{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T02:57:02Z","timestamp":1787021822912,"version":"build-2736575974"},"update-to":[{"DOI":"10.1371\/journal.pntd.0009224","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,11,9]],"date-time":"2021-11-09T00:00:00Z","timestamp":1636416000000}}],"reference-count":69,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T00:00:00Z","timestamp":1635379200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014264","name":"Triangle Comparative and Evolutionary Medicine Center, Duke University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014264","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000861","name":"Burroughs Wellcome Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000861","id-type":"DOI","asserted-by":"publisher"}]},{"name":"molecular genetics and microbiology, duke university"},{"DOI":"10.13039\/100006512","name":"School of Medicine, Duke University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006512","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:p>\n                    Leishmaniasis is a neglected tropical disease with diverse outcomes ranging from self-healing lesions, to progressive non-healing lesions, to metastatic spread and destruction of mucous membranes. Although resolution of cutaneous leishmaniasis is a classic example of type-1 immunity leading to self-healing lesions, an excess of type-1 related inflammation can contribute to immunopathology and metastatic spread.\n                    <jats:italic>Leishmania<\/jats:italic>\n                    genetic diversity can contribute to variation in polarization and robustness of the immune response through differences in both pathogen sensing by the host and immune evasion by the parasite. In this study, we observed a difference in parasite chemokine suppression between the\n                    <jats:italic>Leishmania (L<\/jats:italic>\n                    .\n                    <jats:italic>)<\/jats:italic>\n                    subgenus and the\n                    <jats:italic>Viannia (V<\/jats:italic>\n                    .\n                    <jats:italic>)<\/jats:italic>\n                    subgenus, which is associated with severe immune-mediated pathology such as mucocutaneous leishmaniasis. While\n                    <jats:italic>Leishmania (L<\/jats:italic>\n                    .\n                    <jats:italic>)<\/jats:italic>\n                    subgenus parasites utilize the virulence factor and metalloprotease glycoprotein-63\n                    <jats:italic>(gp63)<\/jats:italic>\n                    to suppress the type-1 associated host chemokine CXCL10,\n                    <jats:italic>L<\/jats:italic>\n                    .\n                    <jats:italic>(V<\/jats:italic>\n                    .\n                    <jats:italic>) panamensis<\/jats:italic>\n                    did not suppress CXCL10. To understand the molecular basis for the inter-species variation in chemokine suppression, we used\n                    <jats:italic>in silico<\/jats:italic>\n                    modeling to identify a putative CXCL10-binding site on GP63. The putative CXCL10 binding site is in a region of\n                    <jats:italic>gp63<\/jats:italic>\n                    under significant positive selection, and it varies from the\n                    <jats:italic>L<\/jats:italic>\n                    .\n                    <jats:italic>major<\/jats:italic>\n                    wild-type sequence in all\n                    <jats:italic>gp63<\/jats:italic>\n                    alleles identified in the\n                    <jats:italic>L<\/jats:italic>\n                    .\n                    <jats:italic>(V<\/jats:italic>\n                    .\n                    <jats:italic>) panamensis<\/jats:italic>\n                    reference genome. Mutating wild-type\n                    <jats:italic>L<\/jats:italic>\n                    .\n                    <jats:italic>(L<\/jats:italic>\n                    .\n                    <jats:italic>) major gp63<\/jats:italic>\n                    to the\n                    <jats:italic>L<\/jats:italic>\n                    .\n                    <jats:italic>(V<\/jats:italic>\n                    .\n                    <jats:italic>) panamensis<\/jats:italic>\n                    sequence at the putative binding site impaired cleavage of CXCL10 but not a non-specific protease substrate. Notably,\n                    <jats:italic>Viannia<\/jats:italic>\n                    clinical isolates confirmed that\n                    <jats:italic>L<\/jats:italic>\n                    .\n                    <jats:italic>(V<\/jats:italic>\n                    .\n                    <jats:italic>) panamensis<\/jats:italic>\n                    primarily encodes non-CXCL10-cleaving\n                    <jats:italic>gp63<\/jats:italic>\n                    alleles. In contrast,\n                    <jats:italic>L<\/jats:italic>\n                    .\n                    <jats:italic>(V<\/jats:italic>\n                    .\n                    <jats:italic>) braziliensis<\/jats:italic>\n                    has an intermediate level of activity, consistent with this species having more equal proportions of both alleles. Our results demonstrate how parasite genetic diversity can contribute to variation in immune responses to\n                    <jats:italic>Leishmania<\/jats:italic>\n                    spp. infection that may play critical roles in the outcome of infection.\n                  <\/jats:p>","DOI":"10.1371\/journal.pntd.0009224","type":"journal-article","created":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T13:56:20Z","timestamp":1635429380000},"page":"e0009224","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["Variation in Leishmania chemokine suppression driven by diversification of the GP63 virulence factor"],"prefix":"10.1371","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4387-6398","authenticated-orcid":true,"given":"Alejandro L.","family":"Antonia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0370-8488","authenticated-orcid":true,"given":"Alyson B.","family":"Barnes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3322-0179","authenticated-orcid":true,"given":"Amelia T.","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9556-2361","authenticated-orcid":true,"given":"Liuyang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0113-5981","authenticated-orcid":true,"given":"Dennis C.","family":"Ko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,10,28]]},"reference":[{"issue":"5","key":"pntd.0009224.ref001","doi-asserted-by":"crossref","first-page":"e35671","DOI":"10.1371\/journal.pone.0035671","article-title":"Leishmaniasis worldwide and global estimates of its incidence","volume":"7","author":"J Alvar","year":"2012","journal-title":"PLoS One"},{"issue":"10151","key":"pntd.0009224.ref002","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/S0140-6736(18)31204-2","volume":"392","author":"S Burza","year":"2018","journal-title":"Leishmaniasis. 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