Multiple gene modules control a balance between immunity and development in .

UNLABELLED

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 gene family expanded to 39 members in the genome, in comparison to a single mammalian ortholog. Our previous studies have revealed that two members of this family, and , 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 - the Orsay virus and the fungus from the microsporidia phylum. In this study, we identify a previously uncharacterized member of the family, , as a newly described negative regulator of the IPR. 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 genes, and , are positive regulators of the IPR, acting downstream of . These positive regulators reverse the effects caused by the loss of 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 genes from the expanded gene family act as ON/OFF switch modules to regulate a balance between organismal development and immunity against natural intracellular pathogens in .

AUTHOR SUMMARY

Immune 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 called that acts as a repressor of the Intracellular Pathogen Response (IPR), a defense response against viral and microsporidian infections. We also found that is required for the normal development of these animals. Furthermore, we identified two other genes, and , as suppressors of 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 .