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Genetic variation in host populations may lead to differential viral susceptibilities. Here, we investigate the role of natural genetic variation in the Intracellular Pathogen Response (IPR), an important antiviral pathway in the model organism  Caenorhabditis elegans  against Orsay virus (OrV). The IPR involves transcriptional activity of 80 genes including the  pals- genes. We examine the genetic variation in the  pals -family for traces of selection and explore the molecular and phenotypic effects of having distinct  pals -gene alleles. Genetic analysis of 330 global  C. elegans  strains reveals that genetic diversity within the IPR-related  pals -genes can be categorized in a few haplotypes worldwide. Importantly, two key IPR regulators,  pals-22  and  pals-25 , are in a genomic region carrying signatures of balancing selection, suggesting that different evolutionary strategies exist in IPR regulation. We infected eleven  C. elegans  strains that represent three distinct  pals-22 pals-25  haplotypes with Orsay virus to determine their susceptibility. For two of these strains, N2 and CB4856, the transcriptional response to infection was also measured. The results indicate that  pals-22 pals-25  haplotype shapes the defense against OrV and host genetic variation can result in constitutive activation of IPR genes. Our work presents evidence for balancing genetic selection of immunity genes in  C. elegans  and provides a novel perspective on the functional diversity that can develop within a main antiviral response in natural host populations.

Balancing Selection of the Intracellular Pathogen Response in Natural Caenorhabditis elegans Populations