The G protein-coupled receptor FSHR-1 is required for the Caenorhabditis elegans innate immune response - PubMed (original) (raw)

The G protein-coupled receptor FSHR-1 is required for the Caenorhabditis elegans innate immune response

Jennifer R Powell et al. Proc Natl Acad Sci U S A. 2009.

Abstract

Innate immunity is an ancient defense system used by both vertebrates and invertebrates. Previously characterized innate immune responses in plants and animals are triggered by detection of pathogens using specific receptors, which typically use a leucine-rich repeat (LRR) domain to bind molecular patterns associated with infection. The nematode Caenorhabditis elegans uses defense pathways conserved with vertebrates; however, the mechanism by which C. elegans detects pathogens is unknown. We screened all LRR-containing transmembrane receptors in C. elegans and identified the G protein-coupled receptor FSHR-1 as an important component of the C. elegans immune response to Gram-negative and Gram-positive bacterial pathogens. FSHR-1 acts in the C. elegans intestine, the primary site of exposure to ingested pathogens. FSHR-1 signals in parallel to the known p38 MAPK pathway but converges to regulate the transcriptional induction of an overlapping but nonidentical set of antimicrobial effectors. FSHR-1 may act generally to boost the nematode immune response, or it may function as a pathogen receptor.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

FSHR-1 is required for innate immunity. (A and B) fshr-1 (RNAi) or fshr-1(ok778) mutant worms are sensitive to killing by pathogenic P. aeruginosa PA14 relative to wild-type control worms. (C) fshr-1(ok778)/nDf31 heterozygotes are just as sensitive to PA14 as fshr-1(ok778) homozygotes. Parent nDf31/+ worms (actual genotype: nDf31/nT1[qIs51]) and sibling fshr-1(ok778)/+ worms (actual genotype: fshr-1(ok778)/nT1[qIs51]) are not sensitive to PA14. (D–F) fshr-1(ok778) mutants are sensitive to killing by pathogenic S. aureus and E. faecalis but not to E. coli OP50.

Fig. 2.

Fig. 2.

FSHR-1 acts in parallel to DAF-2 and the p38 MAPK pathway. (A) daf-2 and fshr-1 single and double mutants were raised at 15 °C and then shifted to the restrictive temperature of 25 °C 4 h before exposure to PA14. (B and C) Loss of components of the p38 MAPK pathway, either by genetic mutation (pmk-1) or RNAi (tir-1 and nsy-1), enhances the pathogen sensitivity of fshr-1(ok778) null mutants. Experiments with pmk-1 and fshr-1 single and double mutants were repeated 5 times, and in all cases the double mutants were significantly more sensitive than either single mutant (P < 0.01 4 out of 5 times; P < 0.05 1 out of 5 times).

Fig. 3.

Fig. 3.

FSHR-1 regulates PA14-response genes. (A and B) qRT-PCR was used to analyze the relative transcription of PA14-response genes in wild-type and mutant worms fed OP50 or PA14. Error bars represent SEM for 3 independent biologic replicates. (A) Fold induction was calculated as the ratio of normalized expression on PA14 divided by expression on OP50. *Genes with greater than 5-fold reduction in their induction in fshr-1(ok778) mutant worms relative to wild-type worms with P < 0.01. **Genes with greater than 10-fold reduction in their induction in fshr-1(ok778) mutants relative to wild-type with P < 0.01. (B) Fold change in basal expression was calculated as the ratio of wild-type expression to mutant expression in worms fed OP50. Troemel et al. (15) reported that F01D5.5 was regulated basally by PMK-1, but in our experiments the difference did not reach statistical significance. *Genes with greater than 5-fold lower basal expression in wild-type worms relative to fshr-1(ok778) mutants. **Genes with greater than 10-fold lower basal expression in wild-type worms relative to fshr-1(ok778) mutants.

Fig. 4.

Fig. 4.

FSHR-1 expression in the intestine is necessary and sufficient for pathogen resistance. (A) Intestinal-specific RNAi of fshr-1 causes worms to be as sensitive to PA14 as systemic RNAi of fshr-1. (B) Wild-type FSHR-1 expressed from endogenous or intestinal promoters fully rescues the fshr-1(ok778) mutant phenotype. FSHR-1 expressed from a neuronal promoter only partially rescues the mutant phenotype.

Fig. 5.

Fig. 5.

A model for a C. elegans innate immune network. (A and B) This model shows the integration of signaling from 3 known innate immune pathways. (A) Each pathway regulates the induction of a set of effectors in response to P. aeruginosa. The FSHR-1 and p38 MAPK pathways regulate partially overlapping sets of pathogen-response genes. Specific examples of target genes mentioned in this work are listed for each category. (B) These signaling pathways also regulate the basal expression in the absence of pathogen of several genes. Examples mentioned here are listed for each category.

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