{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:36:06Z","timestamp":1790775366183,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.pntd.0012803","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T00:00:00Z","timestamp":1736208000000}}],"reference-count":52,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T00:00:00Z","timestamp":1735603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"name":"Division of Intramural research (DIR) of NIAID\/NIH"}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:p>Lymphatic filariasis (LF) is a neglected tropical disease affecting over 51 million people in 72 endemic countries. Causative agents of LF are mosquito-borne parasitic nematodes <jats:italic>Wuchereria bancrofti<\/jats:italic>, <jats:italic>Brugia malayi<\/jats:italic>, and <jats:italic>Brugia timori<\/jats:italic>. The adult parasites impact the integrity of lymphatic vessels and damage valves, leading to a remodeling of the lymphatic system and lymphatic dilation. Chronic infections can develop into severe clinical manifestations, primarily lymphedema, hydrocoele, and elephantiasis. Mechanistic studies on the underlying pathology due to the parasite are necessary to better manage human filariasis. Since parasite molecules, such as microRNAs (miRNAs), can be found in secreted extracellular vesicles (EVs) and are transported between parasite and host cells, we hypothesized that these could also play a role in the development of pathology in LF. In this study, we tested two <jats:italic>B. malayi<\/jats:italic> miRNAs previously detected <jats:italic>in vitro<\/jats:italic> in the culture media of microfilarial stages of worms. While one is <jats:italic>Brugia<\/jats:italic>-specific (bma-miR-5864) and the other nematode-specific (bma-miR-86), both miRNAs are secreted in high abundance. We first examined the <jats:italic>in vitro<\/jats:italic> response by transcriptomic profiling of human lymphatic endothelial cells to treatment with these miRNAs, which allowed us to identify genes involved in maintaining the integrity of the lymphatic endothelium. We then measured the effect of these miRNAs on the regulation of proteins necessary for cell integrity, demonstrating downregulation leading to a significant increase in the permeability of the endothelium monolayer. With this study we identify parasite miRNAs involved in undermining the integrity of endothelial cells, thus potentially contributing to the development of pathology. These findings could pave the way for a novel treatment strategy where the inhibition of parasite-secreted molecules could slow the progression of LF pathology. From a broader perspective, the miRNAs secreted by filarial parasites could potentially be used in the future for diagnosing and monitoring disease progression or treatment efficacy.<\/jats:p>","DOI":"10.1371\/journal.pntd.0012803","type":"journal-article","created":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T19:08:56Z","timestamp":1735672136000},"page":"e0012803","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["MicroRNAs secreted by the parasitic nematode Brugia malayi disrupt lymphatic endothelial cell integrity"],"prefix":"10.1371","volume":"18","author":[{"given":"Hailey","family":"Johnson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Banakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Chung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elodie","family":"Ghedin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2652-0787","authenticated-orcid":true,"given":"Denis","family":"Voronin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,12,31]]},"reference":[{"issue":"1","key":"pntd.0012803.ref001","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1186\/s13071-018-2616-z","article-title":"Economic evaluations of lymphatic filariasis interventions: a systematic review and research needs","volume":"11","author":"LM Gedge","year":"2018","journal-title":"Parasit Vectors"},{"key":"pntd.0012803.ref002","doi-asserted-by":"crossref","first-page":"1538","DOI":"10.12688\/gatesopenres.13065.1","article-title":"The