Year: 2021
Type: article
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 α 1 -antitrypsin (α 1 AT), a highly abundant circulating serine protease inhibitor. Here, we report that α 1 AT 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 α 1 AT binds and inactivates the serine protease TMPRSS2, which enzymatically primes the SARS-CoV-2 spike protein for membrane fusion. Thus, the acute phase protein α 1 AT 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 α 1 AT-containing drugs has prospects for the therapy of COVID-19.
Source: Nature Communications
Authors: 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, Jan Münch
Institutions: Universität Ulm, University Hospital Ulm, University Medical Center of the Johannes Gutenberg University Mainz, Max Planck Institute for Polymer Research, Universitair Ziekenhuis Leuven, KU Leuven, Justus-Liebig-Universität Gießen, University of Duisburg-Essen, German Primate Center, University of Göttingen
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,721
Awards: G1162249279, G1195029094, EXC 2033: RESOLV (Ruhr Explores Solvation), G1743581083, G1937574757, G1992736149, G2616179186, G274347230, G318143557, G3504457557, G3558625346, G424361051, G4395029046, RAPID - Risikobewertung bei präpandemischen respiratorischen Infektionserkrankungen - Effizienz der proteolytischen Aktivierung von respiratorischen Viren als Marker für pandemisches Potenzial, SARS_S1S2 - Bedeutung der optimierten S1/S2 Schnittstelle für die SARS-CoV-2 Infektion, G4722325562, G5068810445, G509426592, G5243825032, G5819821861, G594516436, RAPID: Effizienz der proteolytischen Aktivierung von respiratorischen Viren als Marker für pandemisches Potenzial (Teilprojekt P4-DPZ), G6535948948, RENACO - Repurposing von Nafamostatmesylat zur Behandlung von COVID-19 - Teilvorhaben DPZ, G8076104149, IMMUNOMOD - Erforschung von neuartigen Strategien zur Unterstützung des angeborenen Immunsystems, um virale Erkrankungen zu bekämpfen, G8401052489, G8766836734
OpenAlex ID: W3138747438