Staging an appropriate defense response to a pathogen is the most basic function of the innate immune system. This defense response is regulated by host transcription factors which are activated upon pathogen detection. Transcription factors dictate the severity of a pro- or anti-inflammatory response. In this study, we focused on the host transcriptional response of Caenorhabditis elegans in response to a pathogenic stimulus, infection with the human pathogen Staphylococcus aureus. We recently found that HLH-30/TFEB is a major transcription factor upregulating host defense genes and pro-inflammatory cytokines in C. elegans and murine macrophages respectively. In C. elegans, HLH-30 is required for upregulating 80% of host defense genes induced by S. aureus. However, the HLH-30 binding motif is found in a fraction of these genes, suggesting that these genes are regulated by HLH-30 indirectly. Since HLH-30/TFEB regulates a broad range of processes including autophagy, longevity, metabolism, and host defense, it is important to genetically dissect each downstream pathway. To understand the function of HLH-30 in host defense, it is critical to understand how HLH-30 indirectly regulates host defense genes. Our RNAseq analysis revealed several transcription factors (TFs), which are activated downstream of HLH-30. Interestingly, most of these TFs are nuclear hormone receptors (NHR), a class of TF that has been previously implicated in nematode and mammalian innate immunity. Here, I report validation studies to confirm the role of these HLH-30-induced TFs in host defense. Using qRT-PCR I show the upregulation of these TFs is dependent on HLH-30 upon infection. Furthermore, loss of function experiments demonstrate that these TFs are required for C. elegans survival upon S. aureus infection. Of the genes examined,
nhr-55,
nhr-42, and
nhr-180 are important contributors to the innate immune response. Moreover, NHR-55 and NHR-180 function in the C. elegans intestine to regulate host survival upon infection. These results demonstrate how
hlh-30 controls a vast number of host defense genes via downstream transcription factor effectors, which may confer situmulus-specificity to the transcriptional response to biotic and abiotic stress.