Multiple pals gene modules control a balance between immunity and development in Caenorhabditis elegans

Abstract

The immune system continually battles against pathogen-induced pressures, which often leads to the evolutionary expansion of immune gene families in a species-specific manner. For example, the pals gene family expanded to 39 members in the Caenorhabditis elegans genome, in comparison to a single mammalian pals ortholog. Our previous studies have revealed that two members of this family, pals-22 and pals-25, act as antagonistic paralogs to control the Intracellular Pathogen Response (IPR). The IPR is a protective transcriptional response, which is activated upon infection by two molecularly distinct natural intracellular pathogens of C. elegans - the Orsay virus and the fungus Nematocida parisii from the microsporidia phylum. In this study, we identify a previously uncharacterized member of the pals family, pals-17, as a newly described negative regulator of the IPR. pals-17 mutants show constitutive upregulation of IPR gene expression, increased immunity against intracellular pathogens, as well as impaired development and reproduction. We also find that two other previously uncharacterized pals genes, pals-20 and pals-16, are positive regulators of the IPR, acting downstream of pals-17. These positive regulators reverse the effects caused by the loss of pals-17 on IPR gene expression, immunity and development. We show that the negative IPR regulator protein PALS-17 and the positive IPR regulator protein PALS-20 colocalize inside intestinal epithelial cells, which are the sites of infection for IPR-inducing pathogens. In summary, our study demonstrates that several pals genes from the expanded pals gene family act as ON/OFF switch modules to regulate a balance between organismal development and immunity against natural intracellular pathogens in C. elegans. AUTHOR SUMMARYImmune responses to pathogens induce extensive rewiring of host physiology. In the short term, these changes are generally beneficial as they can promote resistance against infection. However, prolonged activation of immune responses can have serious negative consequences on host health, including impaired organismal development and fitness. Therefore, the balance between activating the immune system and promoting development must be precisely regulated. In this study, we used genetics to identify a gene in the roundworm Caenorhabditis elegans called pals-17 that acts as a repressor of the Intracellular Pathogen Response (IPR), a defense response against viral and microsporidian infections. We also found that pals-17 is required for the normal development of these animals. Furthermore, we identified two other pals genes, pals-20 and pals-16, as suppressors of pals-17 mutant phenotypes. Finally, we found that PALS-17 and PALS-20 proteins colocalize inside intestinal cells, where viruses and microsporidia invade and replicate in the host. Taken together, our study demonstrates a balance between organismal development and immunity that is regulated by several genetic ON/OFF switch modules in C. elegans.