Increased mannosylation of extracellular vesicles in Long COVID plasma provides a potential therapeutic target for Galanthus nivalis agglutinin (GNA) affinity resin

2025 · doi:10.1101/2025.11.21.689519
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Long COVID plasma showed increased mannose-positive extracellular vesicles, which were partially removed by GNA affinity resin, depleting specific miRNAs and potentially rebalancing immune and tissue-repair pathways.

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This study examined whether extracellular vesicle (EV) abundance and EV glycan characteristics differ in plasma from people in the post-acute phase of SARS-CoV-2 infection with Long COVID versus recovered controls, using nanoparticle flow cytometry after isolating large and small EVs. The authors found elevated levels of both large and small EVs in Long COVID, with mannose-positive large EVs significantly increased, and they tested a Galanthus nivalis agglutinin (GNA) affinity resin that preferentially removed small EVs in proportion to mannose-positive EV abundance, alongside NanoString identification of seven EV-associated miRNAs depleted by GNA treatment. Pathway inference from miRNA–mRNA interactions predicted changes involving downregulation of JAK-STAT signaling and altered Estrogen, VEGF, and PI3K pathways, but the caveat is that these pathway effects are inferred rather than directly measured. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

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 (100−500 nm) and small (40−200 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 < 0.05). EV capture assays using Galanthus nivalis agglutinin (GNA) affinity resin demonstrated small EV removal positively correlated with mannose-positive EV abundance (r = 0.341, p < 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.
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Abstract 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 (100−500 nm) and small (40−200 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 < 0.05). EV capture assays using Galanthus nivalis agglutinin (GNA) affinity resin demonstrated small EV removal positively correlated with mannose-positive EV abundance (r = 0.341, p < 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. Competing Interest Statement This study was funded by Aethlon Medical, Inc., manufacturer of the Hemopurifier. Authors R.d.N.C, M.P. and S.P.L. are employees of Aethlon Medical, Inc.

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