{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T19:30:50Z","timestamp":1792092650728,"version":"4.4.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1014206","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T00:00:00Z","timestamp":1780358400000}}],"reference-count":92,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:00:00Z","timestamp":1779235200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01 AI172179"],"award-info":[{"award-number":["R01 AI172179"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["T90 DE021990"],"award-info":[{"award-number":["T90 DE021990"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005819","name":"Florida Education Fund","doi-asserted-by":"publisher","award":["McKnight Doctoral Fellowship"],"award-info":[{"award-number":["McKnight Doctoral Fellowship"]}],"id":[{"id":"10.13039\/100005819","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    <jats:italic>Enterococcus faecalis<\/jats:italic>\n                    is a prolific opportunistic pathogen responsible for a range of life-threatening infections, notorious for its ability to withstand environmental stressors. Second messengers are small molecules that relay signals in response to stimuli and are thought to be crucial for bacteria like\n                    <jats:italic>E. faecalis<\/jats:italic>\n                    to modulate their adaptation to stress. The second messenger nucleotide c-di-AMP has emerged as an essential bacterial signaling molecule due to its impact on physiological processes, including adaptation to osmotic stress, cell wall homeostasis, antibiotic tolerance, and virulence. In addition, c-di-AMP is a pathogen-associated molecular pattern (PAMP) molecule that can trigger a potent stimulation of the host immune system. In previous work, we identified and characterized the enzymes responsible for the synthesis and degradation of intracellular c-di-AMP in\n                    <jats:italic>E. faecalis<\/jats:italic>\n                    , demonstrating that maintenance of c-di-AMP homeostasis is vital for its fitness and virulence. In addition to the intracellular enzymes that regulate c-di-AMP levels, a small number of bacteria encode surface-associated nucleotidases that cleave extracellular c-di-AMP and are potentially associated with immune evasion. Here, we characterize a novel and unique cell wall-anchored nucleotidase, termed EecP (\n                    <jats:italic>\n                      <jats:underline>E<\/jats:underline>\n                      . faecalis\n                    <\/jats:italic>\n                    <jats:underline>e<\/jats:underline>\n                    xtracellular\n                    <jats:underline>c<\/jats:underline>\n                    -di-AMP\n                    <jats:underline>p<\/jats:underline>\n                    hosphodiesterase), which features duplicated catalytic domains and degrades extracellular c-di-AMP. Through competition experiments, we show that EecP likely uses c-di-GMP, and to a lesser extent AMP, as additional substrates. While a \u0394\n                    <jats:italic>eecP<\/jats:italic>\n                    strain failed to display relevant phenotypes under most\n                    <jats:italic>in vitro<\/jats:italic>\n                    conditions, it exhibited increased susceptibility to killing by phagocytic cells, a phenotype at least partly associated with cGAS-STING immune signaling. NanoString analysis revealed distinct innate immune signatures in murine macrophages infected with the parent strain OG1RF or \u0394\n                    <jats:italic>eecP<\/jats:italic>\n                    , uncovering differential expression of host targets known to be impacted by c-di-AMP, as well as novel targets. Using two murine infection models, we show that the impact of\n                    <jats:italic>eecP<\/jats:italic>\n                    deletion and the consequent buildup of extracellular c-di-AMP on\n                    <jats:italic>E. faecalis<\/jats:italic>\n                    pathogenesis might depend on the site of infection. Notably, disseminated infection was more severe in mice infected with \u0394\n                    <jats:italic>eecP,<\/jats:italic>\n                    suggesting that extracellular c-di-AMP influences infection outcomes, likely through modulation of host immune responses.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014206","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T17:44:50Z","timestamp":1779299090000},"page":"e1014206","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Characterization of a novel cell wall-associated nucleotidase of Enterococcus faecalis that degrades extracellular c-di-AMP"],"prefix":"10.1371","volume":"22","author":[{"given":"Adriana G.","family":"Morales Rivera","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anju","family":"Bala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leila G.","family":"Casella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debra N.","family":"Brunson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellsa","family":"Wongso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aria","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilka E.","family":"Cuvilly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro R.","family":"Walker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon M.","family":"Wallet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana L.","family":"Flores-Mireles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0791-5863","authenticated-orcid":true,"given":"Jos\u00e9 A.","family":"Lemos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,5,20]]},"reference":[{"issue":"10369","key":"ppat.1014206.ref001","doi-asserted-by":"crossref","first-page":"2221","DOI":"10.1016\/S0140-6736(22)02185-7","article-title":"Global mortality associated with 33 bacterial pathogens in 2019: a systematic analysis for the Global Burden of Disease Study 2019","volume":"400","author":"GBD 2019 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