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1.
Mol Biol Evol ; 39(4)2022 Apr 11.
Article in English | MEDLINE | ID: covidwho-1758789

ABSTRACT

Among the 30 nonsynonymous nucleotide substitutions in the Omicron S-gene are 13 that have only rarely been seen in other SARS-CoV-2 sequences. These mutations cluster within three functionally important regions of the S-gene at sites that will likely impact (1) interactions between subunits of the Spike trimer and the predisposition of subunits to shift from down to up configurations, (2) interactions of Spike with ACE2 receptors, and (3) the priming of Spike for membrane fusion. We show here that, based on both the rarity of these 13 mutations in intrapatient sequencing reads and patterns of selection at the codon sites where the mutations occur in SARS-CoV-2 and related sarbecoviruses, prior to the emergence of Omicron the mutations would have been predicted to decrease the fitness of any virus within which they occurred. We further propose that the mutations in each of the three clusters therefore cooperatively interact to both mitigate their individual fitness costs, and, in combination with other mutations, adaptively alter the function of Spike. Given the evident epidemic growth advantages of Omicron overall previously known SARS-CoV-2 lineages, it is crucial to determine both how such complex and highly adaptive mutation constellations were assembled within the Omicron S-gene, and why, despite unprecedented global genomic surveillance efforts, the early stages of this assembly process went completely undetected.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , COVID-19/genetics , Humans , Mutation , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics
2.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-311753

ABSTRACT

SARS-CoV-2 Spike amino acid replacements in the receptor binding domain (RBD) occur relatively frequently and some have a consequence for immune recognition. Here we report recurrent emergence and significant onward transmission of a six-nucleotide deletion in the S gene, which results in loss of two amino acids: H69 and V70. Of particular note this deletion, ?H69/V70, often co-occurs with the receptor binding motif amino acid replacements N501Y, N439K and Y453F. One of the ?H69/V70+ N501Y lineages, B.1.1.7, is comprised of over 4000 SARS-CoV-2 genome sequences from the UK and includes eight other S gene mutations: RBD (N501Y and A570D), S1 (?H69/V70 and ?144/145) and S2 (P681H, T716I, S982A and D1118H). Some of these mutations have presumably arisen as a result of the virus evolving from immune selection pressure in infected individuals and at least one, lineage B.1.1.7, potentially from a chronic infection. Given our recent evidence that ?H69/V70 enhances viral infectivity (Kemp et al. 2020), its effect on virus fitness appears to be independent to the RBD changes. Enhanced surveillance for the ?H69/V70 deletion with and without RBD mutations should be considered as a priority. Permissive mutations such as ?H69/V70 have the potential to enhance the ability of SARS-CoV-2 to generate new variants, including vaccine escape variants, that would have otherwise significantly reduced viral fitness.

3.
Genome Biol Evol ; 14(2)2022 02 04.
Article in English | MEDLINE | ID: covidwho-1684680

ABSTRACT

The lack of an identifiable intermediate host species for the proximal animal ancestor of SARS-CoV-2, and the large geographical distance between Wuhan and where the closest evolutionary related coronaviruses circulating in horseshoe bats (members of the Sarbecovirus subgenus) have been identified, is fueling speculation on the natural origins of SARS-CoV-2. We performed a comprehensive phylogenetic study on SARS-CoV-2 and all the related bat and pangolin sarbecoviruses sampled so far. Determining the likely recombination events reveals a highly reticulate evolutionary history within this group of coronaviruses. Distribution of the inferred recombination events is nonrandom with evidence that Spike, the main target for humoral immunity, is beside a recombination hotspot likely driving antigenic shift events in the ancestry of bat sarbecoviruses. Coupled with the geographic ranges of their hosts and the sampling locations, across southern China, and into Southeast Asia, we confirm that horseshoe bats, Rhinolophus, are the likely reservoir species for the SARS-CoV-2 progenitor. By tracing the recombinant sequence patterns, we conclude that there has been relatively recent geographic movement and cocirculation of these viruses' ancestors, extending across their bat host ranges in China and Southeast Asia over the last 100 years. We confirm that a direct proximal ancestor to SARS-CoV-2 has not yet been sampled, since the closest known relatives collected in Yunnan shared a common ancestor with SARS-CoV-2 approximately 40 years ago. Our analysis highlights the need for dramatically more wildlife sampling to: 1) pinpoint the exact origins of SARS-CoV-2's animal progenitor, 2) the intermediate species that facilitated transmission from bats to humans (if there is one), and 3) survey the extent of the diversity in the related sarbecoviruses' phylogeny that present high risk for future spillovers.


