{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T14:13:39Z","timestamp":1790345619562,"version":"4.1.0"},"reference-count":69,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,12,16]],"date-time":"2021-12-16T00:00:00Z","timestamp":1639612800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["WT106203"],"award-info":[{"award-number":["WT106203"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["G1000230"],"award-info":[{"award-number":["G1000230"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Increasing evidence suggests that in hosts infected with parasites of the\n                    <jats:italic>Leishmania donovani<\/jats:italic>\n                    complex, transmission of infection to the sand fly vector is linked to parasite repositories in the host skin. However, a detailed understanding of the dispersal (the mechanism of spread) and dispersion (the observed state of spread) of these obligatory-intracellular parasites and their host phagocytes in the skin is lacking. Using endogenously fluorescent parasites as a proxy, we apply image analysis combined with spatial point pattern models borrowed from ecology to characterize dispersion of parasitized myeloid cells (including Man\n                    <jats:sup>R+<\/jats:sup>\n                    and CD11c\n                    <jats:sup>+<\/jats:sup>\n                    cells) and predict dispersal mechanisms in a previously described immunodeficient model of\n                    <jats:italic>L. donovani<\/jats:italic>\n                    infection. Our results suggest that after initial seeding of infection in the skin, heavily parasite-infected myeloid cells are found in patches that resemble innate granulomas. Spread of parasites from these initial patches subsequently occurs through infection of recruited myeloid cells, ultimately leading to self-propagating networks of patch clusters. This combination of imaging and ecological pattern analysis to identify mechanisms driving the skin parasite landscape offers new perspectives on myeloid cell behavior following parasitism by\n                    <jats:italic>L. donovani<\/jats:italic>\n                    and may also be applicable to elucidating the behavior of other intracellular tissue-resident pathogens and their host cells.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2021.795554","type":"journal-article","created":{"date-parts":[[2021,12,16]],"date-time":"2021-12-16T06:13:56Z","timestamp":1639635236000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Spatial Point Pattern Analysis Identifies Mechanisms Shaping the Skin Parasite Landscape in Leishmania donovani Infection"],"prefix":"10.3389","volume":"12","author":[{"given":"Johannes S. P.","family":"Doehl","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Ashwin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Najmeeyah","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey","family":"Romano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Carmichael","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon W.","family":"Pitchford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M.","family":"Kaye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,12,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-ento-120811-153557","article-title":"Biology of Phlebotomine Sand Flies as Vectors of Disease Agents","volume":"58","author":"Ready","year":"2013","journal-title":"Annu Rev Entomology"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-018-0154-2","article-title":"Revising Leishmania's Life Cycle","volume":"3","author":"Bates","year":"2018","journal-title":"Nat Microbiol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)61689-4","article-title":"Disability-Adjusted Life Years (DALYs) for 291 Diseases and Injuries in 21 Regions, 1990\u20132010: A Systematic Analysis for the Global Burden of Disease Study 2010","volume":"380","author":"Murray","year":"2012","journal-title":"Lancet"},{"key":"B4","doi-asserted-by":"publisher","first-page":"e35671","DOI":"10.1371\/journal.pone.0035671","article-title":"Leishmaniasis Worldwide and Global Estimates of Its Incidence","volume":"7","author":"Alvar","year":"2012","journal-title":"PloS One"},{"key":"B5","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1186\/s13071-016-1553-y","article-title":"Possibilities and Challenges for Developing a Successful Vaccine for Leishmaniasis","volume":"9","author":"Srivastava","year":"2016","journal-title":"Parasites Vectors"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/S1995-7645(12)60084-4","article-title":"Leishmaniasis: Current Status of Available Drugs and New Potential Drug Targets","volume":"5","author":"Singh","year":"2012","journal-title":"Asian Pacific J Trop Med"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.2147\/CLEP.S44267","article-title":"Epidemiology