ACE2-containing defensosomes serve as decoys to inhibit SARS-CoV-2 infection

Extracellular vesicles of endosomal origin, exosomes, mediate intercellular communication by transporting substrates with a variety of functions related to tissue homeostasis and disease. Their diagnostic and therapeutic potential has been recognized for diseases such as cancer in which signaling defects are prominent. However, it is unclear to what extent exosomes and their cargo inform the progression of infectious diseases.

Researchers at the New York University Grossman School of Medicine recently defined a subset of exosomes termed defensosomes that are mobilized during bacterial infection in a manner dependent on autophagy proteins. Through incorporating protein receptors on their surface, defensosomes mediated host defense by binding and inhibiting pore-forming toxins secreted by bacterial pathogens. Given this capacity to serve as decoys that interfere with surface protein interactions, the researchers investigated the role of defensosomes during infection by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent of Coronavirus Disease 2019 (COVID-19). Consistent with a protective function, exosomes containing high levels of the viral receptor ACE2 in bronchoalveolar lavage fluid (BALF) from critically ill COVID-19 patients was associated with reduced intensive care unit (ICU) and hospitalization times. They found ACE2+ exosomes were induced by SARS-CoV-2 infection and activation of viral sensors in cell culture, which required the autophagy protein ATG16L1, defining these as defensosomes. The researchers further demonstrate that ACE2+ defensosomes directly bind and block viral entry. These findings suggest that defensosomes may contribute to the antiviral response against SARS-CoV-2 and expand our knowledge on the regulation and effects of extracellular vesicles during infection.

ACE2+ exosomes are associated with reduced length of stay in ICU for COVID-19 patients

(A) Flow cytometry histograms of ACE2 levels on exosomes in BALF from 8 representative COVID-19 patients. Ctrl: isotype control on exosomes from non-covid patient BALF. (B) Correlation analysis of proportion of ACE2+ exosomes in BALF and length of stay in the ICU (N = 78). Red dots indicate deaths. Simple regression analysis. (C) Correlation analysis of % ACE2 exosome levels with comorbidities colored: hypertension (blue), diabetes (green), both (orange). Red line indicates the average % of ACE2+ exosomes of all patients. (D) Length of stay in the ICU (blue), total hospitalization time (orange), and time on a ventilator (black) for each COVID patient (excluding deaths) plotted against the proportion of ACE2+ exosomes isolated from BALF (N = 59). r, Pearson correlation coefficient. P, p-value. BALF, bronchoalveolar lavage fluid; COVID 19, Coronavirus Disease 2019; ICU, intensive care unit.

Ching KL, de Vries M, Gago J, Dancel-Manning K, Sall J, Rice WJ, et al. (2022) ACE2-containing defensosomes serve as decoys to inhibit SARS-CoV-2 infection. PLoS Biol 20(9): e3001754. [article]

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