SARS-CoV-2 induced damage of the alveolar epithelium in the lung and its inhibition by α1-antitrypsin.

• Applicants: Professor Dr. Manfred Frick; Professor Dr. Jan Münch
• Subject Area: Anatomy and Physiology ; Virology
• Term: from 2021 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 458685747

• Final Report Year: 2022

Final Report Abstract

The primary replication site of SARS-CoV-2 is the upper and lower respiratory tract. To identify antiviral factors that may restrict natural SARS-CoV-2 infection, we screened a protein library from derived from lung fluids and identified the protease inhibitor alpha -1 antitrypsin (α1-AT) as inhibitor of the new Coronavirus. We showed that α1-AT inhibits SARS-CoV-2 infection by blocking the function of the cellular protease TMPRRS2, which primes the viral Spike protein and the makes the virus infectious. Using primary airway epithelial cells as most relevant infection model, we also found that α1-AT prevents SARS-CoV-2 infection and replication. The antiviral activity of the α1-AT is not restricted to the original SARS-CoV-2 virus but also extends to all variants of concerns tested, including Omicron, and other TMPRSS2-depending viruses. Our findings have direct translational potential as α1-AT is an approved drug for the therapy of α1-AT deficiency. Several clinical trials have been initiated whether α1-AT has therapeutic potential in COVID-19 treatment. Applicant Münch is currently evaluating the prophylactic and therapeutic efficacy of nebulized α1-AT in a non-human-primate model of SARS-CoV-2. Thus, the findings of this project might result in novel treatment option of COVID-19 and perhaps other respiratory virus infections.

Publications

• Alpha-1 antitrypsin inhibits TMPRSS2 protease activity and SARS-CoV-2 infection. Nature Communications, 12(1).
  Wettstein, Lukas; Weil, Tatjana; Conzelmann, Carina; Müller, Janis A.; Groß, Rüdiger; Hirschenberger, Maximilian; Seidel, Alina; Klute, Susanne; Zech, Fabian; Prelli, Bozzo Caterina; Preising, Nico; Fois, Giorgio; Lochbaum, Robin; Knaff, Philip Maximilian; Mailänder, Volker; Ständker, Ludger; Thal, Dietmar Rudolf; Schumann, Christian; Stenger, Steffen ... & Münch, Jan
  
• Carrageenan-containing over-the-counter nasal and oral sprays inhibit SARS-CoV-2 infection of airway epithelial cultures. American Journal of Physiology-Lung Cellular and Molecular Physiology, 320(5), L750-L756.
  Schütz, Desiree; Conzelmann, Carina; Fois, Giorgio; Groß, Rüdiger; Weil, Tatjana; Wettstein, Lukas; Stenger, Steffen; Zelikin, Alexander; Hoffmann, Thomas K.; Frick, Manfred; Müller, Janis A. & Münch, Jan
  
• SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas. Nature Metabolism, 3(2), 149-165.
  Müller, Janis A.; Groß, Rüdiger; Conzelmann, Carina; Krüger, Jana; Merle, Uta; Steinhart, Johannes; Weil, Tatjana; Koepke, Lennart; Bozzo, Caterina Prelli; Read, Clarissa; Fois, Giorgio; Eiseler, Tim; Gehrmann, Julia; van Vuuren, Joanne; Wessbecher, Isabel M.; Frick, Manfred; Costa, Ivan G.; Breunig, Markus; Grüner, Beate ... & Kleger, Alexander
  
• SARS-CoV-2 Variants of Concern Hijack IFITM2 for Efficient Replication in Human Lung Cells. Journal of Virology, 96(11).
  Nchioua, Rayhane; Schundner, Annika; Kmiec, Dorota; Prelli, Bozzo Caterina; Zech, Fabian; Koepke, Lennart; Graf, Alexander; Krebs, Stefan; Blum, Helmut; Frick, Manfred; Sparrer, Konstantin M. J. & Kirchhoff, Frank