Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Mar;31(2):e2157.
doi: 10.1002/rmv.2157. Epub 2020 Aug 26.

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

Mariana Braccialli de Loyola  1 , Thaís Tereza Aguiar Dos Reis  1 , Guilherme Xavier Lyra Malcher de Oliveira  1 , Julys da Fonseca Palmeira  1 , Gustavo A Argañaraz  1 , Enrique R Argañaraz  1
Affiliations
Review

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

Mariana Braccialli de Loyola et al. Rev Med Virol. 2021 Mar.

Abstract

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.

Keywords: A1AT; ADAM17; Covid-19; SARS-CoV-2; TMPRSS2.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Possible protective role of A1AT against Covid‐19. Alpha‐1‐antitrypsin (A1AT) inhibits transmembrane serine protease 2‐mediated SARS‐CoV2 infection and ADAM17 protease. A1AT‐mediated ADAM17 inhibition can modulate ACE2 cleavage, protecting pulmonary, and cardiac tissue from deleterious effects of RAS imbalance. In addition, A1AT‐ADAM17 inhibition can exert anti‐inflammatory effects by inhibiting TNF‐α and IL6R cleavage. Moreover, A1AT can regulate neutrophil chemotaxis, degranulation through interactions with neutrophil elastase (NE), IL‐8, and TNF‐α binding to TNFR1 and TNF‐R2 neutrophil receptors, and macrophage activation. Finally, A1AT could inhibit the NE—mediated cleavage of the spike protein of the SARS‐CoV‐2 A2a subtype (not shown)
See this image and copyright information in PMC

References

    1. Munster VJ, Koopmans M, van Doremalen N, van Riel D, de Wit E. A novel coronavirus emerging in China—key questions for impact assessment. N Engl J Med. 2020;382(8):692‐694. 10.1056/NEJMp2000929. - DOI - PubMed
    1. Strnad P, McElvaney NG, Lomas DA. Alpha1‐antitrypsin deficiency. Longo DL, ed. N Engl J Med. 2020;382(15):1443‐1455. 10.1056/NEJMra1910234. - DOI - PubMed
    1. Forssmann W‐G, The Y‐H, Stoll M, et al. Short‐term Monotherapy in HIV‐infected patients with a virus entry inhibitor against the gp41 fusion peptide. Sci Transl Med. 2010;2(63):63re3‐63re3. 10.1126/scitranslmed.3001697. - DOI - PubMed
    1. Bergin DA, Reeves EP, Meleady P, et al. α‐1 antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL‐8. J Clin Invest. 2010;120(12):4236‐4250. 10.1172/JCI41196. - DOI - PMC - PubMed
    1. Azouz NP, Klingler AM, Rothenberg ME. Alpha 1 antitrypsin is an inhibitor of the SARS‐CoV2–priming protease TMPRSS2. bioRxiv. 2020;077826:1–16. 10.1101/2020.05.04.077826. - DOI - PMC - PubMed

Publication types