roadmap towards elimination of lymphatic filariasis by 2030: insights from quantitative and mathematical modelling","volume":"3","author":"Group NTDMCLF","year":"2019","journal-title":"Gates Open Res"},{"issue":"2","key":"pntd.0012803.ref003","doi-asserted-by":"crossref","first-page":"E65","DOI":"10.1055\/a-0918-3678","article-title":"Review of dancing parasites in lymphatic filariasis","volume":"5","author":"CF Dietrich","year":"2019","journal-title":"Ultrasound Int Open"},{"issue":"12","key":"pntd.0012803.ref004","doi-asserted-by":"crossref","first-page":"e1000688","DOI":"10.1371\/journal.ppat.1000688","article-title":"Lymphangiogenesis and lymphatic remodeling induced by filarial parasites: implications for pathogenesis","volume":"5","author":"S Bennuru","year":"2009","journal-title":"PLoS Pathog"},{"issue":"5","key":"pntd.0012803.ref005","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1111\/micc.12031","article-title":"Lymphatic filariasis: perspectives on lymphatic remodeling and contractile dysfunction in filarial disease pathogenesis","volume":"20","author":"S Chakraborty","year":"2013","journal-title":"Microcirculation"},{"issue":"10","key":"pntd.0012803.ref006","doi-asserted-by":"crossref","first-page":"e0005631","DOI":"10.1371\/journal.pntd.0005631","article-title":"Lymphatic pathology in asymptomatic and symptomatic children with Wuchereria bancrofti infection in children from Odisha, India and its reversal with DEC and albendazole treatment","volume":"11","author":"SK Kar","year":"2017","journal-title":"PLoS Negl Trop Dis"},{"key":"pntd.0012803.ref007","first-page":"745","article-title":"The filariases.","volume-title":"Manson\u2019s tropical diseases","author":"PE Simonsen","year":"2024"},{"issue":"8","key":"pntd.0012803.ref008","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1111\/pim.12081","article-title":"Immunology of lymphatic filariasis","volume":"36","author":"S Babu","year":"2014","journal-title":"Parasite Immunol"},{"issue":"6","key":"pntd.0012803.ref009","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1179\/000349802125001348","article-title":"The histopathology of Bancroftian filariasis revisited: the role of the adult worm in the lymphatic-vessel disease","volume":"96","author":"J Figueredo-Silva","year":"2002","journal-title":"Ann Trop Med Parasitol"},{"issue":"2","key":"pntd.0012803.ref010","doi-asserted-by":"crossref","first-page":"128","DOI":"10.4103\/2229-5070.138544","article-title":"Lymphatic filariasis: a view at pathological diversity","volume":"4","author":"PB Mahalingashetti","year":"2014","journal-title":"Trop Parasitol"},{"issue":"5","key":"pntd.0012803.ref011","doi-asserted-by":"crossref","DOI":"10.1172\/JCI140853","article-title":"Tetracyclines improve experimental lymphatic filariasis pathology by disrupting interleukin-4 receptor-mediated lymphangiogenesis","volume":"131","author":"J Furlong-Silva","year":"2021","journal-title":"J Clin Invest"},{"key":"pntd.0012803.ref012","first-page":"104","article-title":"microRNAs in the lymphatic endothelium: master regulators of lineage plasticity and inflammation","volume":"8","author":"D Yee","year":"2017","journal-title":"Front Immunol"},{"key":"pntd.0012803.ref013","doi-asserted-by":"crossref","first-page":"402","DOI":"10.3389\/fendo.2018.00402","article-title":"Overview of MicroRNA biogenesis, mechanisms of actions, and circulation","volume":"9","author":"J O\u2019Brien","year":"2018","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"10","key":"pntd.0012803.ref014","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.pt.2015.06.009","article-title":"Exosomes and other extracellular vesicles: the new communicators in parasite infections","volume":"31","author":"G Coakley","year":"2015","journal-title":"Trends Parasitol"},{"key":"pntd.0012803.ref015","doi-asserted-by":"crossref","first-page":"106431","DOI":"10.1016\/j.actatropica.2022.106431","article-title":"miRNAs in the regulation of mTOR