus infection in C. elegans . However, repression of host defense genes and negative regulation of immunity remain poorly understood. In this study, we identified nhr-42 as a negative regulator of host defense genes functioning downstream of HLH-30/TFEB, with major implications in host survival and metabolism after infection. nhr-42 expression is induced in an HLH-30/TFEB dependent manner mostly in the pharynx upon infection. We find that animals lacking nhr-42 have higher expression of host defense genes, which enables enhanced survival after infection. Antimicrobials expressed in the pharynx such as abf-2 , function downstream of nhr-42 to confer resistance to infection by mitigating pathogen burden. Furthermore, nhr-42 deficient animals are defective in lipid mobilization, having higher lipid stores compared to wild type animals after infection. nhr-42 therefore enables C. elegans to limit the host defense response and reallocate energy resources through lipid mobilization after infection. To our knowledge, this is the first report of a transcription factor that represses host defense genes in C. elegans .