ArticleInfection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases2021
SARS-CoV-2 mutation 614G creates an elastase cleavage site enhancing its spread in high AAT-deficient regions.
Article in Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers, 1 of them a synthesis that pooled it.
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28 citing papers in PubMed, 1 synthesis or guideline pooled it, 43 citations in OpenAlex.
- The D614G Virus Mutation Enhances Anosmia in COVID-19 Patients: Evidence from a Systematic Review and Meta-analysis of Studies from South Asia.ACS chemical neuroscience · 2021Pooled it
- Synergistic activation of bat SARS-like coronaviruses spike protein by elastase and TMPRSS2.Scientific reports · 2025Article
- Functional mass spectrometry indicates anti-protease and complement activity increase with COVID-19 severity.Experimental biology and medicine (Maywood, N.J.) · 2025Article
- Aprotinin (I): Understanding the Role of Host Proteases in COVID-19 and the Importance of Pharmacologically Regulating Their Function.International journal of molecular sciences · 2024Review
- Review
- Neutrophil proteases are protective against SARS-CoV-2 by degrading the spike protein and dampening virus-mediated inflammation.JCI insight · 2024Article
- Review
- The Inhibition of Serine Proteases by Serpins Is Augmented by Negatively Charged Heparin: A Concise Review of Some Clinically Relevant Interactions.International journal of molecular sciences · 2024Review
- Could the Oxidation of α1-Antitrypsin Prevent the Binding of Human Neutrophil Elastase in COVID-19 Patients?International journal of molecular sciences · 2023Article
- Alpha-1-antitrypsin antagonizes COVID-19: a review of the epidemiology, molecular mechanisms, and clinical evidence.Biochemical Society transactions · 2023Review
- Role of elastic fiber degradation in disease pathogenesis.Biochimica et biophysica acta. Molecular basis of disease · 2023Review
- Contrasting Distribution of SARS-CoV-2 Lineages across Multiple Rounds of Pandemic Waves in West Bengal, the Gateway of East and North-East States of India.Microbiology spectrum · 2022Article
- Molecular variants of SARS-CoV-2: antigenic properties and current vaccine efficacy.Medical microbiology and immunology · 2022Review
- Investigating the Link between Alpha-1 Antitrypsin and Human Neutrophil Elastase in Bronchoalveolar Lavage Fluid of COVID-19 Patients.Current issues in molecular biology · 2022Article
- Computational prediction of the molecular mechanism of statin group of drugs against SARS-CoV-2 pathogenesis.Scientific reports · 2022Article
- Enoxaparin augments alpha-1-antitrypsin inhibition of TMPRSS2, a promising drug combination against COVID-19.Scientific reports · 2022Article
- Dominant clade-featured SARS-CoV-2 co-occurring mutations reveal plausible epistasis: An in silico based hypothetical model.Journal of medical virology · 2022Article
- A Review of Alpha-1 Antitrypsin Binding Partners for Immune Regulation and Potential Therapeutic Application.International journal of molecular sciences · 2022Review
- The "Elastic Perspective" of SARS-CoV-2 Infection and the Role of Intrinsic and Extrinsic Factors.International journal of molecular sciences · 2022Review
- Evolutionary Traits and Genomic Surveillance of SARS-CoV-2 in South America.Global health, epidemiology and genomics · 2022Review
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
SARS-CoV-2 was first reported from China. Within three months, it evolved to 10 additional subtypes. Two evolved subtypes (A2 and A2a) carry a non-synonymous Spike protein mutation (D614G). We conducted phylodynamic analysis of over 70,000 SARS-CoV-2 coronaviruses worldwide, sequenced until July2020, and found that the mutant subtype (614G) outcompeted the pre-existing type (614D), significantly faster in Europe and North-America than in East Asia. Bioinformatically and computationally, we identified a novel neutrophil elastase (ELANE) cleavage site introduced in the G-mutant, near the S1-S2 junction of the Spike protein. We hypothesised that elevation of neutrophil elastase level at the site of infection will enhance the activation of Spike protein thus facilitating host cell entry for 614G, but not the 614D, subtype. The level of neutrophil elastase in the lung is modulated by its inhibitor α1-antitrypsin (AAT). AAT prevents lung tissue damage by elastase. However, many individuals exhibit genotype-dependent deficiency of AAT. AAT deficiency eases host-cell entry of the 614G virus, by retarding inhibition of neutrophil elastase and consequently enhancing activation of the Spike protein. AAT deficiency is highly prevalent in European and North-American populations, but much less so in East Asia. Therefore, the 614G subtype is able to infect and spread more easily in populations of the former regions than in the latter region. Our analyses provide a molecular biological and evolutionary model for the higher observed virulence of the 614G subtype, in terms of causing higher morbidity in the host (higher infectivity and higher viral load), than the non-mutant 614D subtype.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.