of Visceral Leishmaniasis","volume":"6","author":"Ready","year":"2014","journal-title":"Clin Epidemiol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"e3288","DOI":"10.1371\/journal.pntd.0003288","article-title":"Quantifying the Contribution of Hosts With Different Parasite Concentrations to the Transmission of Visceral Leishmaniasis in Ethiopia","volume":"8","author":"Miller","year":"2014","journal-title":"PloS Neglected Trop Dis"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/S2666-5247(20)30166-X","article-title":"Xenodiagnosis to Evaluate the Infectiousness of Humans to Sandflies in an Area Endemic for Visceral Leishmaniasis in Bihar, India: A Transmission-Dynamics Study","volume":"2","author":"Singh","year":"2021","journal-title":"Lancet Microbe"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpara.2017.02.005","article-title":"Minimally Invasive Microbiopsies: A Novel Sampling Method for Identifying Asymptomatic, Potentially Infectious Carriers of Leishmania Donovani","volume":"47","author":"Kirstein","year":"2017","journal-title":"Int J Parasitol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1038\/s41467-017-00103-8","article-title":"Skin Parasite Landscape Determines Host Infectiousness in Visceral Leishmaniasis","volume":"8","author":"Doehl","year":"2017","journal-title":"Nat Commun"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jix115","article-title":"Increased Transmissibility of Leishmania Donovani From the Mammalian Host to Vector Sand Flies After Multiple Exposures to Sand Fly Bites","volume":"215","author":"Valverde","year":"2017","journal-title":"J Infect Dis"},{"key":"B13","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1016\/j.vetpar.2013.03.017","article-title":"Asymptomatic Dogs Are Highly Competent to Transmit Leishmania (Leishmania) Infantum Chagasi to the Natural Vector","volume":"196","author":"Laurenti","year":"2013","journal-title":"Vet Parasitol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cix245","article-title":"Infectivity of Post-Kala-Azar Dermal Leishmaniasis Patients to Sand Flies: Revisiting a Proof of Concept in the Context of the Kala-Azar Elimination Program in the Indian Subcontinent","volume":"65","author":"Molina","year":"2017","journal-title":"Clin Infect Dis"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciy891","article-title":"Quantifying the Infectiousness of Post-Kala-Azar Dermal Leishmaniasis Toward Sand Flies","volume":"69","author":"Mondal","year":"2019","journal-title":"Clin Infect Dis"},{"key":"B16","doi-asserted-by":"crossref","DOI":"10.1201\/b19708","volume-title":"Spatial Point Patterns: Methodology and Applications With R","author":"Baddeley","year":"2015"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1037","article-title":"Improved Monomeric Red, Orange and Yellow Fluorescent Proteins Derived From Discosoma Sp. Red Fluorescent Protein","volume":"22","author":"Shaner","year":"2004","journal-title":"Nat Biotechnol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"e1000805","DOI":"10.1371\/journal.ppat.1000805","article-title":"Dynamic Imaging of Experimental Leishmania Donovani-Induced Hepatic Granulomas Detects Kupffer Cell-Restricted Antigen Presentation to Antigen-Specific CD8+ T Cells","volume":"6","author":"Beattie","year":"2010","journal-title":"PloS Pathog"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.exppara.2011.08.010","article-title":"Real-Time PCR to Assess the Leishmania Load in Lutzomyia Longipalpis Sand Flies: Screening of Target Genes and Assessment of Quantitative Methods","volume":"129","author":"Bezerra-Vasconcelos","year":"2011","journal-title":"Exp Parasitology"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1369\/0022155414539963","article-title":"Revisiting Fixation and Embedding Techniques for Optimal Detection of Dendritic Cell Subsets in Tissues","volume":"62","author":"Accart","year":"2014","journal-title":"J Histochem Cytochem"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1172\/JCI41281","article-title":"Inhibition of Receptor Tyrosine Kinases Restores Immunocompetence and Improves Immune-Dependent Chemotherapy Against Experimental Leishmaniasis in Mice","volume":"120","author":"Dalton","year":"2010","journal-title":"J Clin Invest"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An Open-Source Platform for Biological-Image Analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat Methods"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.jphotobiol.2016.03.047","article-title":"The Optical Properties of Mouse Skin in the Visible and Near Infrared Spectral Regions","volume":"160","author":"Sabino","year":"2016","journal-title":"J Photochem Photobiol B"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.6688\/JISE.2001.17.5.1","article-title":"A