1. In plain sight: the role of alpha-1-antitrypsin in COVID-19 pathogenesis and therapeutics
- Author
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Kasopefoluwa Y, Oguntuyo, Christian S, Stevens, Mohammed Na, Siddiquey, Robert M, Schilke, Matthew D, Woolard, Hongbo, Zhang, Joshua A, Acklin, Satoshi, Ikegame, Chuan-Tien, Hung, Jean K, Lim, Robert W, Cross, Thomas W, Geisbert, Stanimir S, Ivanov, Jeremy P, Kamil, and Benhur, Lee
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,SARS-CoV-2 ,viruses ,virus diseases ,COVID-19 ,protease ,Article ,respiratory tract diseases ,Alpha-1-antitrypsin ,convalescent plasma ,SERPINA1 ,skin and connective tissue diseases ,alpha-2-macroglobulin ,TMPRSS2 - 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.
- Published
- 2020