{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T23:42:53Z","timestamp":1790638973396,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1009693","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,11,5]],"date-time":"2021-11-05T00:00:00Z","timestamp":1636070400000}}],"reference-count":45,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2021,10,26]],"date-time":"2021-10-26T00:00:00Z","timestamp":1635206400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RO1AI143790"],"award-info":[{"award-number":["RO1AI143790"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Innate lymphoid cells (ILCs) comprise a heterogeneous population of immune cells that maintain barrier function and can initiate a protective or pathological immune response upon infection. Here we show the involvement of IL-17A-producing ILCs in microbiota-driven immunopathology in cutaneous leishmaniasis. IL-17A-producing ILCs were ROR\u03b3t\n                    <jats:sup>+<\/jats:sup>\n                    and were enriched in\n                    <jats:italic>Leishmania major<\/jats:italic>\n                    infected skin, and topical colonization with\n                    <jats:italic>Staphylococcus epidermidis<\/jats:italic>\n                    before\n                    <jats:italic>L<\/jats:italic>\n                    .\n                    <jats:italic>major<\/jats:italic>\n                    infection exacerbated the skin inflammatory responses and IL-17A-producing ROR\u03b3t\n                    <jats:sup>+<\/jats:sup>\n                    ILC accumulation without impacting type 1 immune responses. IL-17A responses in ILCs were directed by\n                    <jats:italic>Batf3<\/jats:italic>\n                    dependent CD103\n                    <jats:sup>+<\/jats:sup>\n                    dendritic cells and IL-23. Moreover, experiments using\n                    <jats:italic>Rag1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>-\/-<\/jats:italic>\n                    <\/jats:sup>\n                    mice established that IL-17A\n                    <jats:sup>+<\/jats:sup>\n                    ILCs were sufficient in driving the inflammatory responses as depletion of ILCs or neutralization of IL-17A diminished the microbiota mediated immunopathology. Taken together, this study indicates that the skin microbiota promotes ROR\u03b3t\n                    <jats:sup>+<\/jats:sup>\n                    IL-17A-producing ILCs, which augment the skin inflammation in cutaneous leishmaniasis.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1009693","type":"journal-article","created":{"date-parts":[[2021,10,26]],"date-time":"2021-10-26T13:33:33Z","timestamp":1635255213000},"page":"e1009693","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":24,"title":["Microbiota instruct IL-17A-producing innate lymphoid cells to promote skin inflammation in cutaneous leishmaniasis"],"prefix":"10.1371","volume":"17","author":[{"given":"Tej Pratap","family":"Singh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8031-4805","authenticated-orcid":true,"given":"Augusto M.","family":"Carvalho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"La\u00eds Amorim","family":"Sacramento","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3939-2200","authenticated-orcid":true,"given":"Elizabeth A.","family":"Grice","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip","family":"Scott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,10,26]]},"reference":[{"key":"ppat.1009693.ref001","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/nri.2016.72","article-title":"Cutaneous leishmaniasis: immune responses in protection and pathogenesis","volume":"16","author":"P Scott","year":"2016","journal-title":"Nat Rev Immunol"},{"key":"ppat.1009693.ref002","first-page":"11","article-title":"Variable gene expression and parasite load predict treatment outcome in cutaneous leishmaniasis","author":"CF Amorim","year":"2019","journal-title":"Sci Transl Med"},{"key":"ppat.1009693.ref003","doi-asserted-by":"crossref","DOI":"10.1128\/IAI.00764-19","article-title":"Profiles of local and systemic inflammation in the outcome of treatment of human cutaneous leishmaniasis caused by leishmania (viannia).","volume":"88","author":"A Navas","year":"2020","journal-title":"Infect Immun"},{"key":"ppat.1009693.ref004","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.3389\/fimmu.2017.01437","article-title":"The equivocal role of th17 cells and neutrophils on immunopathogenesis of leishmaniasis.","volume":"8","author":"C