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SARS-CoV-2 mutation 614G creates an elastase cleavage site enhancing its spread in high AAT-deficient regions.
Infect Genet Evol. 2021 06; 90:104760.IG

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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Authors+Show Affiliations

Bhattacharyya C

National Institute of Biomedical Genomics, Kalyani 741251, India.

National Institute of Biomedical Genomics, Kalyani 741251, India.

National Institute of Biomedical Genomics, Kalyani 741251, India.

National Institute of Biomedical Genomics, Kalyani 741251, India.

National Institute of Biomedical Genomics, Kalyani 741251, India.

National Institute of Biomedical Genomics, Kalyani 741251, India; Indian Statistical Institute, Kolkata 700108, India.

National Institute of Biomedical Genomics, Kalyani 741251, India.

National Institute of Biomedical Genomics, Kalyani 741251, India. Electronic address: nkb1@nibmg.ac.in.

Pub Type(s)

Journal Article

Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33556558

Citation

Bhattacharyya, Chandrika, et al. "SARS-CoV-2 Mutation 614G Creates an Elastase Cleavage Site Enhancing Its Spread in High AAT-deficient Regions." Infection, Genetics and Evolution : Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases, vol. 90, 2021, p. 104760.

Bhattacharyya C, Das C, Ghosh A, et al. SARS-CoV-2 mutation 614G creates an elastase cleavage site enhancing its spread in high AAT-deficient regions. Infect Genet Evol. 2021;90:104760.

Bhattacharyya, C., Das, C., Ghosh, A., Singh, A. K., Mukherjee, S., Majumder, P. P., Basu, A., & Biswas, N. K. (2021). SARS-CoV-2 mutation 614G creates an elastase cleavage site enhancing its spread in high AAT-deficient regions. Infection, Genetics and Evolution : Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases, 90, 104760. https://doi.org/10.1016/j.meegid.2021.104760

Bhattacharyya C, et al. SARS-CoV-2 Mutation 614G Creates an Elastase Cleavage Site Enhancing Its Spread in High AAT-deficient Regions. Infect Genet Evol. 2021;90:104760. PubMed PMID: 33556558.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - SARS-CoV-2 mutation 614G creates an elastase cleavage site enhancing its spread in high AAT-deficient regions. AU - Bhattacharyya,Chandrika, AU - Das,Chitrarpita, AU - Ghosh,Arnab, AU - Singh,Animesh K, AU - Mukherjee,Souvik, AU - Majumder,Partha P, AU - Basu,Analabha, AU - Biswas,Nidhan K, Y1 - 2021/02/05/ PY - 2020/12/10/received PY - 2021/02/01/revised PY - 2021/02/03/accepted PY - 2021/2/9/pubmed PY - 2021/5/1/medline PY - 2021/2/8/entrez KW - 614G subtype KW - Neutrophil Elastase KW - SARS-CoV-2 KW - SERPINA1 KW - α1-antitrypsin deficiency SP - 104760 EP - 104760 JF - Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases JO - Infect Genet Evol VL - 90 N2 - 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. SN - 1567-7257 UR - https://www.unboundmedicine.com/medline/citation/33556558/SARS_CoV_2_mutation_614G_creates_an_elastase_cleavage_site_enhancing_its_spread_in_high_AAT_deficient_regions_ DB - PRIME DP - Unbound Medicine ER -