signaling and host immune responses: the case of Leishmania infections","volume":"231","author":"S Rashidi","year":"2022","journal-title":"Acta Trop"},{"issue":"1","key":"pntd.0012803.ref016","doi-asserted-by":"crossref","first-page":"e0008884","DOI":"10.1371\/journal.pntd.0008884","article-title":"Extracellular vesicles released from the filarial parasite Brugia malayi downregulate the host mTOR pathway","volume":"15","author":"A Ricciardi","year":"2021","journal-title":"PLoS Negl Trop Dis"},{"issue":"9","key":"pntd.0012803.ref017","doi-asserted-by":"crossref","first-page":"e0004069","DOI":"10.1371\/journal.pntd.0004069","article-title":"Release of small RNA-containing exosome-like vesicles from the human filarial parasite Brugia malayi","volume":"9","author":"M Zamanian","year":"2015","journal-title":"PLoS Negl Trop Dis"},{"issue":"1","key":"pntd.0012803.ref018","doi-asserted-by":"crossref","first-page":"R1","DOI":"10.1186\/gb-2003-5-1-r1","article-title":"MicroRNA targets in Drosophila","volume":"5","author":"AJ Enright","year":"2003","journal-title":"Genome Biol"},{"key":"pntd.0012803.ref019","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/1755-1536-4-21","article-title":"Plasma and cellular fibronectin: distinct and independent functions during tissue repair","volume":"4","author":"WS To","year":"2011","journal-title":"Fibrogenesis Tissue Repair"},{"issue":"9","key":"pntd.0012803.ref020","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1369\/0022155419851103","article-title":"Thrombospondin 1 and its diverse roles as a regulator of extracellular matrix in fibrotic disease","volume":"67","author":"JE Murphy-Ullrich","year":"2019","journal-title":"J Histochem Cytochem"},{"issue":"6","key":"pntd.0012803.ref021","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1111\/j.1469-7580.2010.01306.x","article-title":"Human microvascular lymphatic and blood endothelial cells produce fibrillin: deposition patterns and quantitative analysis","volume":"217","author":"A Rossi","year":"2010","journal-title":"J Anat"},{"key":"pntd.0012803.ref022","doi-asserted-by":"crossref","first-page":"909312","DOI":"10.3389\/fmolb.2022.909312","article-title":"Nematode microRNAs can individually regulate interferon regulatory factor 4 and mTOR in differentiating T helper 2 lymphocytes and modulate cytokine production in macrophages","volume":"9","author":"J Soichot","year":"2022","journal-title":"Front Mol Biosci"},{"key":"pntd.0012803.ref023","doi-asserted-by":"crossref","first-page":"812141","DOI":"10.3389\/fcimb.2021.812141","article-title":"Role of Fasciola hepatica small RNAs in the interaction with the mammalian host","volume":"11","author":"S Fontenla","year":"2021","journal-title":"Front Cell Infect Microbiol"},{"issue":"3","key":"pntd.0012803.ref024","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1645\/14-714.1","article-title":"Secretion of RNA-containing extracellular vesicles by the porcine whipworm, Trichuris suis","volume":"101","author":"EP Hansen","year":"2015","journal-title":"J Parasitol"},{"issue":"1","key":"pntd.0012803.ref025","doi-asserted-by":"crossref","first-page":"1578116","DOI":"10.1080\/20013078.2019.1578116","article-title":"Exploration of extracellular vesicles from Ascaris suum provides evidence of parasite-host cross talk","volume":"8","author":"EP Hansen","year":"2019","journal-title":"J Extracell Vesicles"},{"issue":"9","key":"pntd.0012803.ref026","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/j.ijpara.2020.05.005","article-title":"Uptake of Schistosoma mansoni extracellular vesicles by human endothelial and monocytic cell lines and impact on vascular endothelial cell gene expression","volume":"50","author":"DW Kifle","year":"2020","journal-title":"Int J Parasitol"},{"key":"pntd.0012803.ref027","doi-asserted-by":"crossref","first-page":"5488","DOI":"10.1038\/ncomms6488","article-title":"Exosomes secreted by nematode parasites transfer small RNAs to mammalian cells and modulate innate immunity","volume":"5","author":"AH