Fast Algorithm for Multilevel Thresholding","volume":"17","author":"Liao","year":"2001","journal-title":"J Inf Sci Eng"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.2217\/fmb.14.103","article-title":"Leishmania and the Macrophage: A Multifaceted Interaction","volume":"10","author":"Podinovskaia","year":"2015","journal-title":"Future Microbiol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/npg.els.0003359","article-title":"Cell Size Control","author":"Guertin","year":"2006","journal-title":"Encyclopedia Life Sci"},{"key":"B27","doi-asserted-by":"publisher","first-page":"e1","DOI":"10.5334\/jors.bn","article-title":"ImageJ Plugin for Analysis of Porous Scaffolds Used in Tissue Engineering","volume":"3","author":"Haeri","year":"2015","journal-title":"J Open Res Software"},{"key":"B28","unstructured":"TupperB\n          Graph Plugin and Demo Nih2010"},{"key":"B29","volume-title":"IBM SPSS Statistics for Windows. 25.0","author":"Corp","year":"2017"},{"key":"B30","volume-title":"RStudio: Integrated Development for R. 1.4","author":"Boston","year":"2020"},{"key":"B31","volume-title":"R: A Language and Environment for Statistical Computing. 4.0.2","author":"Core Team","year":"2020"},{"key":"B32","volume-title":"Abind: Combine Multidimensional Arrays. 1.4-5","author":"Plate","year":"2016"},{"key":"B33","volume-title":"Deldir: Delaunay Triangulation and Dirichlet (Voronoi) Tessellation. 0.1-29","author":"Turner","year":"2020"},{"key":"B34","volume-title":"E1071: Misc Functions of the Department of Statistics","author":"Meyer","year":"2020"},{"key":"B35","volume-title":"Ggpubr: 'Ggplot2' Based Publication Ready Plots. 0.4.0","author":"Kassambara","year":"2020"},{"key":"B36","volume-title":"Goftest: Classical Goodness-Of-Fit Tests for Univariate Distributions. 1.2-2","author":"Faraway","year":"2019"},{"key":"B37","volume-title":"Polyclip: Polygon Clipping. 1.10-0","author":"Johnson","year":"2019"},{"key":"B38","volume-title":"RandomFields: Simulation and Analysis of Random Fields","author":"Schlather","year":"2020"},{"key":"B39","volume-title":"Rlist: A Toolbox for Non-Tabular Data Manipulation","author":"Ren","year":"2016"},{"key":"B40","volume-title":"Rms.Gof: Root-Mean-Square Goodness-of-Fit Test for Simple Null Hypothesis","author":"Mukherji","year":"2013"},{"key":"B41","volume-title":"Scales: Scale Functions for Visualization","author":"Wickham","year":"2020"},{"key":"B42","doi-asserted-by":"crossref","first-page":"405 p","DOI":"10.1007\/978-1-4614-7618-4","volume-title":"Applied Spatial Data Analysis With R","author":"Bivand","year":"2013"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1002\/sim.7577","article-title":"Tutorial on Kernel Estimation of Continuous Spatial and Spatiotemporal Relative Risk","volume":"37","author":"Davies","year":"2018","journal-title":"Stat Med"},{"key":"B44","volume-title":"Spatstat.Utils: Utility Functions for 'Spatstat'. 1.17-0","author":"Baddeley","year":"2020"},{"key":"B45","volume-title":"Tensor: Tensor Product of Arrays. 1.5","author":"Rougier","year":"2012"},{"key":"B46","doi-asserted-by":"publisher","first-page":"1686","DOI":"10.21105\/joss.01686","article-title":"Welcome to the Tidyverse","volume":"4","author":"Wickham","year":"2019","journal-title":"J Open Source Software"},{"key":"B47","doi-asserted-by":"publisher","first-page":"e0155249","DOI":"10.1371\/journal.pone.0155249","article-title":"Measuring Spatial Dependence for Infectious Disease Epidemiology","volume":"11","author":"Lessler","year":"2016","journal-title":"PloS One"},{"key":"B48","first-page":"263","volume-title":"Arrangement of Objects. Statistical Analysis of Microstructures in Materials Science","author":"Ohser","year":"2000"},{"key":"B49","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1111\/j.2517-6161.1977.tb01615.x","article-title":"Modeling Spatial Patterns","volume":"39","author":"Ripley","year":"1977","journal-title":"J Roy Stat Soc B Met"},{"key":"B50","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1111\/cgf.12540","article-title":"A Biophysically-Based Model of the Optical Properties of Skin Aging","volume":"34","author":"Iglesias-Guitian","year":"2015","journal-title":"Comput Graphics Forum"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1111\/j.0022-202X.2004.23427.x","article-title":"Macrophages and Dendritic Cells Constitute a Major Subpopulation of Cells in the Mouse Dermis","volume":"123","author":"Dupasquier","year":"2004","journal-title":"J Invest Dermatol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20171389","article-title":"Mannose Receptor High, M2 Dermal Macrophages Mediate Nonhealing Leishmania Major Infection in a Th1 Immune Environment","volume":"215","author":"Lee","year":"2018","journal-title":"J Exp Med"},{"key":"B53","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1146\/annurev-immunol-020711-074950","article-title":"The