ABSTRACT
Elevated serum cytokine production in COVID-19 patients is associated with disease progression and severity. However, the stimuli that initiate cytokine production in patients remain to be fully revealed. Virus-infected cells release virus-associated exosomes, extracellular vesicles of endocytic origin, into the blood to deliver viral cargoes able to regulate immune responses. Here, we report that plasma exosomes of COVID-19 patients contain SARS-CoV-2 double stranded RNA (dsRNA) and stimulate robust production of interleukin-6 (IL-6), IL-8, tumor necrosis factor-α (TNF-α), and other inflammatory cytokines and chemokines by human peripheral mononuclear cells. Exosome depletion abolished these stimulated responses. COVID-19 plasma exosomes induced proinflammatory responses in CD4+ T cells, CD8+ T cells, and CD14+ monocytes but not significantly in regulatory T cells, Th17 T cells, or central memory T cells. COVID-19 plasma exosomes protect the SARS-CoV-2 dsRNA cargo from RNase and deliver the dsRNA into recipient cells. These exosomes significantly increase expression of endosomal toll-like receptor 3 (TLR3), TLR7, TLR8, and TLR9 in peripheral T cells and monocytes. A pharmacological inhibitor of TLR3 considerably reduced cytokine and chemokine production by CD4+ and CD8+ T cells but not by CD14+ monocytes, highlighting divergent signaling pathways of immune cells in response to COVID-19 plasma exosomes. Our results identify a novel model of intercellular crosstalk following SARS-CoV-2 infection that evoke immune responses positioned to contribute to elevated cytokine production associated with COVID-19 progression, severity, and long-haul symptoms.
Subject(s)
COVID-19 , Exosomes , Humans , Exosomes/metabolism , Toll-Like Receptor 3/metabolism , Leukocytes, Mononuclear/metabolism , CD8-Positive T-Lymphocytes/metabolism , SARS-CoV-2/metabolism , COVID-19/metabolism , Cytokines/metabolism , RNA, Double-Stranded/metabolism , ImmunityABSTRACT
Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 is an ongoing viral pandemic marked by increased risk of thrombotic events. However, the role of platelets in the elevated observed thrombotic risk in COVID-19 and utility of antiplatelet agents in attenuating thrombosis is unknown. We aimed to determine if the antiplatelet effect of aspirin may mitigate risk of myocardial infarction, cerebrovascular accident, and venous thromboembolism in COVID-19. We evaluated 22,072 symptomatic patients tested for COVID-19. Propensity-matched analyses were performed to determine if treatment with aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) affected thrombotic outcomes in COVID-19. Neither aspirin nor NSAIDs affected mortality in COVID-19. Thus, aspirin does not appear to prevent thrombosis and death in COVID-19. The mechanisms of thrombosis in COVID-19, therefore, appear distinct and the role of platelets as direct mediators of SARS-CoV-2-mediated thrombosis warrants further investigation.