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

Abstract

The model organism Caenorhabditis elegans 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 C. elegans that were starved or infected with Staphylococcus aureus revealed a large infection-specific transcriptional signature, which was almost completely abrogated by deletion of transcription factor hlh-30/TFEB, except for six genes including a flavin-containing monooxygenase (FMO) gene, fmo-2/FMO5. Deletion of fmo-2/FMO5 severely compromised infection survival, thus identifying the first FMO with innate immunity functions in animals. Moreover, fmo-2/FMO5 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 S. aureus, 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 S. aureus infection, with implications for host defense and inflammation in higher organisms.

Cell nonautonomous roles of NHR‐49 in promoting longevity and innate immunity

“…NHR-49 mediates defense against pathogens such as E. faecalis and S. auerus (Dasgupta et al, 2020;Wani et al, 2021). Together with these reports, our data suggest that it orchestrates pathogenspecific transcriptional and functional outputs.…”

“…Together with these reports, our data suggest that it orchestrates pathogenspecific transcriptional and functional outputs. For instance, acs-2 and fmo-2 are upregulated >10,000 fold and ~150 fold, respectively, upon S. aureus infection, and on E. faecalis, acs-2 is elevated >1,000 fold (Dasgupta et al, 2020;Wani et al, 2021). But, we found fmo-2 to be downregulated by PA14 infection, whereas acs-2 showed a small increase.…”

“…Both genes have been reported to be essential for survival during E. faecalis infection, and fmo-2 mutants are also hyper-susceptible to S. aureus infection (Dasgupta et al, 2020;Wani et al, 2021). But, mutants of neither gene showed reduced survival upon PA14 exposure (Figure 7k).…”

“…These distinct regulatory effects also extended to the expression of well-established NHR-49 target genes, acs-2, and fmo-2, neither of which were required to defend against P. aeruginosa, unlike their known roles against other pathogens (Dasgupta et al, 2020;Wani et al, 2021). Instead, NHR-49 targets encoding antimicrobial factors and xenobiotic-response proteins contributed toward Pseudomonas resistance.…”

“…Our NHR-49 UP group included the well-established nhr-49target gene, acs-2, that encodes an acyl CoA synthetase involved in mitochondrial β-oxidation (Van Gilst, Hadjivassiliou, Jolly, et al, 2005; and is upregulated in glp-1 mutants (Amrit et al, 2016), as well as fmo-2, that encodes a flavin monooxygenase (Table S1a) (Goh et al, 2018;Leiser et al, 2015). Recently, both genes have been reported to be dramatically upregulated upon infection by the gram-positive pathogens, Enterococcus faecalis, and Staphylococcus aureus (Dasgupta et al, 2020;Wani et al, 2021). We tested whether PA14 exposure altered their expression as well.…”