SARS-CoV-2 requires acidic pH to infect cells-Reference-Cited by-同舟云学术

SARS-CoV-2 requires acidic pH to infect cells

Published:2022-09 Issue:38 Volume:119 Page:
ISSN:0027-8424
Container-title:Proceedings of the National Academy of Sciences
language:en
Short-container-title:Proc. Natl. Acad. Sci. U.S.A.

Author:

Kreutzberger Alex J. B.¹²,Sanyal Anwesha¹²,Saminathan Anand¹²,Bloyet Louis-Marie³^ORCID,Stumpf Spencer³,Liu Zhuoming³^ORCID,Ojha Ravi⁴,Patjas Markku T.⁵^ORCID,Geneid Ahmed⁵,Scanavachi Gustavo¹²,Doyle Catherine A.⁶,Somerville Elliott²,Correia Ricardo Bango Da Cunha¹²,Di Caprio Giuseppe²⁷,Toppila-Salmi Sanna⁸,Mäkitie Antti⁵,Kiessling Volker⁹¹⁰^ORCID,Vapalahti Olli⁴¹¹¹²^ORCID,Whelan Sean P. J.³^ORCID,Balistreri Giuseppe⁴¹¹¹³^ORCID,Kirchhausen Tom¹²⁷

Affiliation:

1. Department of Cell Biology, Harvard Medical School, Boston, MA 02115

2. Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA 02115

3. Department of Molecular Microbiology, Washington University in Saint Louis, St. Louis, MO 63110

4. Department of Virology, Faculty of Medicine, University of Helsinki, Helsinki, 00290 Finland

5. Department of Otorhinolaryngology and Phoniatrics - Head and Neck Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, 00290 Finland

6. Department of Pharmacology, University of Virginia, Charlottesville, VA 22903

7. Department of Pediatrics, Harvard Medical School, Boston, MA 02115

8. Department of Allergy, University of Helsinki and Helsinki University Hospital, Helsinki, 00290 Finland

9. Center for Membrane and Cell Physiology, University of Virginia, Charlottesville, VA 22903

10. Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22903

11. Department of Veterinary Biosciences, University of Helsinki, Helsinki, 00290 Finland

12. Virology and Immunology, Helsinki University Hospital Diagnostic Center, Helsinki, 00290 Finland

13. The Queensland Brain Institute, University of Queensland, Brisbane, 4072 Australia

Abstract

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.

Funder

HHS | NIH | National Institute of General Medical Sciences

HHS | NIH | NIAID | Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases

HHS | NIH | National Institute of Allergy and Infectious Diseases

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

Link

https://pnas.org/doi/pdf/10.1073/pnas.2209514119

Reference45 articles.

1. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor