UC San Diego

The innate immune system is critical in protecting against foreign invaders and can be activated by detection of microbe-associated molecules, as well as detection of the consequences of pathogen infection. In the nematode C. elegans, the molecularly diverse intracellular pathogens of microsporidia and virus can induce a common host transcriptional response called the Intracellular Pathogen Response (IPR). The IPR can also be induced by proteotoxic stress, which is often a consequence of intracellular infection. In parallel, the IPR is regulated by antagonistic paralogs in C. elegans called pals-22 and pals-25. The wild-type function of pals-22 is to repress IPR gene expression and increase thermotolerance and pathogen resistance, while the wild-type function of pals-25 is to activate these phenotypes, acting downstream of pals-22. To investigate how pals genes control the IPR, I further characterized the role of pals-22/pals-25, as well as two additional pals pairs: pals-17/pals-20 and pals-23/pals-24. First, I investigated the role of pals-22 and pals-25 in mediating the induction of IPR genes upon proteotoxic stress. Next, I characterized pals-17 as another negative regulator of IPR genes and found that pals-17 may work with an antagonistic paralog pals-20 as an activator. Finally, I knocked out another pals gene pair, pals-23 and pals-24, and found that they do not regulate expression of a GFP reporter for the IPR gene pals-5. Altogether, these findings demonstrate general principles of host gene regulation by antagonistic paralogs, which control expression of genes that promote resistance against natural intracellular pathogens and tolerance of proteotoxic stress.