> We investigated the levels of both Spike protein (Spike) and viral RNA circulating in patients hospitalized with acute COVID-19 and in patients with and without PASC. We found that Spike and viral RNA were more likely to be present in patients with PASC. Among these patients, 30% were positive for both Spike and viral RNA; whereas, none of the individuals without PASC were positive for both. The levels of Spike and/or viral RNA in the PASC-positive patients were found to be increased or remained the same as in the acute phase; whereas, in the PASC-negative group, these viral components decreased or were totally absent. Additionally, this is the first report to show that part of the circulating Spike is linked to extracellular vesicles without any presence of viral RNA in these vesicles. In conclusion, our findings suggest that Spike and/or viral RNA fragments persist in the recovered COVID-19 patients with PASC up to 1 year or longer after acute SARS-CoV-2 infection.
"We have a pretty strong inclination to believe the source of circulating spike in plasma of long covid patients may be from the bone marrow megakaryocytes that get infected during acute COVID. If so, constant exposure to spike on surface of circulating plasma EVs can account for persistent immune stimulation, immune exhaustion, and pro-thrombotic events stemming from spike stimulation. Please bear in mind that megakaryocytes from the bone marrow serve as the largest source of circulating plasma EVs (extracellular vesicles). What if these megakaryocytes are the source of spike in long covid?"
> Extracellular vesicles (EVs) are a means of cell-to-cell communication and can facilitate the exchange of a broad array of molecules between adjacent or distant cells. Platelets are anucleate cells derived from megakaryocytes and are primarily known for their role in maintaining hemostasis and vascular integrity. Upon activation by a variety of agonists, platelets readily generate EVs, which were initially identified as procoagulant particles. However, as both platelets and their EVs are abundant in blood, the role of platelet EVs in hemostasis may be redundant. Moreover, findings have challenged the significance of platelet-derived EVs in coagulation. Looking beyond hemostasis, platelet EV cargo is incredibly diverse and can include lipids, proteins, nucleic acids, and organelles involved in numerous other biological processes. Furthermore, while platelets cannot cross tissue barriers, their EVs can enter lymph, bone marrow, and synovial fluid. This allows for the transfer of platelet-derived content to cellular recipients and organs inaccessible to platelets. This review highlights the importance of platelet-derived EVs in physiological and pathological conditions beyond hemostasis.
> More than 90% of total human plasma immunoglobulin G (IgG) is found in a fucosylated form, but specific IgGs with low core fucosylation (afucosylated IgGs) are found in response to infections with enveloped viruses and to alloantigens on blood cells. Afucosylated IgGs mediate immunopathology in severe COVID-19 and dengue fever in humans. In COVID-19, the early formation of non-neutralizing afucosylated IgG against the spike protein predicts and directly mediates disease progression to severe form. IgG lacking core fucosylation causes dramatically increased antibody-dependent cellular toxicity mediated by intense FcγR-mediated stimulation of macrophages, monocytes, natural killer cells, and platelets. The mechanism and the context within which afucosylated IgG formation occurs in response to enveloped virus antigens have remained elusive thus far in COVID-19, dengue fever, and other infections. This study demonstrates that administration of human bone marrow megakaryocytes infected by SARS-CoV-2 into the circulation of K18-hACE2 transgenic mice drives the formation of pathogenic afucosylated anti-spike IgG antibodies, and is sufficient to reproduce severe COVID-19 manifestations of pulmonary vascular thrombosis, acute lung injury, and death in mice.
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