{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T14:48:53Z","timestamp":1777906133950,"version":"3.51.4"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,8,9]],"date-time":"2022-08-09T00:00:00Z","timestamp":1660003200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005668","name":"Funda\u00e7\u00e3o de Apoio \u00e0 Pesquisa do Distrito Federal","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005668","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>Tegumentary leishmaniasis is a tropical disease caused by protozoa of the genus <jats:italic>Leishmania.<\/jats:italic> Clinically, the disease presents a broad spectrum of symptoms, the mechanisms underlying the development of lesions remaining to be fully elucidated. In the present work, we performed a correlation and multiparametric analysis to evaluate how parasite- and host-related aspects associate with each other, and with the different clinical manifestations of tegumentary leishmaniasis. This cross-sectional study involved 75 individuals from endemic areas of Brazil, grouped according to their symptoms. <jats:italic>Leishmania<\/jats:italic> species were determined by DNA sequencing, and parasite load, antibody production, and cytokine profile were evaluated by kDNA qPCR, ELISA, and flow cytometry. Data were analyzed using the Chi-square test, principal component analysis, canonical discriminant analysis, and correlation analysis. Among the recruited patients, 23 (31%) were asymptomatic, 34 (45%) had primary cutaneous leishmaniasis, 10 (13%) presented recurrent cutaneous leishmaniasis, and eight (11%) had mucocutaneous leishmaniasis. <jats:italic>Leishmania<\/jats:italic> species identified included <jats:italic>L. amazonensis, L. braziliensis<\/jats:italic>, and <jats:italic>L. guyanensis<\/jats:italic>. Surprisingly, no <jats:italic>Leishmania<\/jats:italic> RNA virus infection was detected in any sample. In summary, our work showed that parasite load, antibody production, and cytokine levels alone are not determinants for tegumentary leishmaniasis symptoms. However, the correlation analysis allowed us to observe how these factors are correlated to each other within the groups, which revealed a unique network for each clinical manifestation. Our work reinforces the complexity of tegumentary leishmaniasis outcomes - which are associated with multiple host and parasite-related elements and provides a holistic model of the disease.<\/jats:p>","DOI":"10.3389\/fcimb.2022.956112","type":"journal-article","created":{"date-parts":[[2022,8,9]],"date-time":"2022-08-09T18:06:52Z","timestamp":1660068412000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Multiparametric analysis of host and parasite elements in new world tegumentary leishmaniasis"],"prefix":"10.3389","volume":"12","author":[{"given":"Bruna Caroline","family":"de Carvalho","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tamires","family":"Vital","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaqueline","family":"Osiro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ciro Martins","family":"Gomes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elza","family":"Noronha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruno","family":"Dallago","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana de C\u00e1ssia","family":"Rosa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juliana Lott","family":"Carvalho","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luciana","family":"Hagstr\u00f6m","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariana","family":"Hecht","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadjar","family":"Nitz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,8,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aax4204","article-title":"Variable gene expression and parasite load predict treatment outcome in cutaneous leishmaniasis","volume":"11","author":"Amorim","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"B2","doi-asserted-by":"publisher","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":"Banerjee","year":"2016","journal-title":"Cell. Immunol."},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.44.4.1435-1439.2006","article-title":"Comparison of PCR assays for diagnosis of cutaneous leishmaniasis","volume":"44","author":"Bensoussan","year":"2006","journal-title":"J. Clin. Microbiol."},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/FCIMB.2018.00289\/BIBTEX","article-title":"IFN-\u03b3 response is associated to time exposure among asymptomatic immune responders that visited American tegumentary leishmaniasis endemic areas in Peru","volume":"8","author":"Best","year":"2018","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0004422","article-title":"Induction of IL-10 and TGF\u03b2 from CD4+CD25+FoxP3+ T cells correlates with parasite load in Indian kala-azar patients infected with leishmania donovani","volume":"10","author":"Bhattacharya","year":"2016","journal-title":"PLoS Negl. Trop. Dis."