Gon\u00e7alves-de-Albuquerque S da","year":"2017","journal-title":"Front Immunol"},{"key":"ppat.1009693.ref005","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1002\/eji.201546015","article-title":"The Nlrp3 inflammasome, IL-1\u03b2, and neutrophil recruitment are required for susceptibility to a nonhealing strain of Leishmania major in C57BL\/6 mice","volume":"46","author":"M Charmoy","year":"2016","journal-title":"Eur J Immunol"},{"key":"ppat.1009693.ref006","doi-asserted-by":"crossref","first-page":"e1006196","DOI":"10.1371\/journal.ppat.1006196","article-title":"CD8+ T cell cytotoxicity mediates pathology in the skin by inflammasome activation and IL-1\u03b2 production.","volume":"13","author":"FO Novais","year":"2017","journal-title":"PLoS Pathog."},{"key":"ppat.1009693.ref007","doi-asserted-by":"crossref","first-page":"e1003243","DOI":"10.1371\/journal.ppat.1003243","article-title":"IL-17 mediates immunopathology in the absence of IL-10 following Leishmania major infection.","volume":"9","author":"C Gonzalez-Lombana","year":"2013","journal-title":"PLoS Pathog"},{"key":"ppat.1009693.ref008","doi-asserted-by":"crossref","first-page":"3039","DOI":"10.4049\/jimmunol.0713598","article-title":"IL-17 promotes progression of cutaneous leishmaniasis in susceptible mice","volume":"182","author":"S Lopez Kostka","year":"2009","journal-title":"J Immunol"},{"key":"ppat.1009693.ref009","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.chom.2017.06.006","article-title":"Cutaneous Leishmaniasis Induces a Transmissible Dysbiotic Skin Microbiota that Promotes Skin Inflammation.","volume":"22","author":"C Gimblet","year":"2017","journal-title":"Cell Host Microbe"},{"key":"ppat.1009693.ref010","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1038\/jid.2014.305","article-title":"Genomic profiling of human Leishmania braziliensis lesions identifies transcriptional modules associated with cutaneous immunopathology","volume":"135","author":"FO Novais","year":"2015","journal-title":"J Invest Dermatol"},{"key":"ppat.1009693.ref011","doi-asserted-by":"crossref","first-page":"e0007247","DOI":"10.1371\/journal.pntd.0007247","article-title":"Coinfection with Leishmania major and Staphylococcus aureus enhances the pathologic responses to both microbes through a pathway involving IL-17A.","volume":"13","author":"TY Borb\u00f3n","year":"2019","journal-title":"PLoS Negl Trop Dis."},{"key":"ppat.1009693.ref012","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1126\/science.1225152","article-title":"Compartmentalized control of skin immunity by resident commensals","volume":"337","author":"S Naik","year":"2012","journal-title":"Science"},{"key":"ppat.1009693.ref013","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.immuni.2014.09.006","article-title":"Innate lymphoid cells in inflammation and immunity","volume":"41","author":"ANJ McKenzie","year":"2014","journal-title":"Immunity"},{"key":"ppat.1009693.ref014","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.it.2019.12.004","article-title":"Skin-Resident Innate Lymphoid Cells\u2014Cutaneous Innate Guardians and Regulators","volume":"41","author":"T Kobayashi","year":"2020","journal-title":"Trends Immunol"},{"key":"ppat.1009693.ref015","doi-asserted-by":"crossref","first-page":"2351","DOI":"10.1038\/jid.2014.146","article-title":"Composition of innate lymphoid cell subsets in the human skin: enrichment of NCR(+) ILC3 in lesional skin and blood of psoriasis patients.","volume":"134","author":"MBM Teunissen","year":"2014","journal-title":"J Invest Dermatol"},{"key":"ppat.1009693.ref016","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1038\/s41590-019-0423-0","article-title":"c-Kit-positive ILC2s exhibit an ILC3-like signature that may contribute to IL-17-mediated pathologies","volume":"20","author":"JH Bernink","year":"2019","journal-title":"Nat Immunol"},{"key":"ppat.1009693.ref017","doi-asserted-by":"crossref","first-page":"11394","DOI":"10.1038\/ncomms11394","article-title":"Epidermal Notch1 recruits ROR\u03b3(+) group 3 innate lymphoid cells to orchestrate normal skin repair.","volume":"7","author":"Z Li","year":"2016","journal-title":"Nat Commun."