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

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

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.