Human pathogen Staphylococcus aureus colonizes 30% of the population and causes diverse infections. Recent studies identified a novel helix-loop-helix TF(HLH-30)/Transcription factor EB (TFEB) is activated upon S. aureus infection in Caenorhabditis elegans and murine macrophages respectively. HLH-30 activation leads to upregulation of antimicrobial peptides, lysozymes, together with autophagy genes in C. elegans. This host defense response is conserved in macrophages. Although the signaling cascade leading to TFEB activation has been characterized in both systems, very little is known about mediators downstream of TFEB. Interestingly, 70% of host defense genes regulated by HLH-30 do not possess the promoter sequence required for its binding, indicating a role for other downstream TFs and interactions. RNA-sequencing in WT vs TFEB KO macrophages and C. elegans revealed upregulation of several nuclear receptors (NR) upon S. aureus infection, in a TFEB dependent manner. We identified 17 nuclear hormone receptors (NHR) in C. elegans and 5 NRs in macrophages that are highly upregulated upon infection. NR are involved in regulating a multitude of biological processes including metabolism, development, and immune responses. Our studies found
nhr-55,
nhr-42 in C. elegans and NR1D1 in macrophages, are involved in regulating a host defense response. Animals lacking
nhr-42 are more resistant to S. aureus and E. faecalis infection compared to WT animals. We found that
nhr-42 functions in multiple tissues to confer this resistance. In contrast, animals lacking
nhr-55 are hypersusceptible to infection compared to WT. Moreover,
nhr-55 functions only in the intestine, the site of infection. Importantly, both
nhr-42 and
nhr-55 mutants had no defects in lifespan or fecundity compared to WT. We performed RNA-seq on uninfected and infected animals, comparing the transcriptomic profile of animals lacking NHRs to WT. We found genes involved in host defense and detoxification of xenobiotics downregulated in
nhr-55 mutant animals, compared to WT upon infection. Conversely, uninfected
nhr-42 mutants had a higher expression of around 300 genes when compared to WT. GO analysis showed overrepresentation of innate immune genes. Several antimicrobials including antibacterial factor related peptides, c-type lectins, caenacins, and saposins were upregulated in
nhr-42 mutants. Furthermore,
nhr-42 mutants showed a lower bacterial burden after 24h of infection, compared to WT. Also, infected animals lacking
nhr-42 showed lower expression of lipid metabolism genes compared to infected WT animals. We performed lipid staining on infected and uninfected worms, and found
nhr-42 mutants retain more lipids upon infection as compared to WT. We have found two novel NHRs,
nhr-55 an activator and
nhr-42 a repressor, functioning downstream of an evolutionarily conserved positive regulator of immunity in HLH-30.