{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T02:09:59Z","timestamp":1768529399116,"version":"3.49.0"},"posted":{"date-parts":[[2025,11,21]]},"group-title":"Molecular Biology","reference-count":36,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T00:00:00Z","timestamp":1763683200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  There is no proven therapy for Long COVID, a post-acute illness characterized by a myriad of diverse symptoms including fatigue, dyspnea, and brain fog following SARS-CoV-2 infection. Extracellular vesicles (EVs) have been implicated in Long COVID pathogenesis by promoting viral and inflammatory signaling with their molecular cargo. In this study, we investigated whether EV abundance and glycome characteristics are altered in plasma from people with Long COVID and whether they can be targeted for removal using a glycan-binding affinity resin. Large (100\u2212500 nm) and small (40\u2212200 nm) EVs were isolated from plasma of participants in the post-acute phase of COVID-19 and analyzed by nanoparticle flow cytometry to measure concentration and glycan characteristics. Plasma of those with Long COVID contained elevated levels of both large and small EVs, and mannose-positive large EVs were significantly increased in comparison to recovered controls (p &lt; 0.05). EV capture assays using\n                  <jats:italic>Galanthus nivalis<\/jats:italic>\n                  agglutinin (GNA) affinity resin demonstrated small EV removal positively correlated with mannose-positive EV abundance (r = 0.341, p &lt; 0.05). NanoString analyses identified seven EV-associated miRNAs significantly depleted by GNA affinity resin treatment of plasma. PROGENy pathway inference of validated miRNA-mRNA interactions suggests these reductions may lead to a downregulation of JAK-STAT signaling and upregulation of Estrogen, VEGF, and PI3K pathways, resulting in a favorable rebalancing of immune and tissue-repair networks. These findings reveal specific glycome EV-miRNA cargo signatures in Long COVID and the potential clinical benefits of a lectin capture therapeutic strategy to remove these pathogenic vesicles and their inflammatory cargo.\n                <\/jats:p>","DOI":"10.1101\/2025.11.21.689519","type":"posted-content","created":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T02:40:22Z","timestamp":1763779222000},"source":"Crossref","is-referenced-by-count":0,"title":["Increased mannosylation of extracellular vesicles in Long COVID plasma provides a potential therapeutic target for\n                  <i>Galanthus nivalis<\/i>\n                  agglutinin (GNA) affinity resin"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4551-2284","authenticated-orcid":false,"given":"Miguel A.","family":"Pesqueira Sanchez","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0148-2686","authenticated-orcid":false,"given":"Rosalia","family":"de Necochea Campion","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9132-0496","authenticated-orcid":false,"given":"Thomas","family":"Dalhuisen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily A.","family":"Fehrman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pahul S.","family":"Chhabra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. Daniel","family":"Kelly","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9773-3256","authenticated-orcid":false,"given":"Jeffrey N.","family":"Martin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6371-747X","authenticated-orcid":false,"given":"Steven G.","family":"Deeks","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy J.","family":"Henrich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0585-6230","authenticated-orcid":false,"given":"Michael J.","family":"Peluso","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0773-2816","authenticated-orcid":false,"given":"Steven P.","family":"LaRosa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025112413103082000_2025.11.21.689519v1.1","doi-asserted-by":"crossref","first-page":"101019","DOI":"10.1016\/j.eclinm.2021.101019","article-title":"Characterizing long COVID in an international cohort: 7 months of symptoms and their impact","volume":"38","year":"2021","journal-title":"EClinicalMedicine"},{"key":"2025112413103082000_2025.11.21.689519v1.2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.12603"},{"key":"2025112413103082000_2025.11.21.689519v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinf.2020.08.029"},{"key":"2025112413103082000_2025.11.21.689519v1.4","unstructured":"Bureau, N.C.f.H.S.U.S.C. Household Pulse Survey, 2022\u20132024. Long COVID. . Available from: https:\/\/www.cdc.gov\/nchs\/covid19\/pulse\/long-covid.htm."},{"key":"2025112413103082000_2025.11.21.689519v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-03173-6"},{"key":"2025112413103082000_2025.11.21.689519v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-022-00846-2"},{"key":"2025112413103082000_2025.11.21.689519v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.07.054"},{"issue":"1","key":"2025112413103082000_2025.11.21.689519v1.8","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1186\/s12967-023-04552-2","article-title":"Genomic communication via circulating extracellular vesicles and long-term health consequences of COVID-19","volume":"21","year":"2023","journal-title":"J Transl Med"},{"issue":"3","key":"2025112413103082000_2025.11.21.689519v1.9","first-page":"417","article-title":"Flow cytometry for extracellular vesicle characterization in COVID-19 and post-acute sequelae of SARS-CoV-2 infection","volume":"5","year":"2024","journal-title":"Extracell Vesicles Circ Nucl