},{"key":"ppat.1009693.ref018","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1111\/imr.12580","article-title":"Interplay of innate lymphoid cells and the microbiota","volume":"279","author":"L Britanova","year":"2017","journal-title":"Immunol Rev"},{"key":"ppat.1009693.ref019","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1016\/j.cell.2016.07.043","article-title":"The spectrum and regulatory landscape of intestinal innate lymphoid cells are shaped by the microbiome","volume":"166","author":"M Gury-BenAri","year":"2016","journal-title":"Cell"},{"key":"ppat.1009693.ref020","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1111\/pim.12279","article-title":"Indigenous microbiota and Leishmaniasis","volume":"38","author":"MEM Lopes","year":"2016","journal-title":"Parasite Immunol"},{"key":"ppat.1009693.ref021","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1038\/nature14052","article-title":"Commensal-dendritic-cell interaction specifies a unique protective skin immune signature","volume":"520","author":"S Naik","year":"2015","journal-title":"Nature"},{"key":"ppat.1009693.ref022","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.cellimm.2016.07.004","article-title":"Role of pro-inflammatory cytokine IL-17 in Leishmania pathogenesis and in protective immunity by Leishmania vaccines","volume":"309","author":"A Banerjee","year":"2016","journal-title":"Cell Immunol"},{"key":"ppat.1009693.ref023","doi-asserted-by":"crossref","first-page":"14799","DOI":"10.1073\/pnas.1004204107","article-title":"Longitudinal shift in diabetic wound microbiota correlates with prolonged skin defense response","volume":"107","author":"NISC Comparative Sequencing Program","year":"2010","journal-title":"Proc Natl Acad Sci USA"},{"key":"ppat.1009693.ref024","first-page":"61","article-title":"Topical Antimicrobial Treatments Can Elicit Shifts to Resident Skin Bacterial Communities and Reduce Colonization by Staphylococcus aureus Competitors","author":"AJ SanMiguel","year":"2017","journal-title":"Antimicrob Agents Chemother"},{"key":"ppat.1009693.ref025","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1002\/eji.201444651","article-title":"Batf3-dependent CD103+ dendritic cells are major producers of IL-12 that drive local Th1 immunity against Leishmania major infection in mice","volume":"45","author":"M Mart\u00ednez-L\u00f3pez","year":"2015","journal-title":"Eur J Immunol"},{"key":"ppat.1009693.ref026","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1002\/eji.201344242","article-title":"Cross-presenting dendritic cells are required for control of Leishmania major infection","volume":"44","author":"D Ashok","year":"2014","journal-title":"Eur J Immunol"},{"key":"ppat.1009693.ref027","doi-asserted-by":"crossref","first-page":"e1003504","DOI":"10.1371\/journal.ppat.1003504","article-title":"Cytotoxic T cells mediate pathology and metastasis in cutaneous leishmaniasis.","volume":"9","author":"FO Novais","year":"2013","journal-title":"PLoS Pathog."},{"key":"ppat.1009693.ref028","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1038\/jid.2013.4","article-title":"CD8(+) granzyme B(+)-mediated tissue injury vs. CD4(+)IFN\u03b3(+)-mediated parasite killing in human cutaneous leishmaniasis.","volume":"133","author":"S Santos C da","year":"2013","journal-title":"J Invest Dermatol"},{"key":"ppat.1009693.ref029","doi-asserted-by":"crossref","first-page":"e1003970","DOI":"10.1371\/journal.ppat.1003970","article-title":"Engagement of NKG2D on bystander memory CD8 T cells promotes increased immunopathology following Leishmania major infection.","volume":"10","author":"EJ Crosby","year":"2014","journal-title":"PLoS Pathog."},{"key":"ppat.1009693.ref030","doi-asserted-by":"crossref","first-page":"2830","DOI":"10.1002\/eji.200940115","article-title":"Human mucosal leishmaniasis: neutrophils infiltrate areas of tissue damage that express high levels of Th17-related cytokines","volume":"40","author":"VS Boaventura","year":"2010","journal-title":"Eur J Immunol"},{"key":"ppat.1009693.ref031","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1590\/0074-02760150436","article-title":"The microbiological signature of human cutaneous leishmaniasis lesions exhibits restricted bacterial diversity compared to healthy skin","volume":"111","author":"VR Salgado","year":"2016","journal-title":"Mem Inst Oswaldo Cruz"},{"key":"ppat.1009693.ref032","doi-asserted-by":"crossref","first-page":"2640","DOI":"10.1172\/JCI124617","article-title":"The balance of power: innate lymphoid cells in tissue inflammation and repair","volume":"129","author":"JG Castellanos","year":"2019","journal-title":"J Clin Invest"},{"key":"ppat.1009693.ref033","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1084\/jem.178.2.567","article-title":"Natural killer cells are a source of interferon gamma that drives differentiation of CD4+ T cell subsets and induces early resistance to Leishmania major in