Krystal L. Ching (1), Maren de Vries (2), Juan Gago (2,3), Kristen Dancel-Manning (4,6), Joseph Sall (4,6), William J. Rice (4,5), Clea Barnett (7), Feng-Xia Liang (4,6), Lorna E. Thorpe (3), Bo Shopsin (2,8,9), Leopoldo N. Segal (7), Meike Dittmann (2), Victor J. Torres (2,9), Ken Cadwell (1,2,10)
bioRxiv, December 2021. DOI: 10.1101/2021.12.17.473223

Abstract

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. We 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, we investigated the role of defensosomes during infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19. Consistent with a protective function, exosomes containing high levels of the viral receptor ACE2 in bronchioalveolar lavage fluid from critically ill COVID-19 patients was associated with reduced ICU and hospitalization times. We 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. We 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.

How Our Software Was Used

Dragonfly was used for the manual 3D rendering and refinement of Spike proteins.

Author Affiliation

(1) Kimmel Center for Biology and Medicine at the Skirball Institute, New York University Grossman School of Medicine, New York, NY, 10016.
(2) Department of Microbiology, New York University Grossman School of Medicine, New York, NY, 10016.
(3) Division of Epidemiology, Department of Population Health, New York University Grossman School of Medicine, New York, NY, 10016.
(4) Division of Advanced Research Technologies, New York University Langone Health, New York, NY, 10016.
(5) The Cryo–Electron Microscopy Laboratory at New York University Langone Health, New York, NY, 10016.
(6) The Microscopy Laboratory at New York University Langone Health, New York, NY, 10016.
(7) Division of Pulmonary and Critical Care Medicine, New York University Grossman School of Medicine, New York, New York, 10016.
(8) Division of Infectious Diseases and Immunology, Department of Medicine, New York University Grossman School of Medicine, New York, NY, 10016.
(9) Antimicrobial-Resistant Pathogens Program, NYU Langone Health, New York, NY 10016.
(10)Division of Gastroenterology and Hepatology, Department of Medicine, New York University Grossman School of Medicine, New York, NY, 10016.