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Neuronal GPCR NMUR-1 regulates distinct immune responses to different pathogens.

ABSTRACT: A key question in current immunology is how the innate immune system generates high levels of specificity. Using the Caenorhabditis elegans model system, we demonstrate that functional loss of NMUR-1, a neuronal G-protein-coupled receptor homologous to mammalian receptors for the neuropeptide neuromedin U, has diverse effects on C. elegans innate immunity against various bacterial pathogens. Transcriptomic analyses and functional assays reveal that NMUR-1 modulates C. elegans transcription activity by regulating the expression of transcription factors involved in binding to RNA polymerase II regulatory regions, which, in turn, controls the expression of distinct immune genes in response to different pathogens. These results uncover a molecular basis for the specificity of C. elegans innate immunity. Given the evolutionary conservation of NMUR-1 signaling in immune regulation across multicellular organisms, our study could provide mechanistic insights into understanding the specificity of innate immunity in other animals, including mammals.

SUBMITTER: Wibisono P

PROVIDER: S-EPMC8869846 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Neuronal GPCR NMUR-1 regulates distinct immune responses to different pathogens.

Wibisono Phillip P Wibisono Shawndra S Watteyne Jan J Chen Chia-Hui CH Sellegounder Durai D Beets Isabel I Liu Yiyong Y Sun Jingru J

Cell reports 20220201 6

A key question in current immunology is how the innate immune system generates high levels of specificity. Using the Caenorhabditis elegans model system, we demonstrate that functional loss of NMUR-1, a neuronal G-protein-coupled receptor homologous to mammalian receptors for the neuropeptide neuromedin U, has diverse effects on C. elegans innate immunity against various bacterial pathogens. Transcriptomic analyses and functional assays reveal that NMUR-1 modulates C. elegans transcription activ ...[more]

PMID: 35139379

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Project description:BackgroundInsects react against pathogens through innate immunity. The cotton bollworm Helicoverpa armigera (H. armigera) is an important defoliator and an extremely destructive pest insect of many crops. The elucidation of the mechanism of the immune response of H. armigera to various pathogens can provide a theoretical basis for new approaches to biologically control this pest.ResultsFour kinds of pathogens Bacillus thuringiensis, Klebsiella pneumoniae, Candida albicans, and Autographa californica multiple nucleocapsid nucleopolyhedrovirus harbored green fluorescence protein and polyhedron (AcMNPV-GFP) were used to challenge the insect. The cellular and humoral immune responses to the pathogens were analyzed in the challenged H. armigera. The results show that in the five kinds of haemocytes, only granulocytes phagocytized the Gram-negative and Gram-positive bacteria and fungi. All haemocytes can be infected by AcMNPV. Fourteen immune-related genes including pattern recognition receptors (PRRs) such as peptidoglycan recognition proteins (HaPGRP and HaPGRP C) and Gram-Negative Bacteria-Binding Protein (HaGNBP), and antimicrobial peptides (AMPs) such as cecropin-1, 2 and 3 (HaCec-1, 2 and 3), lysozyme (HaLys), attacin (HaAtt), gallerimycin-like (HaGall), gloverin-like (HaGlo), moricin-like (HaMor), cobatoxin-like (HaCob), galiomicin-like (HaGali), and immune inducible protein (HaIip) appeared in different expression profiles to different pathogen infections. The transcripts of 13 immune related genes (except HaPGRPC) are obviously up-regulated by Gram-positive bacteria. HaCec-1 and 3, HaMor, HaAtt, HaLys, HaIip, HaPGRP and HaGNBP are greatly up-regulated after fungal infection. HaGNBP, HaCec-2, HaGall, HaGlo, HaMor, HaCob, HaGali obviously increased in Gram-negative bacterial infection. Only five genes, HaGNBP, HaCec-1, HaGali, HaGlo, and HaLys, are weakly up-regulated after viral infection. The AMP transcripts had higher expression levels than the PRR transcripts after the microbial challenge.ConclusionsThese data suggest that the granulocytes are the major phagocytes in H. armigera. All haemocytes can be infected by AcMNPV. The transcripts of 14 immune related genes have different expression patterns in H. armigera infected by different pathogens, which means that the immune-related genes may have different functions against various kinds of pathogens.

Project description:The cocktails of antibiotics are utilized to study the functions of microbiota. There have been studies on the alteration of not only the microbiota composition but also the host's metabolism or immunity. However, the bacterial species associated with these altered physiologic markers are still unclear. Therefore, we supplied mice with drinking water containing ampicillin (AMP), vancomycin (VAN), neomycin (NEO), or metronidazole (MET) to observe the effect of each antibiotic on helper T cells and inflammation-related gene expression and metabolism, including amino acid metabolism and changes in gut microbiota. We observed major changes in gut microbiota in mice treated with AMP and VAN, respectively, immediately after administration. The abundance of the genera Parabacteroides and Akkermansia increased in the AMP and VAN groups, while Prevotella almost disappeared from both groups. The compositional changes in intestinal metabolites in the AMP and VAN groups were more distinct than those in the NEO and MET groups, which was similar to the microbiome results. In particular, the most distinct changes were observed in amino acid related metabolism in AMP and VAN groups; the amounts of phenylalanine and tyrosine were increased in the AMP group while those were decreased in the VAN group. The changed amounts of intestinal amino acids in each of the AMP and VAN groups were correlated with increases in the abundance of the genera Parabacteroides and Akkermansia in the AMP and VAN groups, respectively. The most distinctive changes in intestinal gene expression were observed in the ileum, especially the expression Th17-related genes such as rorgt, il17a, and il17f, which decreased dramatically in the guts of most of the antibiotic-treated groups. These changes were also associated with a significant decrease in Prevotella in both the AMP and VAN groups. Taken together, these findings indicate that changes in gut microbiota as well as host physiology, including host metabolism and immunity, differ depending on the types of antibiotics, and the antibiotic-induced gut microbiota alteration has a correlation with host physiology such as host metabolic or immunological status. Thus, the immune and metabolic status of the host should be taken into account when administering antibiotics.

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Neuronal GPCR NMUR-1 regulates distinct immune responses to different pathogens.

Publications

Neuronal GPCR NMUR-1 regulates distinct immune responses to different pathogens.

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