mice","volume":"178","author":"TM Scharton","year":"1993","journal-title":"J Exp Med"},{"key":"ppat.1009693.ref034","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1126\/science.aat4326","article-title":"Microbial guardians of skin health","volume":"363","author":"A Stacy","year":"2019","journal-title":"Science"},{"key":"ppat.1009693.ref035","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.chom.2020.06.014","article-title":"The impact of the microbiome on immunity to vaccination in humans","volume":"28","author":"SE de Jong","year":"2020","journal-title":"Cell Host Microbe"},{"key":"ppat.1009693.ref036","doi-asserted-by":"crossref","first-page":"e1005852","DOI":"10.1371\/journal.ppat.1005852","article-title":"Leishmaniavirus-Dependent Metastatic Leishmaniasis Is Prevented by Blocking IL-17A.","volume":"12","author":"M-A Hartley","year":"2016","journal-title":"PLoS Pathog."},{"key":"ppat.1009693.ref037","doi-asserted-by":"crossref","first-page":"242","DOI":"10.3389\/fimmu.2020.00242","article-title":"Innate lymphocytes in psoriasis.","volume":"11","author":"B Polese","year":"2020","journal-title":"Front Immunol"},{"key":"ppat.1009693.ref038","doi-asserted-by":"crossref","first-page":"2252","DOI":"10.1172\/JCI61862","article-title":"Ror\u03b3t+ innate lymphocytes and \u03b3\u03b4 T cells initiate psoriasiform plaque formation in mice","volume":"122","author":"S Pantelyushin","year":"2012","journal-title":"J Clin Invest"},{"key":"ppat.1009693.ref039","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1017\/S0031182005008073","article-title":"Germ-free mice produce high levels of interferon-gamma in response to infection with Leishmania major but fail to heal lesions","volume":"131","author":"MR Oliveira","year":"2005","journal-title":"Parasitology"},{"key":"ppat.1009693.ref040","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.immuni.2011.12.011","article-title":"Interleukin 23 production by intestinal CD103(+)CD11b(+) dendritic cells in response to bacterial flagellin enhances mucosal innate immune defense.","volume":"36","author":"MA Kinnebrew","year":"2012","journal-title":"Immunity"},{"key":"ppat.1009693.ref041","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/s40168-017-0263-9","article-title":"Microbiota-activated CD103+ DCs stemming from microbiota adaptation specifically drive \u03b3\u03b4T17 proliferation and activation.","volume":"5","author":"C Fleming","year":"2017","journal-title":"Microbiome"},{"key":"ppat.1009693.ref042","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.chom.2017.12.002","article-title":"Gut Microbes Egested during Bites of Infected Sand Flies Augment Severity of Leishmaniasis via Inflammasome-Derived IL-1\u03b2.","volume":"23","author":"R Dey","year":"2018","journal-title":"Cell Host Microbe."},{"key":"ppat.1009693.ref043","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1086\/599380","article-title":"Interleukin 17 production among patients with American cutaneous leishmaniasis","volume":"200","author":"O Bacellar","year":"2009","journal-title":"J Infect Dis"},{"key":"ppat.1009693.ref044","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1006\/expr.2001.4656","article-title":"A lipophosphoglycan-independent method for isolation of infective Leishmania metacyclic promastigotes by density gradient centrifugation","volume":"99","author":"GF Sp\u00e4th","year":"2001","journal-title":"Exp Parasitol"},{"key":"ppat.1009693.ref045","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1016\/j.immuni.2015.10.016","article-title":"A Wave of Regulatory T Cells into Neonatal Skin Mediates Tolerance to Commensal Microbes","volume":"43","author":"TC Scharschmidt","year":"2015","journal-title":"Immunity"}],"updated-by":[{"DOI":"10.1371\/journal.ppat.1009693","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,11,5]],"date-time":"2021-11-05T00:00:00Z","timestamp":1636070400000}}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1009693","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,5]],"date-time":"2021-11-05T13:36:03Z","timestamp":1636119363000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1009693"}},"subtitle":[],"editor":[{"given":"Simona","family":"St\u00e4ger","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,10,26]]},"references-count":45,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10,26]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1009693","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.06.08.447514","asserted-by":"object"}]},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,26]]}}}