{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T14:13:35Z","timestamp":1790345615854,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.pntd.0012363","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,11,20]],"date-time":"2024-11-20T00:00:00Z","timestamp":1732060800000}}],"reference-count":50,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2024,11,8]],"date-time":"2024-11-08T00:00:00Z","timestamp":1731024000000},"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 AI171971"],"award-info":[{"award-number":["R01 AI171971"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["T32AI007260"],"award-info":[{"award-number":["T32AI007260"]}],"id":[{"id":"10.13039\/100006492","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>Dogs represent the primary reservoir for <jats:italic>Leishmania infantum<\/jats:italic> human visceral leishmaniasis (VL) transmitted through phlebotomine sand flies. Public health initiatives targeting zoonotic VL commonly focus on dogs with severe clinical disease, often in renal failure, as they have previously been considered the most infectious to sand flies. However, more recent studies suggest that dogs with mild to moderate clinical disease may be more infectious than dogs with severe disease. The mechanisms of infectiousness from the skin and how this relates to transmissibility as clinical disease progresses is largely unknown. We evaluated dermal parasitism in dogs naturally infected with <jats:italic>L<\/jats:italic>. <jats:italic>infantum<\/jats:italic> across the four LeishVet clinical stages of disease. We establish the relationship between dermal parasitism, critical, frequently observed, clinical parameters such as anemia and creatinine, and infectiousness. Using RNAscope and confocal microscopy, we found notable variation in dermal parasitism between dogs, particularly within LeishVet II. Dogs with mild disease had significantly less dermal inflammation and parasitism than dogs with moderate or severe disease. We found significant correlations between anemia, dermal parasitism, and infectiousness (p = 0.0098, r = -0.4798; p = 0.0022, r = -0.8364). In contrast, we did not observe significant correlation between creatinine, a measure of renal function, and dermal parasitism or infectiousness. Host blood cell abnormalities, including anemia, correlate with infectiousness to sand flies. As these signs of disease often appear earlier in the course of disease, this indicates that classical measures of disease severity do not necessarily correlate with infectiousness or epidemiological importance. Public health initiatives attempting to break the zoonotic cycle of <jats:italic>L<\/jats:italic>. <jats:italic>infantum<\/jats:italic> infection should therefore focus on preventing transmission from infectious, anemic dogs, and not those with the most severe disease.<\/jats:p>","DOI":"10.1371\/journal.pntd.0012363","type":"journal-article","created":{"date-parts":[[2024,11,8]],"date-time":"2024-11-08T18:40:51Z","timestamp":1731091251000},"page":"e0012363","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Clinical anemia predicts dermal parasitism and reservoir infectiousness during progressive visceral leishmaniosis"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8136-0280","authenticated-orcid":true,"given":"Max C.","family":"Waugh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen I.","family":"Cyndari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom J.","family":"Lynch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soomin","family":"Koh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferney","family":"Henao-Ceballos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob J.","family":"Oleson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M.","family":"Kaye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine A.","family":"Petersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,11,8]]},"reference":[{"issue":"1","key":"pntd.0012363.ref001","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1128\/CMR.00067-12","article-title":"Transmission and epidemiology of zoonotic protozoal diseases of companion animals","volume":"26","author":"KJ Esch","year":"2013","journal-title":"Clin Microbiol Rev"},{"key":"pntd.0012363.ref002","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1186\/1756-3305-4-86","article-title":"LeishVet guidelines for the practical management of canine leishmaniosis.","volume":"4","author":"L Solano-Gallego","year":"2011","journal-title":"Parasit Vectors."},{"key":"pntd.0012363.ref003","doi-asserted-by":"crossref","first-page":"795554","DOI":"10.3389\/fimmu.2021.795554","article-title":"Spatial Point Pattern Analysis Identifies Mechanisms Shaping the Skin Parasite Landscape in Leishmania donovani Infection.","volume":"12","author":"JSP Doehl","year":"2021","journal-title":"Front Immunol"},{"issue":"1","key":"pntd.0012363.ref004","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/s41467-017-00103-8","article-title":"Skin parasite landscape determines host infectiousness in visceral leishmaniasis.","volume":"8","author":"JSP Doehl","year":"2017","journal-title":"Nat Commun."