COVID-19 plasma exosomes promote proinflammatory immune responses in peripheral blood mononuclear cells

• Published in: Scientific reports 2022-12, Vol.12 (1), p.21779-21779, Article 21779
• Main Authors: Chen, Lechuang, Chen, Rui, Yao, Min, Feng, Zhimin, Yuan, Guoxiang, Ye, Fengchun, Nguyen, Kien, Karn, Jonathan, McComsey, Grace A., McIntyre, Thomas M., Jin, Ge
• Format: Article
• Language: English
• Subjects: 631/326; 631/326/596; 631/326/596/4130; 692/699; 692/699/255; CD14 antigen; CD4 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - metabolism; Chemokines; Coronaviruses; COVID-19; COVID-19 - metabolism; Cytokines; Cytokines - metabolism; Double-stranded RNA; Exosomes; Exosomes - metabolism; Extracellular vesicles; Helper cells; Humanities and Social Sciences; Humans; Immunity; Immunological memory; Immunoregulation; Inflammation; Interferon; Interleukin 6; Interleukin 8; Leukocytes (mononuclear); Leukocytes, Mononuclear - metabolism; Lymphocytes; Lymphocytes T; Memory cells; Monocytes; multidisciplinary; Peripheral blood mononuclear cells; Plasma; Ribonuclease; RNA, Double-Stranded - metabolism; SARS-CoV-2 - metabolism; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; TLR3 protein; TLR7 protein; TLR9 protein; Toll-Like Receptor 3 - metabolism; Toll-like receptors; Tumor necrosis factor-TNF; Tumor necrosis factor-α
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-26457-8

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.