Antagonistic paralogs control a switch between growth and pathogen resistance in C. elegans

Immune genes are under intense, pathogen-induced pressure, which causes these genes to diversify over evolutionary time and become species-specific. Through a forward genetic screen we recently described a C. elegans-specific gene called pals-22 to be a repressor of “Intracellular Pathogen Response” or IPR genes. Here we describe pals-25, which, like pals-22, is a species-specific gene of unknown biochemical function. We identified pals-25 in a screen for suppression of pals-22 mutant phenotypes and found that mutations in pals-25 suppress all known phenotypes caused by mutations in pals-22. These phenotypes include increased IPR gene expression, thermotolerance, and immunity against natural pathogens, including Nematocida parisii microsporidia and the Orsay virus. Mutations in pals-25 also reverse the reduced lifespan and slowed growth of pals-22 mutants. Transcriptome analysis indicates that pals-22 and pals-25 control expression of genes induced not only by natural pathogens of the intestine, but also by natural pathogens of the epidermis. Indeed, in an independent forward genetic screen we identified pals-22 as a repressor and pals-25 as an activator of epidermal defense gene expression. In summary, the species-specific pals-22 and pals-25 genes act as a switch to regulate a program of gene expression, growth, and defense against diverse natural pathogens in C. elegans.
Author summary Infection by microbial pathogens imposes selective pressure on animal and plant hosts. For this reason, host immune genes tend to vary in DNA sequence over evolutionary time and become ‘species-specific’. In this work we describe a pair of species-specific genes called pals-22/pals-25 that promote resistance against natural pathogens of the small roundworm Caenorhabditis elegans. This gene pair acts as an on/off switch for genes that are activated after infection and rewires the physiology of worms to either be in an immune state or a growth state. In particular, the pals-22 gene promotes development and increases lifespan, while the pals-25 gene promotes resistance against heat shock and natural pathogens including virus and fungal-related microbes. While the DNA sequence of pals-22 and pals-25 appears specific to worms, the way that these two genes affect physiology may provide insight into how organisms balance growth and immunity.