},{"issue":"3","key":"pntd.0012363.ref005","doi-asserted-by":"crossref","first-page":"e0007193","DOI":"10.1371\/journal.pntd.0007193","article-title":"Insecticide-impregnated dog collars reduce infantile clinical visceral leishmaniasis under operational conditions in NW Iran: A community-wide cluster randomised trial.","volume":"13","author":"O Courtenay","year":"2019","journal-title":"PLoS Negl Trop Dis"},{"key":"pntd.0012363.ref006","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.rvsc.2020.02.004","article-title":"The balancing act: Immunology of leishmaniosis","volume":"130","author":"AJ Toepp","year":"2020","journal-title":"Res Vet Sci"},{"issue":"2","key":"pntd.0012363.ref007","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1177\/0300985814521248","article-title":"Pathologic mechanisms underlying the clinical findings in canine leishmaniasis due to Leishmania infantum\/chagasi","volume":"51","author":"AF Koutinas","year":"2014","journal-title":"Vet Pathol"},{"issue":"8","key":"pntd.0012363.ref008","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1016\/j.ajpath.2015.04.017","article-title":"Activation of autophagy and nucleotide-binding domain leucine-rich repeat-containing-like receptor family, pyrin domain-containing 3 inflammasome during Leishmania infantum-associated glomerulonephritis","volume":"185","author":"KJ Esch","year":"2015","journal-title":"Am J Pathol"},{"issue":"8","key":"pntd.0012363.ref009","first-page":"469","article-title":"Circulating immune complexes and renal function in canine leishmaniasis.","volume":"43","author":"R Lopez","year":"1996","journal-title":"Zentralbl Veterinarmed B"},{"issue":"128","key":"pntd.0012363.ref010","article-title":"Prognostic Factors and Life Expectancy in Canine Leishmaniosis.","volume":"7","author":"M Aires Pereira","year":"2020","journal-title":"Veterinary Sciences."},{"issue":"4","key":"pntd.0012363.ref011","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1111\/j.1939-1676.2008.0129.x","article-title":"Factors associated with the occurrence of epistaxis in natural canine leishmaniasis (Leishmania infantum).","volume":"22","author":"TA Petanides","year":"2008","journal-title":"J Vet Intern Med"},{"issue":"2","key":"pntd.0012363.ref012","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1007\/s00436-016-5313-x","article-title":"Prevalence, severity, and pathogeneses of anemia in visceral leishmaniasis","volume":"116","author":"Y Goto","year":"2017","journal-title":"Parasitol Res"},{"key":"pntd.0012363.ref013","doi-asserted-by":"crossref","first-page":"1261074","DOI":"10.3389\/fcimb.2023.1261074","article-title":"Elucidating the role played by bone marrow in visceral leishmaniasis","volume":"13","author":"PST Veras","year":"2023","journal-title":"Front Cell Infect Microbiol"},{"issue":"8","key":"pntd.0012363.ref014","doi-asserted-by":"crossref","DOI":"10.3390\/microorganisms9081618","article-title":"Hematological Changes in Dogs with Visceral Leishmaniasis Are Associated with Increased IFN-gamma and TNF Gene Expression Levels in the Bone Marrow","volume":"9","author":"V Almeida","year":"2021","journal-title":"Microorganisms"},{"issue":"20","key":"pntd.0012363.ref015","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1136\/vr.158.20.690","article-title":"Pathological changes in the bone marrow of dogs with leishmaniosis","volume":"158","author":"V Foglia Manzillo","year":"2006","journal-title":"Vet Rec"},{"issue":"12","key":"pntd.0012363.ref016","doi-asserted-by":"crossref","first-page":"e82947","DOI":"10.1371\/journal.pone.0082947","article-title":"Clinical forms of canine visceral Leishmaniasis in naturally Leishmania infantum-infected dogs and related myelogram and hemogram changes.","volume":"8","author":"C Nicolato Rde","year":"2013","journal-title":"PLoS One"},{"key":"pntd.0012363.ref017","doi-asserted-by":"crossref","first-page":"541571","DOI":"10.1155\/2012\/541571","article-title":"Cytokine and Phenotypic Cell Profiles of Leishmania infantum Infection in the Dog","volume":"2012","author":"C Maia","year":"2012","journal-title":"J Trop Med"},{"issue":"3","key":"pntd.0012363.ref018","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/j.tvjl.2006.11.006","article-title":"Canine visceral leishmaniasis: relationships between clinical status, humoral immune response, haematology and Lutzomyia (Lutzomyia) longipalpis infectivity.","volume":"174","author":"AP da Costa-Val","year":"2007","journal-title":"Vet J."