Alpha-1 antitrypsin inhibits TMPRSS2 protease activity and SARS-CoV-2 infection

Lukas Wettstein, Tatjana Weil, Carina Conzelmann, Janis A. Müller, Rüdiger Groß, Maximilian Hirschenberger, Alina Seidel, Susanne Klute, Fabian Zech, Caterina Prelli Bozzo, Nico Preising, Giorgio Fois, Robin Lochbaum, Philip Maximilian Knaff, Volker Mailänder, Ludger Ständker, Dietmar Rudolf Thal, Christian Schumann, Steffen Stenger, Alexander Kleger, Günter Lochnit, Benjamin Mayer, Yasser B. Ruiz-Blanco, Markus Hoffmann, Konstantin M. J. Sparrer, Stefan Pöhlmann, Elsa Sanchez-Garcia, Frank Kirchhoff, Manfred Frick and Jan Münch ()
Additional contact information
Lukas Wettstein: Ulm University Medical Center
Tatjana Weil: Ulm University Medical Center
Carina Conzelmann: Ulm University Medical Center
Janis A. Müller: Ulm University Medical Center
Rüdiger Groß: Ulm University Medical Center
Maximilian Hirschenberger: Ulm University Medical Center
Alina Seidel: Ulm University Medical Center
Susanne Klute: Ulm University Medical Center
Fabian Zech: Ulm University Medical Center
Caterina Prelli Bozzo: Ulm University Medical Center
Nico Preising: Ulm University Medical Center
Giorgio Fois: Ulm University
Robin Lochbaum: Ulm University
Philip Maximilian Knaff: University Medicine Mainz
Volker Mailänder: University Medicine Mainz
Ludger Ständker: Ulm University Medical Center
Dietmar Rudolf Thal: KU-Leuven and Department of Pathology, UZ-Leuven
Christian Schumann: Clinics Allgäu
Steffen Stenger: Ulm University Medical Center
Alexander Kleger: Ulm University Hospital
Günter Lochnit: Justus-Liebig University Giessen
Benjamin Mayer: Ulm University
Yasser B. Ruiz-Blanco: University of Duisburg-Essen
Markus Hoffmann: German Primate Center- Leibniz institute for Primate Research
Konstantin M. J. Sparrer: Ulm University Medical Center
Stefan Pöhlmann: German Primate Center- Leibniz institute for Primate Research
Elsa Sanchez-Garcia: University of Duisburg-Essen
Frank Kirchhoff: Ulm University Medical Center
Manfred Frick: Ulm University
Jan Münch: Ulm University Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: Abstract SARS-CoV-2 is a respiratory pathogen and primarily infects the airway epithelium. As our knowledge about innate immune factors of the respiratory tract against SARS-CoV-2 is limited, we generated and screened a peptide/protein library derived from bronchoalveolar lavage for inhibitors of SARS-CoV-2 spike-driven entry. Analysis of antiviral fractions revealed the presence of α1-antitrypsin (α1AT), a highly abundant circulating serine protease inhibitor. Here, we report that α1AT inhibits SARS-CoV-2 entry at physiological concentrations and suppresses viral replication in cell lines and primary cells including human airway epithelial cultures. We further demonstrate that α1AT binds and inactivates the serine protease TMPRSS2, which enzymatically primes the SARS-CoV-2 spike protein for membrane fusion. Thus, the acute phase protein α1AT is an inhibitor of TMPRSS2 and SARS-CoV-2 entry, and may play an important role in the innate immune defense against the novel coronavirus. Our findings suggest that repurposing of α1AT-containing drugs has prospects for the therapy of COVID-19.

Date: 2021
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DOI: 10.1038/s41467-021-21972-0

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