Abstract: Innate immune responses usually rely on signalling events triggered by the detection of pathogen-associated molecular patterns or damage-related host biomolecules by specific host receptors in specialized immune cells, such as macrophages and dendritic cells. In the absence of such cells in C. elegans, this role has been assigned to epithelial and neuronal cells that interact to orchestrate responses in a pathogen-specific way. However, how C. elegans senses different pathogens remains elusive. We recently identified oomycetes as natural pathogens of C. elegans and described a protective transcriptional program that is activated by recognition of the pathogen leading to induction of multiple chitinase-like (chil) genes in the epidermis. CHIL proteins enable worms to modify their cuticle and thereby antagonize infection by reducing oomycete attachment. Through a forward genetic screen aimed at discovering the regulators of this response, we identified a pair of transmembrane C-type lectin receptors that are required in sensory neurons and the anterior intestine for oomycete recognition. While the CLEC-27/CLEC-35 pair is essential for recognition of the oomycete Myzocytiopsis humicola, another pair formed by CLEC-26 and CLEC-36, is required for animals to detect the phylogenetically divergent oomycete Haptoglossa zoospora. Interestingly, in both cases, these clec pairs are encoded by adjacent genes in the genome, share a common promoter, and are regulated by a conserved homeodomain transcription factor CEH-37(OTX2) to trigger a protective immune response in the epidermis.

Oomycete recognition in neurons and intestine is followed by activation of a kinase-pseudokinase pair in the epidermal membrane formed by OLD-1 and FLOR-1 respectively leading to the induction of chil genes in the epidermis. We also identify the PAX6 homolog VAB-3, another homeodomain transcription factor commonly studied for its conserved role in animal development, as the transcription factor regulating old-1 gene expression, and consequently the response to oomycete recognition. In summary, our work establishes a paradigm for oomycete specific recognition by animal hosts wherein canonical pattern recognition receptors act redundantly in non-specialized epithelial and neuronal cells to mount a protective immune response in the skin through cross-tissue communication.