},{"key":"B6","doi-asserted-by":"publisher","first-page":"11 2, 1054","DOI":"10.1038\/ni725","article-title":"IL-4 instructs TH1 responses and resistance to leishmania major in susceptible BALB\/c mice","volume":"2","author":"Biedermann","year":"2001","journal-title":"Nat. Immunol."},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0194383","article-title":"Toll-like receptors 2, 4, and 9 expressions over the entire clinical and immunopathological spectrum of American cutaneous leishmaniasis due to leishmania (V.) braziliensis and leishmania (L.) amazonensis","volume":"13","author":"Campos","year":"2018","journal-title":"PLoS One"},{"key":"B8","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1111\/J.1365-3024.2007.00940.X","article-title":"Differential immune regulation of activated T cells between cutaneous and mucosal leishmaniasis as a model for pathogenesis","volume":"29","author":"Carvalho","year":"2007","journal-title":"Parasite Immunol."},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/J.EXPPARA.2019.107773","article-title":"PCR primers designed for new world leishmania: A systematic review","volume":"207","author":"Conter","year":"2019","journal-title":"Exp. Parasitol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1128\/JCM.01764-16","article-title":"Detection and differentiation of leishmania spp. in clinical specimens by use of a SYBR green-based real-time PCR assay","volume":"55","author":"De Almeida","year":"2017","journal-title":"J. Clin. Microbiol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"5273","DOI":"10.1038\/s41467-019-13356-2","article-title":"Leishmania RNA virus exacerbates Leishmaniasis by subverting innate immunity via TLR3-mediated NLRP3 inflammasome inhibition","volume":"10","author":"de Carvalho","year":"2019","journal-title":"Nat. Commun."},{"key":"B12","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1016\/B978-0-12-419998-9.00007-9","article-title":"Cytokines of the immune system: Chemokines","author":"Dembic","year":"2015","journal-title":"Cytokines Immune System"},{"key":"B13","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1590\/0074-0276108052013021","article-title":"Severity of tegumentary leishmaniasis is not exclusively associated with leishmania RNA virus 1 infection in Brazil","volume":"108","author":"de Pereira","year":"2013","journal-title":"Mem\u00f3rias do Instituto. Oswaldo. Cruz"},{"key":"B14","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1016\/J.IJID.2017.01.036","article-title":"Is leishmania (Viannia) braziliensis parasite load associated with disease pathogenesis","volume":"57","author":"de Pereira","year":"2017","journal-title":"Int. J. Infect. Dis."},{"key":"B15","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1590\/S0037-86822012000500011","article-title":"The effect of age on the frequency of adverse reactions caused by antimony in the treatment of American tegumentary leishmaniasis in governador valadares, state of minas gerais, Brazil","volume":"45","author":"Diniz","year":"2012","journal-title":"Rev. Soc. Bras. Med. Trop."},{"key":"B16","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1093\/biohorizons\/hzp004","article-title":"Leishmania vaccines: from leishmanization to the era of DNA technology","volume":"2","author":"Dunning","year":"2009","journal-title":"Biosci. Horizons"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0004570","article-title":"Down-regulation of TLR and JAK\/STAT pathway genes is associated with diffuse cutaneous leishmaniasis: A gene expression analysis in NK cells from patients infected with leishmania mexicana","volume":"10","author":"Fern\u00e1ndez-Figueroa","year":"2016","journal-title":"PLoS Negl. Trop. Dis."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/S12866-018-1384-4\/TABLES\/4","article-title":"Assessment of intralesional cytokine profile of cutaneous leishmaniasis caused by leishmania donovani in Sri Lanka","volume":"19","author":"Galgamuwa","year":"2019","journal-title":"BMC Microbiol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1186\/s13071-018-2859-8","article-title":"Real-time PCR applications for diagnosis of leishmaniasis","volume":"11","author":"Galluzzi","year":"2018","journal-title":"Parasites Vectors"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1590\/s1678-9946201759091","article-title":"American Tegumentary leishmaniasis: epidemiological and molecular characterization of prevalent leishmania species in the state of tocantins, brazil 2011-2015","volume":"59","author":"Gosch","year":"2017","journal-title":"Rev. do Instituto. Med. Trop. S\u00e3o Paulo"},{"key":"B21","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1586\/eri.10.19","article-title":"Current diagnosis and treatment of cutaneous and mucocutaneous leishmaniasis","volume":"8","author":"Goto","year":"2010","journal-title":"Expert Rev. Anti-infective Ther."