AcNR1F orchestrates epidermal remodeling to enable host adaptation in Angiostrongylus cantonensis
- 1State Key Laboratory for Animal Disease Control and Prevention, Center for Emerging and Zoonotic Diseases, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
Abstract
Nuclear receptor NR1F regulates circadian rhythms in mammals, metamorphosis in insects, and molting in free-living Caenorhabditis elegans; however, its role in parasitic nematode development remains elusive. Angiostrongylus cantonensis, a zoonotic pathogen that causes eosinophilic meningitis in humans, exhibits distinct host adaptation, with mice and most mammals serving as non-permissive hosts and rats as the permissive host. We combined multi-omic analyses, lentivirus-mediated RNAi, LC-MS/MS, and dual-luciferase assays to elucidate AcNR1F functions in development and host adaptation. Acnr1f was expressed in the intestine, uterus, and seminal vesicle by in situ hybridization. Acnr1f showed high expression in L5 larvae and adults but low expression in L1-L4 larvae. Acnr1f expression was significantly higher in worms derived from rats than from mice; approximately 25% of co-expressed genes (918) were identified as potential downstream targets that may be integrated to regulate parasitic adaptation. RNAi reduced Acnr1f transcripts by 38.11% in female adults, resulting in significantly decreased recovery of L4 and L5 larvae and adults, a 64% reduction in egg production, and abnormal eggs with low hatching rate. Histological and ultrastructural analyses revealed thinned cuticle, reduced collagen fibers, and disrupted epidermal integrity. Transcriptomic analysis showed that differentially expressed genes were enriched in structural constituent of cuticle, metalloendopeptidase activity, extracellular matrix structural constituent. Dual-luciferase assays showed that the down-regulated collagen genes col-12 and col-144 were direct AcNR1F targets (>300-fold and >40-fold induction, respectively). Differential levels of cholesterol, corticosterone, and 7α,25-dihydroxycholesterol between worms from rats and mice were identified as AcNR1F ligands by LC-MS/MS and ligand-binding assays. Thus, AcNR1F is a ligand-activated nuclear receptor that directly regulates target genes to influence development and reproduction of A. cantonensis. The distinct availability of host-derived ligands and differential AcNR1F expressive level between worms from rodents highlights this receptor as a critical molecular switch for parasitic adaptation, providing mechanistic insights into host-pathogen interactions. Author summary: NR1F, a member of the nuclear receptor superfamily, regulates circadian rhythms in mammals, directs metamorphosis in insects, and controls molting in the free-living nematode Caenorhabditis elegans. However, its functional significance in parasitic nematodes has yet to be determined. Angiostrongylus cantonensis, the rat lungworm, is a zoonotic pathogen that causes eosinophilic meningitis in humans and exhibits striking host-dependent developmental differences between permissive (rat) and non-permissive (mouse) hosts. Elucidating the molecular mechanisms underlying this host adaptation is critical for developing novel intervention strategies. In this study, we characterized AcNR1F, which possesses canonical DNA-binding and ligand-binding domains. Using lentivirus-mediated RNA interference combined with transcriptomic analyses, we demonstrated that AcNR1F regulated development and reproduction, maintained epidermal integrity, and associated with host adaptation in A. cantonensis. We further showed that cholesterol, corticosterone, and 7α,25-dihydroxycholesterol from rodent hosts served as ligands for AcNR1F, and identified the collagen genes col-12 and col-144 as direct downstream targets. These findings illuminate how helminth parasites sense and respond to host environments through AcNR1F. This work identifies a druggable nuclear receptor pathway that may be exploited to disrupt parasite survival across different host species.
