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.