},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0062390","article-title":"Sex bias in infectious disease epidemiology: Patterns and processes","volume":"8","author":"Guerra-Silveira","year":"2013","journal-title":"PLoS One"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0005100","article-title":"Atypical manifestations of cutaneous leishmaniasis in a region endemic for leishmania braziliensis: Clinical, immunological and parasitological aspects","volume":"10","author":"Guimar\u00e3es","year":"2016","journal-title":"PLoS Negl. Trop. Dis."},{"key":"B24","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/B978-0-12-407679-2.00005-3","article-title":"Mechanisms of immune evasion in leishmaniasis","volume":"82","author":"Gupta","year":"2013","journal-title":"Adv. Appl. Microbiol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1016\/j.jaad.2014.08.051","article-title":"Cutaneous and mucocutaneous leishmaniasis: Clinical perspectives","volume":"73","author":"Handler","year":"2015","journal-title":"J. Am. Acad. Dermatol."},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0002657","article-title":"Strong association between serological status and probability of progression to clinical visceral leishmaniasis in prospective cohort studies in India and Nepal","volume":"8","author":"Hasker","year":"2014","journal-title":"PLoS Negl. Trop. Dis."},{"key":"B27","unstructured":"IL-2 is necessary for the progression of leishmaniasis in susceptible murine hosts\n            HeinzelF. P.\n            RerkoR. M.\n            HatamF.\n            LocksleyR. M.\n          1993"},{"key":"B28","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/J.IMLET.2013.12.022","article-title":"The role of IL-4 and IL-13 in cutaneous leishmaniasis","volume":"161","author":"Hurdayal","year":"2014","journal-title":"Immunol. Lett."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13071-021-05129-y","article-title":"Identification of asymptomatic leishmania infections: a scoping review","volume":"15","author":"Ibarra-Meneses","year":"2022","journal-title":"Parasites Vectors"},{"key":"B30","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1016\/j.bjorl.2015.07.014","article-title":"Correlation between presence of leishmania RNA virus 1 and clinical characteristics of nasal mucosal leishmaniosis","volume":"81","author":"Ito","year":"2015","journal-title":"Braz. J. Otorhinolaryngol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1126\/science.1199326","article-title":"Leishmania RNA virus controls the severity of mucocutaneous leishmaniasis","volume":"331","author":"Ives","year":"2011","journal-title":"Science"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1826","DOI":"10.1128\/JCM.00208-13","article-title":"Real-time PCR assay for detection and quantification of leishmania (Viannia) organisms in skin and mucosal lesions: exploratory study of parasite load and clinical parameters","volume":"51","author":"Jara","year":"2013","journal-title":"J. Clin. Microbiol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"4906","DOI":"10.1128\/IAI.69.8.4906-4915.2001","article-title":"Heterogeneity of wild leishmania major isolates in experimental murine pathogenicity and specific immune response","volume":"69","author":"K\u00e9ba\u00efer","year":"2001","journal-title":"Infect. Immun."},{"key":"B34","doi-asserted-by":"publisher","first-page":"E811","DOI":"10.1073\/pnas.1619114114","article-title":"Antiviral screening identifies adenosine analogs targeting the endogenous dsRNA leishmania RNA virus 1 (LRV1) pathogenicity factor","volume":"114","author":"Kuhlmann","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U. S. A"},{"key":"B35","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1111\/J.1574-695X.2009.00607.X","article-title":"Correlation of parasitic load with interleukin-4 response in patients with cutaneous leishmaniasis due to leishmania tropica","volume":"57","author":"Kumar","year":"2009","journal-title":"FEMS Immunol. Med. Microbiol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1080\/1744666X.2021.1906650","article-title":"Genetic variations in the human immune system influence susceptibility to tegumentary leishmaniasis: a systematic review and meta-analysis","volume":"17","author":"Lera-Nonose","year":"2021","journal-title":"Expert Rev. Clin. Immunol."},{"key":"B37","unstructured":"Ear, nose and throat manifestations of mucocutaneous leishmaniasis: a literature review\n            MarraF.\n            ChiappettaM. C.\n            VincentiV.\n          2014"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.5812\/ircmj.5410","article-title":"Interleukin-2 expression in lupoid and usual types of old world cutaneous leishmaniasis","volume":"16","author":"Mashayekhi Goyonlo","year":"2014","journal-title":"Iran Red Crescent. Med. J."