Buck","year":"2014","journal-title":"Nat Commun"},{"issue":"11","key":"pntd.0012803.ref028","doi-asserted-by":"crossref","first-page":"e0007811","DOI":"10.1371\/journal.pntd.0007811","article-title":"Comparative analysis of small RNAs released by the filarial nematode Litomosoides sigmodontis in vitro and in vivo","volume":"13","author":"JF Quintana","year":"2019","journal-title":"PLoS Negl Trop Dis"},{"issue":"1","key":"pntd.0012803.ref029","doi-asserted-by":"crossref","first-page":"e47882","DOI":"10.15252\/embr.201947882","article-title":"Schistosomal extracellular vesicle-enclosed miRNAs modulate host T helper cell differentiation","volume":"21","author":"T Meningher","year":"2020","journal-title":"EMBO Rep"},{"issue":"7","key":"pntd.0012803.ref030","doi-asserted-by":"crossref","first-page":"e2971","DOI":"10.1371\/journal.pntd.0002971","article-title":"Detection of circulating parasite-derived microRNAs in filarial infections","volume":"8","author":"L Tritten","year":"2014","journal-title":"PLoS Negl Trop Dis"},{"issue":"4","key":"pntd.0012803.ref031","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1089\/lrb.2009.0022","article-title":"Lymphatics in human lymphatic filariasis: in vitro models of parasite-induced lymphatic remodeling","volume":"7","author":"S Bennuru","year":"2009","journal-title":"Lymphat Res Biol"},{"issue":"4","key":"pntd.0012803.ref032","doi-asserted-by":"crossref","first-page":"1685844","DOI":"10.1080\/21688370.2019.1685844","article-title":"Integrin-dependent regulation of the endothelial barrier","volume":"7","author":"FE Pulous","year":"2019","journal-title":"Tissue Barriers"},{"issue":"1","key":"pntd.0012803.ref033","doi-asserted-by":"crossref","first-page":"e1283385","DOI":"10.1080\/21688370.2017.1283385","article-title":"Helminths and intestinal barrier function","volume":"5","author":"DM McKay","year":"2017","journal-title":"Tissue Barriers"},{"issue":"9","key":"pntd.0012803.ref034","article-title":"Giardia duodenalis induces apoptosis in intestinal epithelial cells via reactive oxygen species-mediated mitochondrial pathway in vitro","volume":"9","author":"L Liu","year":"2020","journal-title":"Pathogens"},{"issue":"7","key":"pntd.0012803.ref035","doi-asserted-by":"crossref","first-page":"4114","DOI":"10.1128\/IAI.00328-06","article-title":"Blastocystis ratti induces contact-independent apoptosis, F-actin rearrangement, and barrier function disruption in IEC-6 cells","volume":"74","author":"MK Puthia","year":"2006","journal-title":"Infect Immun"},{"issue":"5","key":"pntd.0012803.ref036","doi-asserted-by":"crossref","DOI":"10.3390\/biom10050674","article-title":"The influence of selected gastrointestinal parasites on apoptosis in intestinal epithelial cells","volume":"10","author":"P Kapczuk","year":"2020","journal-title":"Biomolecules"},{"issue":"5","key":"pntd.0012803.ref037","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1111\/imcb.12749","article-title":"Modulation of intestinal epithelial permeability by chronic small intestinal helminth infections","volume":"102","author":"TC Mules","year":"2024","journal-title":"Immunol Cell Biol"},{"key":"pntd.0012803.ref038","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1007\/978-1-61779-166-6_27","article-title":"Integrins in tumor angiogenesis and lymphangiogenesis","volume":"757","author":"P Foubert","year":"2012","journal-title":"Methods Mol Biol"},{"key":"pntd.0012803.ref039","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1111\/j.1749-6632.1998.tb10112.x","article-title":"Fibronectin and integrins in cell adhesion, signaling, and morphogenesis","volume":"857","author":"S Miyamoto","year":"1998","journal-title":"Ann N Y Acad Sci"},{"issue":"7","key":"pntd.0012803.ref040","doi-asserted-by":"crossref","first-page":"82","DOI":"10.3390\/cancers9070082","article-title":"Inside the cell: integrins as new governors of nuclear alterations?","volume":"9","author":"E Madrazo","year":"2017","journal-title":"Cancers (Basel)"},{"issue":"7","key":"pntd.0012803.ref041","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/s41389-020-00254-2","article-title":"The