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Negative regulation of innate immunity by novel nuclear receptor NHR-42/NR1D1 with implications in infection survival, metabolism, and fitness

Goswamy, Debanjan
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Faculty Advisor
Javier Irazoqui
Academic Program
Immunology and Microbiology
Document Type
Doctoral Dissertation
Publication Date
2022-11-16
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Abstract

Detection of pathogenic signals leads to extensive changes in cellular transcriptional programs mediated by transcription factors. Positive and negative regulators of this host defense response work together to maintain immune homeostasis. Over the past two decades, several evolutionary conserved positive regulators of innate immunity have been identified in C. elegans. However, negative regulators remain unknown, and repression of the host defense response poorly understood. We previously discovered that HLH-30/TFEB is a positive regulator of immunity in C. elegans and murine macrophages after S. aureus infection, respectively. In this study, I identify nhr-42 as a negative regulator of immunity functioning downstream of HLH-30, with major implications for host survival, metabolism, and fitness. In nhr-42 mutants, several host defense genes, such as antimicrobial peptides, C-type lectins, and lysozymes, are upregulated constitutively. This enables nhr-42 mutants to have enhanced survival and lower pathogen burden after infection compared to wild type animals. I show that nhr-42 expression is induced in the pharynx and pharyngeal-intestinal valve after infection. Furthermore, I find that antimicrobial peptides abf-2 and cnc-2 are required for enhanced survival and lower pathogen burden in nhr-42 mutants. Moreover, induction of nhr-42 after infection leads to upregulation of lipid catabolism genes involved in beta-oxidation, driving lipid mobilization. These data show that nhr-42 functions to limit the host defense response to maintain immune homeostasis and reallocate energy resources through lipid mobilization towards other cellular processes. Additionally, I identify Nr1d1 (Rev-Erbα) as a functional homolog of nhr-42. I show that Nr1d1 functions downstream of TFEB to negatively regulate pro-inflammatory cytokines Il-6 and Il1b in macrophages, after S. aureus infection. These data open up new research avenues into mammalian nuclear receptor mediated regulation of immunity.

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10.13028/3hyp-mr45
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Copyright © 2022 Goswamy