Extracellular ATP released fromCandida albicansactivates non-peptidergic neurons to augment host defense
Authors: Edwards Tara N , Zhang Shiqun , Liu Andrew , Cohen Jonathan A. , Zhou Paul Yifan , Mogavero Selene , Hube Bernhard , Berman Judith , Bougnoux Marie-Elisabeth , Mathers Alicia R. , Gaffen Sarah L. , Albers Kathryn M. , Koerber H. Richard , Davis Brian M. , D’Enfert Christophe , Kaplan Daniel H 
Published: January 2020

AbstractIntestinal microbes release ATP to modulate local immune responses. Herein we demonstrates thatCandida albicans, an opportunistic commensal fungus, also modulates immune responses via secretion of ATP. We found that ATP secretion fromC. albicansvaried between standard laboratory strains. A survey of eighty-nine clinical isolates revealed heterogeneity in ATP secretion, independent of growth kinetics and intracellular ATP levels. Isolates from blood released less ATP than commensals, suggesting that ATP secretion assists with commensalism. To confirm this, cohorts of mice were infected with strains matched for origin, and intracellular ATP concentration, but high or low extracellular ATP. In all cases fungal burden was inversely correlated with ATP secretion. Mice lacking P2RX7, the key ATP receptor expressed by immune cells in the skin, showed no alteration in fungal burden. Rather, treatments with a P2RX2/3 antagonist result in increased fungal burden. P2RX2/3 is expressed by non-peptidergic neurons that terminate in the epidermis. Cultured sensory neurons flux Ca2+when exposed to supernatant from heat-killedC. albicans(HKCA), and these non-peptidergic fibers are the dominant subset that respond to HKCA. Ca2+flux, but not CGRP-release, can be abrogated by pretreatment of HKCA supernatant with apyrase. To determine whether non-peptidergic neurons participate in host defense, we generated MRGPRD-DTR mice. Infection in these mice resulted in increased CFU only for thoseC. albicansstrains with high ATP secretion. Taken together, our findings indicate thatC. albicansreleases ATP, which is recognized by non-peptidergic nerves in the skin resulting in augmented anti-Candidaimmune responses.Author SummaryBacterial release of ATP has been shown to modulate immune responses.Candida albicansdisplays heterogeneity in ATP release among laboratory strains and commensal clinical isolates release more ATP than invasive isolates.C. albicansstrains with high ATP secretion show lower fungal burden following epicutaneous infection. Mice lacking P2RX7, the key ATP receptor expressed by immune cells, showed no alteration in fungal burden. In contrast, treatment with P2RX2/3 antagonists resulted in increased fungal burden. P2RX3 is expressed by a subset of non-peptidergic neurons that terminate in the epidermis. These non-peptidergic fibers are the predominant responders when cultured sensory neurons are exposed to heat-killedC. albicans in vitro. Mice lacking non-peptidergic neurons have increased infection when exposed to high but not low ATP-secreting isolates ofC. albicans.Taken together, our findings indicate thatC. albicansreleases ATP which is recognized by non-peptidergic nerves in the skin resulting in augmented anti-Candidaimmune responses.Bullet pointsATP released from heat killedC. albicansactivates non-peptidergic sensory neuronsLiveC. albicansclinical isolates release variable amounts of ATPElevated levels of ATP released byC. albicanscorrelates with reduced infectivityin vivoMRGPRD-expressing cutaneous neurons are required for defense against ATP-secretingC. albicans