Alpha‐1‐antitrypsin: A possible host protective factor against Covid‐19

Abstract

Summary Understanding Covid‐19 pathophysiology is crucial for a better understanding of the disease and development of more effective treatments. Alpha‐1‐antitrypsin (A1AT) is a constitutive tissue protector with antiviral and anti‐inflammatory properties. A1AT inhibits SARS‐CoV‐2 infection and two of the most important proteases in the pathophysiology of Covid‐19: the transmembrane serine protease 2 (TMPRSS2) and the disintegrin and metalloproteinase 17 (ADAM17). It also inhibits the activity of inflammatory molecules, such as IL‐8, TNF‐α, and neutrophil elastase (NE). TMPRSS2 is essential for SARS‐CoV‐2‐S protein priming and viral infection. ADAM17 mediates ACE2, IL‐6R, and TNF‐α shedding. ACE2 is the SARS‐CoV‐2 entry receptor and a key component for the balance of the renin‐angiotensin system, inflammation, vascular permeability, and pulmonary homeostasis. In addition, clinical findings indicate that A1AT levels might be important in defining Covid‐19 outcomes, potentially partially explaining associations with air pollution and with diabetes. In this review, we focused on the interplay between A1AT with TMPRSS2, ADAM17 and immune molecules, and the role of A1AT in the pathophysiology of Covid‐19, opening new avenues for investigating effective treatments.

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

“…Thus, we believe that there is substantial evidence to warrant further studies involving measurement of serum SERPIN levels including alpha 1 antitrypsin status along with the smoking history in COVID-19 patients and also study of therapeutic efficacy of Alpha 1 antitrypsin in animal models of this infection. Indeed there is already a clinical trial already underway in Ireland investigating [11] , [12] the efficacy of Alpha 1 antitrypsin pharmacological treatment on inflammatory marker levels ( https://www.clinicaltrialsarena.com/news/ireland-alpha-1-antitrypsin-trial/ ). As of now, based on the available evidence we advocate, the potential role of Alpha 1 antitrypsin and another SERPIN status as a predictor of the disease outcome.…”

In Vitro Investigations on Optimizing and Nebulization of IVT-mRNA Formulations for Potential Pulmonary Based Alpha-1-Antitrypsin Deficiency Treatment

“…A1AT could inhibit caspase 1 and 3, therefore it is able to protect cells from apoptosis [33]. Apart from the constitutive tissue protector function, recent data indicate that A1AT is also an inhibitor of SARS-CoV-2 infection and two of the most important proteases in the pathophysiology of COVID-19: the transmembrane serine protease 2 (TMPRSS2) and the disintegrin and metalloproteinase17 (ADAM17) [34]. TMPRSS2 is essential for SARS-CoV-2-S protein priming and viral infection [35].…”

“…TMPRSS2 is essential for SARS-CoV-2-S protein priming and viral infection [35]. ADAM17 mediates ACE2 (angiotensin I converting enzyme II, the SARS-CoV-2 entry receptor), IL-6R, and TNF-α shedding [34]. In addition, clinical findings indicate that lower A1AT levels are related to worse prognosis inCOVID-19 patients [36].…”

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

“…Among those, cysteine-aspartic proteases are caspases, calpain-1, kallikreins 7 and 14, and TNF-α-converting enzyme ADAM-17 [34,36]. 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].…”