Emerging roles of extracellular vesicles in COVID-19, a double-edged sword?

Abstract

The sudden outbreak of SARS-CoV-2-infected disease (COVID-19), initiated from Wuhan, China, has rapidly grown into a global pandemic. Emerging evidence has implicated extracellular vesicles (EVs), a key intercellular communicator, in the pathogenesis and treatment of COVID-19. In the pathogenesis of COVID-19, cells that express ACE2 and CD9 can transfer these viral receptors to other cells via EVs, making recipient cells more susceptible for SARS-CoV-2 infection. Once infected, cells release EVs packaged with viral particles that further facilitate viral spreading and immune evasion, aggravating COVID-19 and its complications. In contrast, EVs derived from stem cells, especially mesenchymal stromal/stem cells, alleviate severe inflammation (cytokine storm) and repair damaged lung cells in COVID-19 by delivery of anti-inflammatory molecules. These therapeutic beneficial EVs can also be engineered into drug delivery platforms or vaccines to fight against COVID-19. Therefore, EVs from diverse sources exhibit distinct effects in regulating viral infection, immune response, and tissue damage/repair, functioning as a double-edged sword in COVID-19. Here, we summarize the recent progress in understanding the pathological roles of EVs in COVID-19. A comprehensive discussion of the therapeutic effects/potentials of EVs is also provided.

Keywords: COVID-19; Cytokine storm; Extracellular vesicle; Inflammation; SARS-CoV-2.

FIGURE 1

The biogenesis of extracellular vesicles (EVs). EVs contain three main types, exosomes, microvesicles (MVs), and apoptotic bodies. The biogenesis of exosomes initiates from the endocytosis of plasma membrane and the inward budding of endosomal membranes to from multiple vesicular bodies (MVBs). Exosomes are then released into extracellular space after the fusion of MVB with cell membrane. MVs are generated by the outward budding of cell membrane. Apoptotic bodies are formed by membrane‐blebbing of cells undergoing apoptosis.

FIGURE 2

Roles of extracellular vesicles (EVs) in COVID‐19. (a) The pathological roles of EVs in COVID‐19. EVs transfer viral receptors ACE2 and CD9 among lung cells, making cells more susceptible to SARS‐CoV‐2 infection. Infected epithelial cells release EVs to enhance microphage activation and immune cell infiltration. Stimulated macrophages secrete EVs cause epithelial damage and accelerate neutrophil influx. Endothelial cells and recruited neutrophils generate EVs to increase capillary permeability and cytokine release from inflammatory cells, ultimately resulting in cytokine storm and acute lung injury. The detailed information of the EV‐based delivery of viral receptors/particles is provided on the top of the panel. (b) The therapeutic roles of EVs in COVID‐19. Mesenchymal stromal/stem cell‐derived EVs (MSC‐EVs) decrease inflammatory cell influx, block cytokines accumulation in the lung, elevate intracellular ATP levels and reduce oxidative stress, thus attenuating exudative pneumonia. EVs can be further equipped with viral proteins and receptors, leading to the production of neutralizing antibody in B cells, the competitive occupation of viral receptors on cell surface and the direct binding of virus to prevent the virus–host interaction. The detailed information of EVs engineering for viral binding and blocking viral receptors on cell membrane is provided on the top of the panel.