Exploring extracellular vesicles as mediators of clinical disease and vehicles for viral therapeutics: Insights from the COVID-19 pandemic

The COVID-19 pandemic has challenged researchers to rapidly understand the capabilities of the SARS-CoV-2 virus and investigate potential therapeutics for SARS-CoV-2 infection. COVID-19 has been associated with devastating lung and cardiac injury, profound inflammation, and a heightened coagulopathic state, which may, in part, be driven by cellular crosstalk facilitated by extracellular vesicles (EVs). In recent years, EVs have emerged as important biomarkers of disease, and while extracellular vesicles may contribute to the spread of COVID-19 infection from one cell to the next, they also may be engineered to play a protective or therapeutic role as decoys or “delivery drivers” for therapeutic agents. University of Kansas Medical Center researchers explore these roles and areas for future study.

Potential role of EVs in COVID-19 disease pathogenesis and therapeutics

SARS-CoV-2 virions enter the host via the large airways and can travel into alveoli where they infect type II pneumocytes. Infection of type II pneumocytes by SARS-CoV-2 induces a proinflammatory response that activates alveolar macrophages and damages the alveolar epithelium. It is speculated that EV crosstalk between alveolar macrophages and alveolar epithelial cells could intensify inflammation and further enhance alveolar epithelial permeability. This may lead to increased permeability of the alveolar-capillary barrier, causing pulmonary edema and decreased functional capacity of the lungs, thereby allowing SARS-CoV-2 virions, EVs, and other inflammatory mediators to enter the bloodstream and progress to systemic infection. SARS-CoV-2 virions in the blood are suggested to infect endothelial cells and cause endothelial dysfunction, which ultimately leads to blood clots that can cause major thrombotic events as well as activation of circulating immune cells. On the contrary, engineered EVs could also be used as a therapeutic tool against COVID-19. EVs modified to express ACE2 may be injected into the bloodstream or nebulized and could potentially prevent SARS-CoV-2 from infecting healthy cells in either the bloodstream or alveolar space. These ACE2-expressing EVs may also be taken up by endothelial cells, increasing the amount of surface ACE2 expression on these cells, and maintaining the appropriate function of RAAS. In addition, injected MSC-EVs have anti-inflammatory properties that can promote tissue repair and prevent hyperinflammation during SARS-CoV-2 infection and ARDS. In COVID-19, they might be particularly useful for decreasing endothelial damage and preventing immune activation. (The copyright is retained by the authors).

Craddock VD, Cook CM, Dhillon NK. (2022) Exploring extracellular vesicles as mediators of clinical disease and vehicles for viral therapeutics: Insights from the COVID-19 pandemic. Extracell Vesicles Circ Nucl Acids 3(3):172-188. [article]

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