In plain sight: the role of alpha-1-antitrypsin in COVID-19 pathogenesis and therapeutics
cell biology immunology/immunity
First Author: Kasopefoluwa Y Oguntuyo
Journal/preprint name: bioRxiv
Paper DOI: https://doi.org/10.1101/2020.08.14.248880
Tags: Immunology/Immunity, Cell Biology
Summary
The authors explore endogenous and exogenous proteases activity in SARS-CoV-2 pathogenesis. SARS-CoV-2 naïve serum exhibits significant inhibition of SARS-CoV-2 entry through protease inhibitors alpha-1-antitrypsin (AAT) and alpha-2-macroglobulin (A2M). AAT inhibition of protease-mediated SARS-CoV-2 entry in vitro occurs at lower concertation of what is present in serum and bronchoalveolar tissues, suggesting that AAT activity is physiologically relevant. In addition, AAT-deficient individuals display manifestations associated with risk factors linked to SARS-CoV-2 severity. Collectively, the study suggests that the anti-inflammatory and regulatory functions of AAT have implications for SARS-CoV-2 pathogenicity, SARS-CoV-2 tissue restriction, convalescent plasma therapies, and potentially AAT therapy.
Research Highlights
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Sera from patients not exposed to SARS-CoV-2 was capable of neutralizing SARS-CoV-2 pseudoviruses.
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AAT is neutralizing factor regulating protease-mediated SARS-CoV-2 entry in SARS-CoV-2 naïve serum.
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AAT-deficiency is associated with clinical manifestations linked to risk factors in SARS-CoV-2 pathogenicity.
Impact for COVID-19 research:
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The data suggest that AAT may may affect SARS-CoV-2 pathogenicity and could be a potential therapeutic target.
Methodologies:
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Study Type: in vitro, SARS-CoV-2 pseudoviruses
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Important cell lines/viral models used: Vero-CCL81, parental 293T, and isogenic 293T cells
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Key Techniques:
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VSVΔG pseudotyped particles and neutralization assays
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Plaque reduction neutralization titration (PRNT)
Limitations:
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While the authors link the AAT activity to the SARS-CoV-2 pathogenesis, minimal data was presented in the level of AAT activity in serum of COVID-19 patients with different disease outcomes.
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Minimal evidence was reported for impact of variant AAT genotypes on the relative severity of COVID-19.
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While the authors link the AAT activity to the SARS-CoV-2 pathogenesis, no data was presented in the level of AAT activity in serum of COVID-19 patients with different disease outcomes.
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Further studies could investigate biologically contribution of AAT in tissue restriction in SARS-CoV-2 infection.