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BibTeX
@article{lv2026acnr1f,
title = {{AcNR1F orchestrates epidermal remodeling to enable host adaptation in Angiostrongylus cantonensis}},
author = {Jinwei Lv and Yanling Ma and Jiaying Lai and Song Li and Ke Ning and Kangping Lu and Lihua Xiao and Yaoyu Feng and Dongjuan Yuan},
journal = {PLOS Pathogens},
year = {2026},
month = oct,
doi = {10.1371/journal.ppat.1014691},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014691},
note = {CC BY},
}
RIS
TY - JOUR
TI - AcNR1F orchestrates epidermal remodeling to enable host adaptation in Angiostrongylus cantonensis
AU - Jinwei Lv
AU - Yanling Ma
AU - Jiaying Lai
AU - Song Li
AU - Ke Ning
AU - Kangping Lu
AU - Lihua Xiao
AU - Yaoyu Feng
AU - Dongjuan Yuan
PY - 2026
DA - 2026/10/01
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014691
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014691
AB - Nuclear receptor NR1F regulates circadian rhythms in mammals, metamorphosis in insects, and molting in free-living Caenorhabditis elegans; however, its role in parasitic nematode development remains elusive. Angiostrongylus cantonensis, a zoonotic pathogen that causes eosinophilic meningitis in humans, exhibits distinct host adaptation, with mice and most mammals serving as non-permissive hosts and rats as the permissive host. We combined multi-omic analyses, lentivirus-mediated RNAi, LC-MS/MS, and dual-luciferase assays to elucidate AcNR1F functions in development and host adaptation. Acnr1f was expressed in the intestine, uterus, and seminal vesicle by in situ hybridization. Acnr1f showed high expression in L5 larvae and adults but low expression in L1-L4 larvae. Acnr1f expression was significantly higher in worms derived from rats than from mice; approximately 25% of co-expressed genes (918) were identified as potential downstream targets that may be integrated to regulate parasitic adaptation. RNAi reduced Acnr1f transcripts by 38.11% in female adults, resulting in significantly decreased recovery of L4 and L5 larvae and adults, a 64% reduction in egg production, and abnormal eggs with low hatching rate. Histological and ultrastructural analyses revealed thinned cuticle, reduced collagen fibers, and disrupted epidermal integrity. Transcriptomic analysis showed that differentially expressed genes were enriched in structural constituent of cuticle, metalloendopeptidase activity, extracellular matrix structural constituent. Dual-luciferase assays showed that the down-regulated collagen genes col-12 and col-144 were direct AcNR1F targets (>300-fold and >40-fold induction, respectively). Differential levels of cholesterol, corticosterone, and 7α,25-dihydroxycholesterol between worms from rats and mice were identified as AcNR1F ligands by LC-MS/MS and ligand-binding assays. Thus, AcNR1F is a ligand-activated nuclear receptor that directly regulates target genes to influence development and reproduction of A. cantonensis. The distinct availability of host-derived ligands and differential AcNR1F expressive level between worms from rodents highlights this receptor as a critical molecular switch for parasitic adaptation, providing mechanistic insights into host-pathogen interactions. Author summary: NR1F, a member of the nuclear receptor superfamily, regulates circadian rhythms in mammals, directs metamorphosis in insects, and controls molting in the free-living nematode Caenorhabditis elegans. However, its functional significance in parasitic nematodes has yet to be determined. Angiostrongylus cantonensis, the rat lungworm, is a zoonotic pathogen that causes eosinophilic meningitis in humans and exhibits striking host-dependent developmental differences between permissive (rat) and non-permissive (mouse) hosts. Elucidating the molecular mechanisms underlying this host adaptation is critical for developing novel intervention strategies. In this study, we characterized AcNR1F, which possesses canonical DNA-binding and ligand-binding domains. Using lentivirus-mediated RNA interference combined with transcriptomic analyses, we demonstrated that AcNR1F regulated development and reproduction, maintained epidermal integrity, and associated with host adaptation in A. cantonensis. We further showed that cholesterol, corticosterone, and 7α,25-dihydroxycholesterol from rodent hosts served as ligands for AcNR1F, and identified the collagen genes col-12 and col-144 as direct downstream targets. These findings illuminate how helminth parasites sense and respond to host environments through AcNR1F. This work identifies a druggable nuclear receptor pathway that may be exploited to disrupt parasite survival across different host species.
SN - 1553-7374
SN - 1553-7366
ER -