SARS-CoV-2 requires acidic pH to infect cells

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Kreutzberger, Alex J.B. and Sanyal, Anwesha and Saminathan, Anand and Bloyet, Louis Marie and Stumpf, Spencer and Liu, Zhuoming and Ojha, Ravi and Patjas, Markku T. and Geneid, Ahmed and Scanavachi, Gustavo and Doyle, Catherine A. and Somerville, Elliott and Da Cunha Correia, Ricardo Bango and Toppila-Salmi, Sanna and Mäkitie, Antti and Kiessling, Volker and Vapalahti, Olli and Whelan, Sean P.J. and Balistreri, Giuseppe and Kirchhausen, Tom (2022) SARS-CoV-2 requires acidic pH to infect cells. Proceedings of the National Academy of Sciences of the United States of America, 119 (38). e2209514119. ISSN 0027-8424 (https://doi.org/10.1073/pnas.2209514119)

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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.

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