Inactivation of SARS-CoV-2 at acidic pH is driven by partial unfolding of spike

  • Commun Biol. 2025 Jul 21;8(1):1082. doi: 10.1038/s42003-025-08514-w.
Irina Glas  1 ,  Liv Zimmermann  2  3 ,  Beiping Luo  4 ,  Marie O Pohl  1 ,  Antoni G Wrobel  5 ,  Aline Schaub  6 ,  Liviana K Klein  4 ,  Shannon C David  6 ,  Elisabeth Gaggioli  1 ,  Nir Bluvshtein  4 ,  Michael Huber  1 ,  Athanasios Nenes  7  8 ,  Ulrich K Krieger  4 ,  Thomas Peter  4 ,  Tamar Kohn  6 ,  Petr Chlanda  2  3 ,  Silke Stertz  9
Affiliations
  • 1. Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
  • 2. Schaller Research Group, Department for Infectious Diseases, Virology, Heidelberg University, Heidelberg, Germany.
  • 3. BioQuant - Research Center for Quantitative Analysis of Molecular and Cellular Systems, Heidelberg University, Heidelberg, Germany.
  • 4. Institute for Atmospheric and Climate Science, ETH Zurich, Zurich, Switzerland.
  • 5. Department of Biochemistry, University of Oxford, Oxford, UK.
  • 6. Environmental Chemistry Laboratory, School of Architecture, Civil and Environmental Engineering, Swiss Federal Institute of Technology in Lausanne, Lausanne, Switzerland.
  • 7. Laboratory of Atmospheric Processes and their Impacts, School of Architecture, Civil and Environmental Engineering, Swiss Federal Institute of Technology in Lausanne, Lausanne, Switzerland.
  • 8. Institute of Chemical Engineering Sciences, Foundation for Research and Technology Hellas, Patras, Greece.
  • 9. Institute of Medical Virology, University of Zurich, Zurich, Switzerland. [email protected].
PMID: 40691508 DOI: 10.1038/s42003-025-08514-w
Abstract

SARS-CoV-2, the causative agent of COVID-19, is predominantly transmitted by respiratory aerosol and contaminated surfaces. Recent studies demonstrated that aerosols can become acidic, and acidification has been proposed as decontamination method. Here, we investigate how SARS-CoV-2 reacts to acidic pH and by which mechanism the virus is inactivated. We show that a pH below 3 is required to inactivate SARS-CoV-2 in a period of seconds to minutes. While we measured a 1000 to 10,000-fold drop in infectivity, virion structure remained intact under these conditions. Using super-resolution microscopy, we found that the attachment of virions to target cells is abrogated after acidic treatment, revealing spike protein (S) as the major inactivation target. Limited proteolysis of S combined with testing spike-specific antibodies for binding under low pH conditions revealed that exposure of SARS-CoV-2 to pH below 3 results in partial unfolding of S, thereby preventing binding of virions to target cells.

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