identification of nuclear alphavbeta3 integrin in ovarian cancer: non-paradigmal localization with cancer promoting actions","volume":"9","author":"C Seraya-Bareket","year":"2020","journal-title":"Oncogenesis"},{"issue":"8","key":"pntd.0012803.ref042","doi-asserted-by":"crossref","first-page":"110","DOI":"10.13107\/jocr.2022.v12.i08.2988","article-title":"Angiosarcoma in chronic filarial lymphedema\u2013a report of two cases","volume":"12","author":"A Kamat","year":"2022","journal-title":"J Orthop Case Rep"},{"issue":"1","key":"pntd.0012803.ref043","doi-asserted-by":"crossref","first-page":"59","DOI":"10.4103\/ijabmr.IJABMR_309_18","article-title":"Filariasis with squamous cell carcinoma: a hidden surprise","volume":"10","author":"G Sahu","year":"2020","journal-title":"Int J Appl Basic Med Res"},{"key":"pntd.0012803.ref044","volume-title":"Endothelial cells as targets of the intravascular parasitic disease schistosomiasis","author":"CLM Silva","year":"2016"},{"issue":"1","key":"pntd.0012803.ref045","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1038\/s41598-017-01575-w","article-title":"A robust in vitro model for trans-lymphatic endothelial migration","volume":"7","author":"Y Xiong","year":"2017","journal-title":"Sci Rep"},{"issue":"3","key":"pntd.0012803.ref046","doi-asserted-by":"crossref","first-page":"119","DOI":"10.3347\/kjp.2008.46.3.119","article-title":"Clinical and pathological aspects of filarial lymphedema and its management","volume":"46","author":"RK Shenoy","year":"2008","journal-title":"Korean J Parasitol"},{"key":"pntd.0012803.ref047","doi-asserted-by":"crossref","first-page":"708952","DOI":"10.3389\/fcimb.2021.708952","article-title":"Parasitic helminth-derived microRNAs and extracellular vesicle cargos as biomarkers for helminthic infections","volume":"11","author":"Y Mu","year":"2021","journal-title":"Front Cell Infect Microbiol"},{"issue":"17","key":"pntd.0012803.ref048","doi-asserted-by":"crossref","first-page":"i884","DOI":"10.1093\/bioinformatics\/bty560","article-title":"fastp: an ultra-fast all-in-one FASTQ preprocessor","volume":"34","author":"S Chen","year":"2018","journal-title":"Bioinformatics"},{"issue":"4","key":"pntd.0012803.ref049","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/nmeth.4197","article-title":"Salmon provides fast and bias-aware quantification of transcript expression","volume":"14","author":"R Patro","year":"2017","journal-title":"Nat Methods"},{"issue":"12","key":"pntd.0012803.ref050","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"MI Love","year":"2014","journal-title":"Genome Biol"},{"issue":"5","key":"pntd.0012803.ref051","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an R package for comparing biological themes among gene clusters","volume":"16","author":"G Yu","year":"2012","journal-title":"OMICS"},{"key":"pntd.0012803.ref052","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/1471-2164-10-22","article-title":"BioMart--biological queries made easy","volume":"10","author":"D Smedley","year":"2009","journal-title":"BMC Genomics"}],"updated-by":[{"DOI":"10.1371\/journal.pntd.0012803","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T00:00:00Z","timestamp":1736208000000}}],"container-title":["PLOS Neglected Tropical Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0012803","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T18:56:27Z","timestamp":1736276187000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0012803"}},"subtitle":[],"editor":[{"given":"Siddhartha","family":"Mahanty","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,12,31]]},"references-count":52,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2024,12,31]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pntd.0012803","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pntd.0012803","asserted-by":"object"}]},"ISSN":["1935-2735"],"issn-type":[{"value":"1935-2735","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,31]]}}}