Dendritic Cell Lineage: Ontogeny and Function of Dendritic Cells and Their Subsets in the Steady State and the Inflamed Setting","volume":"31","author":"Merad","year":"2013","journal-title":"Annu Rev Immunol"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.03071","article-title":"IRF-5 Expression in Myeloid Cells Is Required for Splenomegaly in L. Donovani Infected Mice","volume":"10","author":"Mai","year":"2019","journal-title":"Front Immunol"},{"key":"B55","volume-title":"Fundamental Statistics for Social Research","author":"Duncan","year":"1997"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2012.00083","article-title":"The Early Interaction of Leishmania With Macrophages and Dendritic Cells and Its Influence on the Host Immune Response","volume":"2","author":"Liu","year":"2012","journal-title":"Front Cell Infect Microbiol"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2013.481","article-title":"A Three-Dimensional Atlas of Human Dermal Leukocytes, Lymphatics, and Blood Vessels","volume":"134","author":"Wang","year":"2014","journal-title":"J Invest Dermatol"},{"key":"B58","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1038\/jid.2014.289","article-title":"The Skin Immune Atlas: Three-Dimensional Analysis of Cutaneous Leukocyte Subsets by Multiphoton Microscopy","volume":"135","author":"Tong","year":"2015","journal-title":"J Invest Dermatol"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.15251","article-title":"Pivotal Role for Skin Transendothelial Radio-Resistant Anti-Inflammatory Macrophages in Tissue Repair","author":"Barreiro","year":"2016","journal-title":"Elife"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2018.00883","article-title":"Leishmania Hijacks Myeloid Cells for Immune Escape","volume":"9","author":"Martinez-Lopez","year":"2018","journal-title":"Front Microbiol"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2007.12.010","article-title":"Macrophage and T Cell Dynamics During the Development and Disintegration of Mycobacterial Granulomas","volume":"28","author":"Egen","year":"2008","journal-title":"Immunity"},{"key":"B62","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1016\/S1074-7613(02)00475-2","article-title":"Real-Time Visualization of Mycobacterium-Macrophage Interactions Leading to Initiation of Granuloma Formation in Zebrafish Embryos","volume":"17","author":"Davis","year":"2002","journal-title":"Immunity"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2608","article-title":"Leishmaniasis: Complexity at the Host-Pathogen Interface","volume":"9","author":"Kaye","year":"2011","journal-title":"Nat Rev Microbiol"},{"key":"B64","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.cell.2008.11.014","article-title":"The Role of the Granuloma in Expansion and Dissemination of Early Tuberculous Infection","volume":"136","author":"Davis","year":"2009","journal-title":"Cell"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.177.12.8476","article-title":"Structurally Distinct Membrane Nanotubes Between Human Macrophages Support Long-Distance Vesicular Traffic or Surfing of Bacteria","volume":"177","author":"Onfelt","year":"2006","journal-title":"J Immunol"},{"key":"B66","doi-asserted-by":"publisher","first-page":"e1007015","DOI":"10.1371\/journal.ppat.1007015","article-title":"Direct Cell-to-Cell Transmission of Respiratory Viruses: The Fast Lanes","volume":"14","author":"Cifuentes-Munoz","year":"2018","journal-title":"PloS Pathog"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00260","article-title":"Mechanisms for Cell-To-Cell Transmission of HIV-1","volume":"9","author":"Bracq","year":"2018","journal-title":"Front Immunol"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1619265114","article-title":"Continual Renewal and Replication of Persistent Leishmania Major Parasites in Concomitantly Immune Hosts","volume":"114","author":"Mandell","year":"2017","journal-title":"Proc Natl Acad Sci USA"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1111\/imcb.12394","article-title":"Immunometabolism of Leishmania Granulomas","volume":"98","author":"Saunders","year":"2020","journal-title":"Immunol Cell Biol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.795554\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,16]],"date-time":"2021-12-16T06:14:15Z","timestamp":1639635255000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.795554\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,16]]},"references-count":69,"alternative-id":["10.3389\/fimmu.2021.795554"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.795554","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.05.07.443107","asserted-by":"object"}]},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,16]]},"article-number":"795554"}}