Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 119, Issue 38, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2209514119
Keywords
SARS-CoV-2; live-cell imaging; virus entry; 3D imaging; infection route
Categories
Funding
- NIH Maximizing Investigators' Research Award (MIRA) [GM130386]
- NIH [AI030557, AI163019]
- Danish Technical University
- Sana Biotechnology
- Harvard Virology Program, NIH [T32 AI07245]
- Academy of Finland [336490, 318434]
- Helsinki University Hospital Funds [TYH2021343]
- Jane and Aatos Erkko Foundation
- University of Helsinki Graduate Program in Microbiology and Biotechnology
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A study found that the cell entry of SARS-CoV-2 requires an acidic environment, even after the furin and TMPRSS2 cleavage. The stepwise dissociation of the S1 fragment, fusion, and content release can only be observed in TMPRSS2-overexpressing cells exposed to acidic pH.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry starts with membrane attachment and ends with spike (S) protein-catalyzed membrane fusion depending on two cleavage steps, namely, one usually by furin in producing cells and the second by TMPRSS2 on target cells. Endosomal cathepsins can carry out both. Using real-time three-dimensional single-virion tracking, we show that fusion and genome penetration require virion exposure to an acidic milieu of pH 6.2 to 6.8, even when furin and TMPRSS2 cleavages have occurred. We detect the sequential steps of S1-fragment dissociation, fusion, and content release from the cell surface in TMPRRS2-overexpressing cells only when exposed to acidic pH. We define a key role of an acidic environment for successful infection, found in endosomal compartments and at the surface of TMPRSS2-expressing cells in the acidic milieu of the nasal cavity.
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