},{"issue":"9","key":"pntd.0012363.ref019","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1086\/344312","article-title":"Infectiousness in a cohort of brazilian dogs: why culling fails to control visceral leishmaniasis in areas of high transmission","volume":"186","author":"O Courtenay","year":"2002","journal-title":"J Infect Dis"},{"issue":"1\u20132","key":"pntd.0012363.ref020","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.vetpar.2007.03.004","article-title":"Infectivity of seropositive dogs, showing different clinical forms of leishmaniasis, to Lutzomyia longipalpis phlebotomine sand flies","volume":"147","author":"EM Michalsky","year":"2007","journal-title":"Vet Parasitol"},{"key":"pntd.0012363.ref021","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.vetpar.2016.10.004","article-title":"Parasite load in the blood and skin of dogs naturally infected by Leishmania infantum is correlated with their capacity to infect sand fly vectors","volume":"229","author":"LS Borja","year":"2016","journal-title":"Vet Parasitol"},{"key":"pntd.0012363.ref022","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/0035-9203(94)90446-4","article-title":"Infectivity of dogs naturally infected with Leishmania infantum to colonized Phlebotomus perniciosus","volume":"88","author":"R Molina","year":"1994","journal-title":"Transactions of the Royal Society of Tropical Medicine and Hygiene"},{"key":"pntd.0012363.ref023","year":"2024","journal-title":"LeishVet. Canine Leishmaniosis: A brief for the practicing veterinarian"},{"issue":"10","key":"pntd.0012363.ref024","doi-asserted-by":"crossref","first-page":"e0009366","DOI":"10.1371\/journal.pntd.0009366","article-title":"Leishmania infantum xenodiagnosis from vertically infected dogs reveals significant skin tropism.","volume":"15","author":"BM Scorza","year":"2021","journal-title":"PLoS Negl Trop Dis"},{"issue":"3","key":"pntd.0012363.ref025","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1590\/2176-9451.20.3.013-015.ebo","article-title":"CONSORT: when and how to use it.","volume":"20","author":"SG Falci","year":"2015","journal-title":"Dental Press J Orthod"},{"issue":"3","key":"pntd.0012363.ref026","doi-asserted-by":"crossref","first-page":"440","DOI":"10.3201\/eid1203.050811","article-title":"Canine visceral leishmaniasis, United States and Canada, 2000\u20132003","volume":"12","author":"ZH Duprey","year":"2006","journal-title":"Emerg Infect Dis"},{"issue":"44","key":"pntd.0012363.ref027","doi-asserted-by":"crossref","first-page":"5225","DOI":"10.1016\/j.vaccine.2016.09.016","article-title":"Recovery of antigen-specific T cell responses from dogs infected with Leishmania (L.) infantum by use of vaccine associated TLR-agonist adjuvant","volume":"34","author":"RG Schaut","year":"2016","journal-title":"Vaccine"},{"issue":"6","key":"pntd.0012363.ref028","first-page":"1361","article-title":"Leishmania major-like antigen for specific and sensitive serodiagnosis of human and canine visceral leishmaniasis","volume":"9","author":"R Barbosa-De-Deus","year":"2002","journal-title":"Clin Diagn Lab Immunol"},{"issue":"3\u20134","key":"pntd.0012363.ref029","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.vetimm.2006.02.001","article-title":"Isotype patterns of immunoglobulins: hallmarks for clinical status and tissue parasite density in Brazilian dogs naturally infected by Leishmania (Leishmania) chagasi.","volume":"112","author":"AB Reis","year":"2006","journal-title":"Vet Immunol Immunopathol"},{"issue":"1","key":"pntd.0012363.ref030","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1007\/s00253-016-7925-6","article-title":"Semi-quantitative measurement of asymptomatic L. infantum infection and symptomatic visceral leishmaniasis in dogs using Dual-Path Platform CVL","volume":"101","author":"M Larson","year":"2017","journal-title":"Appl Microbiol Biotechnol"},{"key":"pntd.0012363.ref031","volume-title":"RNAscope Multiplex Fluorescent Reagent Kit v2 With Sample Preparation and Pretreatment [User Manual].","author":"I. Advanced Cell Diagnostics","year":"2022"},{"issue":"7","key":"pntd.0012363.ref032","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: an open-source platform for biological-image analysis.","volume":"9","author":"J Schindelin","year":"2012","journal-title":"Nat Methods."},{"issue":"1","key":"pntd.0012363.ref033","doi-asserted-by":"crossref","first-page":"16878","DOI":"10.1038\/s41598-017-17204-5","article-title":"QuPath: Open source software for digital pathology image analysis.","volume":"7","author":"P Bankhead","year":"2017","journal-title":"Sci Rep."},{"issue":"1","key":"pntd.0012363.ref034","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/S0021-9975(03)00063-X","article-title":"Histological and immunohistochemical study of clinically normal skin of Leishmania infantum-infected dogs","volume":"130","author":"L Solano-Gallego","year":"2004","journal-title":"J Comp Pathol"},{"issue":"1","key":"pntd.0012363.ref035","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1186\/s13071-017-2051-6","article-title":"Histological and parasitological distinctive findings in clinically-lesioned and normal-looking skin of dogs with different clinical stages of leishmaniosis.","volume":"10","author":"L Ordeix","year":"2017","journal-title":"Parasit Vectors."