Unveiling alternate pathways for SARS-CoV-2 infection via extracellular vesicle-mediated transfer of ACE2 and TMPRSS2

The COVID-19 pandemic, caused by SARS-CoV-2, has underscored the urgency of understanding viral entry mechanisms to develop effective therapeutic strategies. SARS-CoV-2 primarily exploits angiotensin-converting enzyme 2 (ACE2) as its entry receptor and relies on the serine protease TMPRSS2 to prime its spike protein, enabling membrane fusion and infection. Traditionally, TMPRSS2 has been described as a cell surface protein, but our study reveals that in human lung epithelial cells, TMPRSS2 is largely absent from the plasma membrane and instead resides intracellularly. We show that TMPRSS2 is secreted together with ACE2 in extracellular vesicles (EVs) from lung epithelial cells, which are subsequently taken up by non-epithelial cells, specifically alveolar macrophages, endothelial cells, and pericytes, that do not express TMPRSS2 or ACE2 mRNAs under homeostatic conditions. This EV uptake deposits ACE2 and TMPRSS2 protein onto recipient cells, equipping them for SARS-CoV-2 entry. By transferring these viral entry proteins, EVs expand the spectrum of susceptible cell types in the lung, offering a new explanation for how the virus can infect diverse cell populations and cause widespread tissue damage. Identifying EVs as vehicles for delivering functional ACE2 and TMPRSS2 across cell types reveals a previously unrecognized pathway of viral entry with important implications for not only COVID-19 pathogenesis but also for other viral infections that exploit similar entry mechanisms. These findings open new avenues for therapeutic intervention aimed at disrupting EV-mediated protein transfer, potentially limiting viral dissemination and severity, and may also represent a generalizable mechanism exploited by other viral pathogens, highlighting the potential relevance of EV-mediated protein transfer beyond SARS-CoV-2.

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Publication Details

Journal
Nature Communications
Published
2026-04-10
DOI
https://doi.org/10.1038/s41467-026-71680-w
Primary Topic
Extracellular vesicles in disease
Type
article
Field-Weighted Citation Impact
0.00

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article

Unveiling alternate pathways for SARS-CoV-2 infection via extracellular vesicle-mediated transfer of ACE2 and TMPRSS2

Martha Rea-Moreno, Megan N. Januska, Daniel Laskey, Helena Bugacov et al.
Nature Communications
Extracellular vesicles in disease
article

Unveiling alternate pathways for SARS-CoV-2 infection via extracellular vesicle-mediated transfer of ACE2 and TMPRSS2

Martha Rea-Moreno, Megan N. Januska, Daniel Laskey, Helena Bugacov, Alfin G. Vicencio, Nicole Min Qian Pek, Gbalekan Dawodu, Paula M. Cannon, Tara N. Tavakol, Min A Yu, Hsu-Yu Chen, Justin K. Ichida, Remi V. Klotz, Heng Pan, Diana Yu, Brandon A. Guenthart, Caterina Tiozzo, Huachao Huang, Jianwen Que, Susmita Sahoo, Jeffrey Johnson, Lu Tian, Irving M. Garcia, Chennan C. Zhang, Scott A. Scheinin, Cristina Cusmai, Mingxia Gu, Xisheng Li, Min-Chi Yang, Andrea S. Wolf, Shubham Gulati
article en

Abstract

The COVID-19 pandemic, caused by SARS-CoV-2, has underscored the urgency of understanding viral entry mechanisms to develop effective therapeutic strategies. SARS-CoV-2 primarily exploits angiotensin-converting enzyme 2 (ACE2) as its entry receptor and relies on the serine protease TMPRSS2 to prime its spike protein, enabling membrane fusion and infection. Traditionally, TMPRSS2 has been described as a cell surface protein, but our study reveals that in human lung epithelial cells, TMPRSS2 is largely absent from the plasma membrane and instead resides intracellularly. We show that TMPRSS2 is secreted together with ACE2 in extracellular vesicles (EVs) from lung epithelial cells, which are subsequently taken up by non-epithelial cells, specifically alveolar macrophages, endothelial cells, and pericytes, that do not express TMPRSS2 or ACE2 mRNAs under homeostatic conditions. This EV uptake deposits ACE2 and TMPRSS2 protein onto recipient cells, equipping them for SARS-CoV-2 entry. By transferring these viral entry proteins, EVs expand the spectrum of susceptible cell types in the lung, offering a new explanation for how the virus can infect diverse cell populations and cause widespread tissue damage. Identifying EVs as vehicles for delivering functional ACE2 and TMPRSS2 across cell types reveals a previously unrecognized pathway of viral entry with important implications for not only COVID-19 pathogenesis but also for other viral infections that exploit similar entry mechanisms. These findings open new avenues for therapeutic intervention aimed at disrupting EV-mediated protein transfer, potentially limiting viral dissemination and severity, and may also represent a generalizable mechanism exploited by other viral pathogens, highlighting the potential relevance of EV-mediated protein transfer beyond SARS-CoV-2.

Nature Communications
University of Southern California (US), University of Maryland, Baltimore (US), Cincinnati Children's Hospital Medical Center (US), Hastings Center (US), University of California, Los Angeles (US), University of California, San Francisco (US), Columbia University Irving Medical Center (US), University of California System (US), Hackensack Meridian Health (US), Broad Center (US), UNC Lineberger Comprehensive Cancer Center, University of Cincinnati Medical Center (US), Stanford University (US), Icahn School of Medicine at Mount Sinai (US)
W. M. Keck Foundation, Parker Foundation, American Lung Association, Donald E. and Delia B. Baxter Foundation, National Heart, Lung, and Blood Institute, National Institute of Allergy and Infectious Diseases, Congressionally Directed Medical Research Programs
Openalex Percentile: Top 24%
Extracellular vesicles in disease
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