Adenosine deaminase and deoxyadenosine regulate intracellular immune response in C. elegans

Summary Adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) are enzymes in the purine salvage pathway, which recycles purines to meet cellular demands. Mutations of these enzymes in humans cause inflammatory and immunodeficiency syndromes, but the mechanisms are not well understood. Prior work in the nematode Caenorhabditis elegans demonstrated that loss of PNP ortholog PNP-1 induced an immune response called the intracellular pathogen response (IPR). Here, we show that loss of the enzyme upstream of PNP-1 called ADAH-1 (ADA homolog) also induces the IPR and promotes resistance against intracellular pathogens. Unlike PNP-1, ADAH-1 is essential for organismal development. Importantly, we find that supplementation of deoxyadenosine, a substrate for ADA, induces the IPR and promotes resistance to intracellular pathogens in C. elegans, a finding we extend to human cells. Thus, mutations in ADA and PNP induce innate immunity through increased deoxyadenosine, a phenomenon that is conserved from C. elegans to humans.