{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T19:02:31Z","timestamp":1780513351425,"version":"3.54.1"},"update-to":[{"DOI":"10.1371\/journal.ppat.1014197","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:00:00Z","timestamp":1780444800000}}],"reference-count":73,"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":[{"name":"LOEWE Zentrum DRUID","award":["D3; B3"],"award-info":[{"award-number":["D3; B3"]}]},{"DOI":"10.13039\/501100021213","name":"LOEWE-Zentrum f\u00c3\u00bcr Translationale Medizin und Pharmakologie","doi-asserted-by":"publisher","award":["Core Facility Chemoinformatics & Molecular AI; B3"],"award-info":[{"award-number":["Core Facility Chemoinformatics & Molecular AI; B3"]}],"id":[{"id":"10.13039\/501100021213","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["SPP 2225 # 446496937 and 446605368"],"award-info":[{"award-number":["SPP 2225 # 446496937 and 446605368"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["SPP 2225 #446605368 and SFB1292\/2 #318346496"],"award-info":[{"award-number":["SPP 2225 #446605368 and SFB1292\/2 #318346496"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    3\u2019-nucleotidases\/nucleases, distinct class I nucleases of protozoan parasites, play a pivotal role in extracellular purine salvage. As\n                    <jats:italic>Leishmania<\/jats:italic>\n                    are purine auxotrophs and lack\n                    <jats:italic>de novo<\/jats:italic>\n                    synthesis, ectoenzymes facilitating nucleotide and nucleic acid cleavage are indispensable for subsequent uptake. Employing quantitative proteomics, we characterized a class I nuclease\n                    <jats:italic>p1\/s1<\/jats:italic>\n                    cluster in\n                    <jats:italic>L. major<\/jats:italic>\n                    that comprises enzymes exhibiting dual 3\u2019-nucleotidase and endonuclease activity. Expression of these enzymes is induced upon miltefosine or staurosporine treatment and was specifically detected in stationary-phase, but not in logarithmic-phase promastigotes. After confirming secretion of p1\/s1, ecto-enzymatic activity was detected on parasites and in the culture supernatant. Viable null mutants deficient for the\n                    <jats:italic>p1\/s1<\/jats:italic>\n                    cluster were only obtained when a diCre-based inducible knockout system was applied, whereas direct deletion approaches were lethal. The viable knockout strains exhibited significantly reduced 3\u2019-nucleotidase\/nuclease activity. Notably, these parasites adapted by compensatory enrichment of various alternative purine salvage proteins at the proteomic level. Furthermore, both enzymatic functions implied mechanisms of host-pathogen interactions to facilitate infection establishment: Utilizing 3\u2019-nucleotidase activity,\n                    <jats:italic>Leishmania<\/jats:italic>\n                    generate extracellular adenosine to suppress inflammatory cytokine secretion from macrophages and reduce lymphocyte proliferation in a human primary cell model. The presence of ecto-nucleases also allowed these parasites to degrade and survive neutrophil extracellular traps, a potent first-line innate immune mechanism in pathogen defense. In summary, our integrative approach combining proteomics, immunological and genome editing methods expands current knowledge about\n                    <jats:italic>Leishmania major<\/jats:italic>\n                    3\u2019-nucleotidases\/nucleases. By offering new insights into the diverse involvements in host-pathogen interactions, we highlight p1\/s1 as pivotal factor during infection and potential drug target.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014197","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T17:44:30Z","timestamp":1779299070000},"page":"e1014197","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["p1\/s1, a 3\u2019-nucleotidase\/nuclease, allows Leishmania major to circumvent host innate immune response mechanisms"],"prefix":"10.1371","volume":"22","author":[{"given":"Stella M.","family":"Schmelzle","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela","family":"Bergmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca","family":"Walber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamal","family":"Shamsara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanja","family":"Ziesmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ute","family":"Distler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Csaba","family":"Miskey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liam","family":"Childs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Kolb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Tenzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin","family":"Bagola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5218-4962","authenticated-orcid":true,"given":"Ger","family":"van Zandbergen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,5,20]]},"reference":[{"issue":"3","key":"ppat.1014197.ref001","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/0166-6851(84)90117-8","article-title":"Purine and pyrimidine metabolism in the Trypanosomatidae","volume":"13","author":"DJ Hammond","year":"1984","journal-title":"Mol Biochem Parasitol"},{"issue":"2","key":"ppat.1014197.ref002","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/0304-4165(78)90104-6","article-title":"Purine metabolism in Leishmania donovani and Leishmania braziliensis","volume":"544","author":"JJ Marr","year":"1978","journal-title":"Biochim Biophys Acta"},{"issue":"13","key":"ppat.1014197.ref003","doi-asserted-by":"crossref","first-page":"7236","DOI":"10.1016\/S0021-9258(19)39104-5","article-title":"An inducible 3\u2019-nucleotidase\/nuclease from the trypanosomatid Crithidia luciliae. 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