},{"key":"B39","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1080\/20477724.2016.1232042","article-title":"Pro- and anti-inflammatory cytokines in cutaneous leishmaniasis: a review","volume":"110","author":"Maspi","year":"2016","journal-title":"Pathog. Glob. Health"},{"key":"B40","doi-asserted-by":"publisher","first-page":"4088","DOI":"10.1128\/IAI.00490-08","article-title":"Accelerated control of visceral leishmania donovani infection in interleukin-6-deficient mice","volume":"76","author":"Murray","year":"2008","journal-title":"Infect. Immun."},{"key":"B41","doi-asserted-by":"publisher","first-page":"5317","DOI":"10.4049\/jimmunol.0803868","article-title":"A functional IL-13 receptor is expressed on polarized murine CD4+ Th17 cells and IL-13 signaling attenuates Th17 cytokine production","volume":"182","author":"Newcomb","year":"2009","journal-title":"J. Immunol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/j.cyto.2013.12.016","article-title":"The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of human tegumentary leishmaniasis","volume":"66","author":"Oliveira","year":"2014","journal-title":"Cytokine"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/J.CYTOX.2020.100043","article-title":"Unravelling the unsolved paradoxes of cytokine families in host resistance and susceptibility to leishmania infection","volume":"2","author":"Osero","year":"2020","journal-title":"Cytokine X"},{"key":"B44","doi-asserted-by":"publisher","first-page":"S10","DOI":"10.1016\/j.jinf.2014.07.016","article-title":"Leishmaniasis","volume":"69","author":"Pace","year":"2014","journal-title":"J. Infect."},{"key":"B45","doi-asserted-by":"publisher","first-page":"79","DOI":"10.4269\/AJTMH.1986.35.79","article-title":"Selection of a skin test antigen for American visceral leishmaniasis","volume":"35","author":"Reed","year":"1986","journal-title":"Am. J. Trop. Med. Hygiene"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/505134","article-title":"Performance of an ELISA and indirect immunofluorescence assay in serological diagnosis of zoonotic cutaneous leishmaniasis in iran","volume":"2014","author":"Sarkari","year":"2014","journal-title":"Interdiscip. Perspect. Infect. Dis."},{"key":"B47","doi-asserted-by":"publisher","first-page":"e20170415","DOI":"10.1590\/0037-8682-0415-2017","article-title":"GF-\u03b21 polymorphism in American tegumentary leishmaniasis in a southern Brazilian population","volume":"52","author":"Shehadeh","year":"2019","journal-title":"Rev. Soc. Bras. Med. Trop."},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0006015","article-title":"Dynamics of American tegumentary leishmaniasis in a highly endemic region for leishmania (Viannia) braziliensis infection in northeast Brazil","volume":"11","author":"Silva","year":"2017","journal-title":"PLoS Negl. Trop. Dis."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1424","DOI":"10.1093\/cid\/ciu102","article-title":"Asymptomatic leishmania infection: A new challenge for leishmania control","volume":"58","author":"Singh","year":"2014","journal-title":"Clin. Infect. Dis."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1839","DOI":"10.1007\/s00436-018-5871-1","article-title":"Characterization of leishmania species from central-West region of Brazil","volume":"117","author":"Souza Castro","year":"2018","journal-title":"Parasitol. Res."},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0010162","article-title":"Leishmania RNA virus-1 is similarly detected among metastatic and non-metastatic phenotypes in a prospective cohort of American tegumentary leishmaniasis","volume":"16","author":"Valencia","year":"2022","journal-title":"PLoS Negl. Trop. Dis."},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1371\/JOURNAL.PONE.0010107","article-title":"Quantification of parasite load in clinical samples of leishmaniasis patients: IL-10 level correlates with parasite load in visceral leishmaniasis","volume":"5","author":"Verma","year":"2010","journal-title":"PLoS One"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofv184","article-title":"Disseminated leishmaniasis by leishmania viannia subgenus: A series of 18 cases in southeastern Brazil","volume":"3","author":"Vernal","year":"2016","journal-title":"Open Forum Infect. Dis."},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2021.685296","article-title":"Mechanisms of immunopathogenesis in cutaneous leishmaniasis and post kala-azar dermal leishmaniasis (PKDL)","volume":"11","author":"Volpedo","year":"2021","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"B55","unstructured":"Leishmaniasis"}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.956112\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,9]],"date-time":"2022-08-09T18:07:00Z","timestamp":1660068420000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.956112\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,9]]},"references-count":55,"alternative-id":["10.3389\/fcimb.2022.956112"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2022.956112","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,9]]},"article-number":"956112"}}