In plain sight: The role of alpha-1-antitrypsin in COVID-19 pathogenesis and therapeutics

Kasopefoluwa Y. Oguntuyo, Christian S. Stevens, Mohammed N.A. Siddiquey, Robert M. Schilke, Matthew D. Woolard, Hongbo Zhang, Joshua A. Acklin, Satoshi Ikegame, Chuan Tien Huang, Jean K. Lim, Robert W. Cross, Thomas W. Geisbert, Stanimir S. Ivanov, Jeremy P. Kamil, Benhur Lee

Research output: Contribution to journalArticlepeer-review

Abstract

Entry of SARS-CoV-2 is facilitated by endogenous and exogenous proteases. These proteases proteolytically activate the SARS-CoV-2 spike glycoprotein and are key modulators of virus tropism. We show that SARS-CoV-2 naïve serum exhibits significant inhibition of SARS-CoV-2 entry. We identify alpha-1-antitrypsin (AAT) as the major serum protease inhibitor that potently restrict protease-mediated entry of SARS-CoV-2. AAT inhibition of protease-mediated SARS-CoV-2 entry in vitro occurs at concentrations far below what is present in serum and bronchoalveolar tissues, suggesting that AAT effects are physiologically relevant. Moreover, AAT deficiency affects up to 20% of the population and its symptomatic manifestations coincides with many risk factors associated with severe COVID-19 disease. In addition to the effects that AAT may have on viral entry itself, we argue that the anti-inflammatory and coagulation regulatory activity of AAT have implications for coronavirus disease 2019 (COVID-19) pathogenicity, SARS-CoV-2 tissue restriction, convalescent plasma therapies, and even potentially AAT therapy.

Original languageEnglish (US)
JournalUnknown Journal
DOIs
StatePublished - Aug 15 2020

Keywords

  • Alpha-1-antitrypsin
  • Alpha-2macroglobulin
  • Convalescent plasma
  • COVID-19
  • Protease
  • SARS-CoV-2
  • SERPINA1
  • TMPRSS2

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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