},{"key":"pntd.0012363.ref036","article-title":"Diagnosing, Staging, and Treating Chronic Kidney Disease in Dogs and Cats.","author":"IRI Society","year":"2023"},{"key":"pntd.0012363.ref037","first-page":"376","volume-title":"Jubb, Kennedy, and Palmer\u2019s Pathology of Domestic Animals. 2.","author":"RE Cianciolo","year":"2015","edition":"6"},{"key":"pntd.0012363.ref038","doi-asserted-by":"crossref","first-page":"675573","DOI":"10.3389\/fmed.2021.675573","article-title":"Uremia-Associated Immunological Aging and Severity of COVID-19 Infection.","volume":"8","author":"MGH Betjes","year":"2021","journal-title":"Front Med (Lausanne)."},{"issue":"7","key":"pntd.0012363.ref039","doi-asserted-by":"crossref","DOI":"10.3390\/toxins12070439","article-title":"Immune Dysfunction in Uremia 2020.","volume":"12","author":"G. Cohen","year":"2020","journal-title":"Toxins (Basel)."},{"issue":"1","key":"pntd.0012363.ref040","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1053\/j.jrn.2011.10.020","article-title":"Effect of uremia on structure and function of immune system.","volume":"22","author":"ND Vaziri","year":"2012","journal-title":"J Ren Nutr."},{"key":"pntd.0012363.ref041","first-page":"12","article-title":"Monocytes in Uremia","author":"M Girndt","year":"2020","journal-title":"Toxins (Basel)"},{"key":"pntd.0012363.ref042","first-page":"143","volume-title":"Schalm\u2019s veterinary hematology","author":"H Tvedten","year":"2000","edition":"5"},{"issue":"2\u20133","key":"pntd.0012363.ref043","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.jcpa.2006.06.005","article-title":"Relationship between canine visceral leishmaniosis and the Leishmania (Leishmania) chagasi burden in dermal inflammatory foci.","volume":"135","author":"RC Giunchetti","year":"2006","journal-title":"J Comp Pathol"},{"key":"pntd.0012363.ref044","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.vetimm.2017.06.007","article-title":"Phenotypic heterogeneity of peripheral monocytes in healthy dogs","volume":"190","author":"N Gibbons","year":"2017","journal-title":"Vet Immunol Immunopathol"},{"issue":"6","key":"pntd.0012363.ref045","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1007\/s10875-010-9447-9","article-title":"Characterization of canine dendritic cells in healthy, atopic, and non-allergic inflamed skin","volume":"30","author":"ME Ricklin","year":"2010","journal-title":"J Clin Immunol"},{"issue":"9","key":"pntd.0012363.ref046","doi-asserted-by":"crossref","first-page":"113097","DOI":"10.1016\/j.celrep.2023.113097","article-title":"Dual-scRNA-seq analysis reveals rare and uncommon parasitized cell populations in chronic L. donovani infection","volume":"42","author":"K Karagiannis","year":"2023","journal-title":"Cell Rep"},{"issue":"9","key":"pntd.0012363.ref047","article-title":"Immune disorders in dogs with chronic kidney disease: Review.","volume":"16","author":"Souza APd Sousa GRd","year":"2022","journal-title":"PUBVET"},{"issue":"16","key":"pntd.0012363.ref048","doi-asserted-by":"crossref","first-page":"2479","DOI":"10.1182\/blood-2014-04-568451","article-title":"Impact of interferon-gamma on hematopoiesis","volume":"124","author":"AM de Bruin","year":"2014","journal-title":"Blood"},{"issue":"9","key":"pntd.0012363.ref049","first-page":"928","article-title":"Tumor necrosis factor-alpha and hematopoietic progenitors: effects of tumor necrosis factor on the growth of erythroid progenitors CFU-E and BFU-E and the hematopoietic cell lines K562, HL60, and HEL cells","volume":"15","author":"GD Roodman","year":"1987","journal-title":"Exp Hematol"},{"issue":"10","key":"pntd.0012363.ref050","doi-asserted-by":"crossref","first-page":"4149","DOI":"10.1182\/blood.V87.10.4149.bloodjournal87104149","article-title":"Interferon-gamma constitutively expressed in the stromal microenvironment of human marrow cultures mediates potent hematopoietic inhibition","volume":"87","author":"C Selleri","year":"1996","journal-title":"Blood"}],"updated-by":[{"DOI":"10.1371\/journal.pntd.0012363","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,11,20]],"date-time":"2024-11-20T00:00:00Z","timestamp":1732060800000}}],"container-title":["PLOS Neglected Tropical Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0012363","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,20]],"date-time":"2024-11-20T18:41:35Z","timestamp":1732128095000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0012363"}},"subtitle":[],"editor":[{"given":"Johan","family":"Van Weyenbergh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,11,8]]},"references-count":50,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2024,11,8]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pntd.0012363","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pntd.0012363","asserted-by":"object"}]},"ISSN":["1935-2735"],"issn-type":[{"value":"1935-2735","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,8]]}}}