Alpha-1-antitrypsin and its variant-dependent role in COVID-19 pathogenesis

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), and to a lesser degree, alpha-2-macroglobulin (A2M) as highly abundant serum protease inhibitors 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 mutations that have been characterized to affect abundance or function are highly prevalent. 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.

Targeting host cell proteases as a potential treatment strategy to limit the spread of SARS‐CoV‐2 in the respiratory tract

“…We encourage that these agents are to be administered-as stated above-together with camostat or dutasteride once patients are admitted to the hospital and continued throughout the hospitalization period to provide adequate prophylaxis against COVID-19 respiratory complications particularly ARDS. 46,47,49 We also emphasize here that such antiprote- patients, there are at least six published randomized controlled trials. [111][112][113][114][115][116] Most of the trials are of small sample size and show either no benefit or only a mild reduction in time to symptoms resolution with low certainty.…”

“…Similar to HNE inhibitors, these properties make AAT a promising candidate for managing COVID-19 patients. 49 Like sivelestat, the toxicity profile of AAT therapy should not limit its use in COVID-19 patients. The most common adverse reactions are typical of intravenous infusion of proteins and include fever, chills, urticaria, nausea, vomiting, and fatigue.…”

“…We propose here a number of protease-targeting drug combinations that we believe would provide potential therapeutic benefit for hospitalized COVID- TMPRSS2 inhibitors as an alternative to sivelestat since both of them are expected to exert similar beneficial effects in terms of mitigating elastase-induced lung damage and inflammation. 46,49 Dexamethasone (which inhibits cathepsins B and L 83,84 ) can be added to these combinations once the patient develops a severe respiratory deficit and requires oxygen support since this drug has already been shown to reduce mortality in this particular clinical scenario. 97 Another potential candidate to add to such combinations is the oral secretolytic agent bromhexine hydrochloride which showed inhibitory activity against TMPRSS2 and is generally safe to use.…”

Host genomics of COVID-19: Evidence point towards Alpha 1 antitrypsin deficiency as a putative risk factor for higher mortality rate

“…Concerning other genetic predisposing factors, of particular interest is a study that experimentally demonstrated that Alpha 1 antitrypsin is an inhibitor of Transmembrane protease serine 2 (TMPRSS2) enzyme in a dose-dependent manner and this may explain the preventive effect of COVID-19 infection naïve plasma for viral entry in model systems [1] , [4] . Indeed, the Structure-based computational predictions of protein-protein interactions (Struct2Net – http://cb.csail.mit.edu/cb/struct2net/webserver ) also showed the probability of interaction to be 0.386 using the 1k9o and 1ezx PDB crystal structures.…”

Post-Translational Modifications of Circulating Alpha-1-Antitrypsin Protein

“…Importantly, a recent study identified AAT as a novel inhibitor of TMPRSS2, which plays a role in the cellular entry of several coronaviruses, including severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2, SARS-CoV, and Middle East respiratory syndrome-CoV, as well as influenza viruses [37][38][39][40]. AAT impedes SARS-CoV2 cellular entry and prevents the main clinical complications of severe COVID-19, such as acute inflammation and acute respiratory failure [41]. Therefore, it could be hypothesized that the geographical distribution of pathogenic variants of AAT protein is to a certain extent linked to differences in COVID-19 epidemiology and severity throughout Europe [42].…”