The purine nucleoside phosphorylasepnp-1regulates epithelial cell resistance to infection inC. elegans

Abstract

Intestinal epithelial cells are subject to attack by a diverse array of microbes, including intracellular as well as extracellular pathogens. While defense in epithelial cells can be triggered by pattern recognition receptor-mediated detection of microbe-associated molecular patterns, there is much to be learned about how they sense infection via perturbations of host physiology, which often occur during infection. A recently described host defense response in the nematode C. elegans called the Intracellular Pathogen Response (IPR) can be triggered by infection with diverse natural intracellular pathogens, as well as by perturbations to protein homeostasis. From a forward genetic screen we identified the C. elegans ortholog of purine nucleoside phosphorylase pnp-1 as a negative regulator of IPR gene expression, as well as a negative regulator of genes induced by extracellular pathogens. Accordingly, pnp-1 mutants have resistance to both intracellular and extracellular pathogens. Metabolomics analysis indicates that C. elegans pnp-1 likely has enzymatic activity similar to its human ortholog, serving to convert purine nucleosides into free bases. Classic genetic studies have shown how mutations in human purine nucleoside phosphorylase cause immunodeficiency due to T-cell dysfunction. Here we show that C. elegans pnp-1 acts in intestinal epithelial cells to regulate defense. Altogether these results indicate that perturbations in purine metabolism are likely monitored as a cue to promote defense against epithelial infection in the nematode C. elegans .

A TIR-1/SARM1 phase transition underlies p38 immune pathway activation in theC. elegansintestine

“…In this model, the p38 PMK-1 pathway functions as a rheostat that receives inputs from signals associated with potentially dangerous environmental conditions to prime host immune effector genes. Indeed, inputs from chemosensory neurons, bacterial density, tissue damage and nucleotide metabolism also regulate the tonic level of p38 PMK-1 pathway activity [3,[53][54][55][56][57], suggesting that p38 PMK-1 phosphorylation is adjusted to anticipate dangerous threats during periods of vulnerability. Thus, upon encountering a pathogen, immune defenses can be further augmented by other mechanisms that detect pathogen specifically.…”