Acids"},{"key":"2025112413103082000_2025.11.21.689519v1.10","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.28568"},{"issue":"1","key":"2025112413103082000_2025.11.21.689519v1.11","doi-asserted-by":"crossref","first-page":"1442985","DOI":"10.1080\/20013078.2018.1442985","article-title":"Glycosylation of extracellular vesicles: current knowledge, tools and clinical perspectives","volume":"7","year":"2018","journal-title":"J Extracell Vesicles"},{"issue":"11","key":"2025112413103082000_2025.11.21.689519v1.12","doi-asserted-by":"crossref","first-page":"2348","DOI":"10.1021\/acsinfecdis.2c00421","article-title":"alpha2,6-Sialylation Is Upregulated in Severe COVID-19, Implicating the Complement Cascade","volume":"8","year":"2022","journal-title":"ACS Infect Dis"},{"key":"2025112413103082000_2025.11.21.689519v1.13","first-page":"744141","article-title":"Removal of COVID-19 Spike Protein, Whole Virus, Exosomes, and Exosomal MicroRNAs by the Hemopurifier(R) Lectin-Affinity Cartridge in Critically Ill Patients With COVID-19 Infection","volume":"8","year":"2021","journal-title":"Front Med (Lausanne)"},{"key":"2025112413103082000_2025.11.21.689519v1.14","doi-asserted-by":"crossref","unstructured":"de Necochea Campion, R. , M. Pesqueira , and S.P. LaRosa , Ex Vivo Removal of CD41 positive platelet microparticles from Plasma by a Medical Device containing a <em>Galanthus nivalis agglutinin<\/em> (GNA) affinity resin. bioRxiv, 2025: p. 2025.05.09.652772.","DOI":"10.1101\/2025.05.09.652772"},{"key":"2025112413103082000_2025.11.21.689519v1.15","doi-asserted-by":"crossref","first-page":"104101","DOI":"10.1016\/j.ebiom.2022.104101","article-title":"IgG N-glycome changes during the course of severe COVID-19: An observational study","volume":"81","year":"2022","journal-title":"EBioMedicine"},{"key":"2025112413103082000_2025.11.21.689519v1.16","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofab640"},{"key":"2025112413103082000_2025.11.21.689519v1.17","unstructured":"Organization, W.H. Post COVID-19 condition (Long COVID). 2022; Available from: https:\/\/www.who.int\/europe\/news-room\/fact-sheets\/item\/post-covid-19-condition."},{"key":"2025112413103082000_2025.11.21.689519v1.18","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMsb2408466"},{"key":"2025112413103082000_2025.11.21.689519v1.19","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab1079"},{"key":"2025112413103082000_2025.11.21.689519v1.20","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-02391-6"},{"key":"2025112413103082000_2025.11.21.689519v1.21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0245824"},{"key":"2025112413103082000_2025.11.21.689519v1.22","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb9983"},{"key":"2025112413103082000_2025.11.21.689519v1.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.02.052"},{"key":"2025112413103082000_2025.11.21.689519v1.24","doi-asserted-by":"publisher","DOI":"10.1038\/S41579-020-00468-6"},{"key":"2025112413103082000_2025.11.21.689519v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.05.042"},{"key":"2025112413103082000_2025.11.21.689519v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2020.08.004.32841605"},{"key":"2025112413103082000_2025.11.21.689519v1.27","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-44211-0"},{"issue":"1","key":"2025112413103082000_2025.11.21.689519v1.28","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1186\/s40246-025-00810-0","article-title":"MicroRNAs in long COVID: roles, diagnostic biomarker potential and detection","volume":"19","year":"2025","journal-title":"Hum Genomics"},{"issue":"1","key":"2025112413103082000_2025.11.21.689519v1.29","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1186\/s12964-025-02095-1","article-title":"COVID-19 patient serum-derived extracellular vesicles deliver miR-20b-5p induces neutrophil extracellular traps","volume":"23","year":"2025","journal-title":"Cell Commun Signal"},{"key":"2025112413103082000_2025.11.21.689519v1.30","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-021-01113x"},{"issue":"2","key":"2025112413103082000_2025.11.21.689519v1.31","doi-asserted-by":"crossref","first-page":"189079","DOI":"10.1016\/j.bbcan.2024.189079","article-title":"VEGF signaling: Role in angiogenesis and beyond","volume":"1879","year":"2024","journal-title":"Biochim Biophys Acta Rev Cancer"},{"key":"2025112413103082000_2025.11.21.689519v1.32","doi-asserted-by":"publisher","DOI":"10.1210\/er.2001-0045"},{"key":"2025112413103082000_2025.11.21.689519v1.33","doi-asserted-by":"crossref","unstructured":"Yanai, H. , et al., The Significance of Endothelial Dysfunction in Long COVID-19 for the Possible Future Pandemic of Chronic Kidney Disease and Cardiovascular Disease. Biomolecules, 2024. 14(8).","DOI":"10.3390\/biom14080965"},{"key":"2025112413103082000_2025.11.21.689519v1.34","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-38682-4"},{"key":"2025112413103082000_2025.11.21.689519v1.35","doi-asserted-by":"crossref","unstructured":"Ai, J. , et al., Integrated multi-omics characterization across clinically relevant subgroups of long COVID. Natl Sci Rev, 2025. 12(8): p. nwae410.","DOI":"10.1093\/nsr\/nwae410"},{"key":"2025112413103082000_2025.11.21.689519v1.36","doi-asserted-by":"crossref","unstructured":"Abbasi, A. , et al., Possible long COVID biomarker: identification of SARC-CoV-2 related protein(s) in Serum Extracellular Vesicles. Infection, 2025.","DOI":"10.1007\/s15010-025-02612-x"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.11.21.689519","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T10:04:24Z","timestamp":1768471464000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.11.21.689519"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,21]]},"references-count":36,"URL":"https:\/\/doi.org\/10.1101\/2025.11.21.689519","relation":{},"subject":[],"published":{"date-parts":[[2025,11,21]]},"subtype":"preprint"}}