Subject(s)
Chiroptera/virology , Coronavirus/genetics , Pangolins/virology , Phylogeny , Recombination, Genetic , Animals , Humans , Phylogeography
4.
Science ; 374(6567): eabj3624, 2021 Oct 29.
Article in English | MEDLINE | ID: covidwho-1440797

ABSTRACT

Inherited genetic factors can influence the severity of COVID-19, but the molecular explanation underpinning a genetic association is often unclear. Intracellular antiviral defenses can inhibit the replication of viruses and reduce disease severity. To better understand the antiviral defenses relevant to COVID-19, we used interferon-stimulated gene (ISG) expression screening to reveal that 2'-5'-oligoadenylate synthetase 1 (OAS1), through ribonuclease L, potently inhibits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We show that a common splice-acceptor single-nucleotide polymorphism (Rs10774671) governs whether patients express prenylated OAS1 isoforms that are membrane-associated and sense-specific regions of SARS-CoV-2 RNAs or if they only express cytosolic, nonprenylated OAS1 that does not efficiently detect SARS-CoV-2. In hospitalized patients, expression of prenylated OAS1 was associated with protection from severe COVID-19, suggesting that this antiviral defense is a major component of a protective antiviral response.


Subject(s)
2',5'-Oligoadenylate Synthetase/genetics , 2',5'-Oligoadenylate Synthetase/metabolism , COVID-19/genetics , COVID-19/physiopathology , RNA, Double-Stranded/metabolism , RNA, Viral/metabolism , SARS-CoV-2/physiology , 5' Untranslated Regions , A549 Cells , Animals , COVID-19/enzymology , COVID-19/immunology , Chiroptera/genetics , Chiroptera/virology , Coronaviridae/enzymology , Coronaviridae/genetics , Coronaviridae/physiology , Endoribonucleases/metabolism , Humans , Interferons/immunology , Isoenzymes/genetics , Isoenzymes/metabolism , Phosphoric Diester Hydrolases/genetics , Phosphoric Diester Hydrolases/metabolism , Polymorphism, Single Nucleotide , Protein Prenylation , RNA, Double-Stranded/chemistry , RNA, Double-Stranded/genetics , RNA, Viral/chemistry , RNA, Viral/genetics , Retroelements , SARS-CoV-2/genetics , Severity of Illness Index , Virus Replication
8.
Cell Rep ; 35(13): 109292, 2021 06 29.
Article in English | MEDLINE | ID: covidwho-1281394

ABSTRACT

We report severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike ΔH69/V70 in multiple independent lineages, often occurring after acquisition of receptor binding motif replacements such as N439K and Y453F, known to increase binding affinity to the ACE2 receptor and confer antibody escape. In vitro, we show that, although ΔH69/V70 itself is not an antibody evasion mechanism, it increases infectivity associated with enhanced incorporation of cleaved spike into virions. ΔH69/V70 is able to partially rescue infectivity of spike proteins that have acquired N439K and Y453F escape mutations by increased spike incorporation. In addition, replacement of the H69 and V70 residues in the Alpha variant B.1.1.7 spike (where ΔH69/V70 occurs naturally) impairs spike incorporation and entry efficiency of the B.1.1.7 spike pseudotyped virus. Alpha variant B.1.1.7 spike mediates faster kinetics of cell-cell fusion than wild-type Wuhan-1 D614G, dependent on ΔH69/V70. Therefore, as ΔH69/V70 compensates for immune escape mutations that impair infectivity, continued surveillance for deletions with functional effects is warranted.


Subject(s)
COVID-19/immunology , COVID-19/virology , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Cell Line , Chlorocebus aethiops , HEK293 Cells , Humans , Immune Evasion , Mutation , Pandemics , Phylogeny , Protein Binding , Recurrence , SARS-CoV-2/immunology , Vero Cells
9.
PLoS Biol ; 19(3): e3001115, 2021 03.
Article in English | MEDLINE | ID: covidwho-1133664

ABSTRACT

Virus host shifts are generally associated with novel adaptations to exploit the cells of the new host species optimally. Surprisingly, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has apparently required little to no significant adaptation to humans since the start of the Coronavirus Disease 2019 (COVID-19) pandemic and to October 2020. Here we assess the types of natural selection taking place in Sarbecoviruses in horseshoe bats versus the early SARS-CoV-2 evolution in humans. While there is moderate evidence of diversifying positive selection in SARS-CoV-2 in humans, it is limited to the early phase of the pandemic, and purifying selection is much weaker in SARS-CoV-2 than in related bat Sarbecoviruses. In contrast, our analysis detects evidence for significant positive episodic diversifying selection acting at the base of the bat virus lineage SARS-CoV-2 emerged from, accompanied by an adaptive depletion in CpG composition presumed to be linked to the action of antiviral mechanisms in these ancestral bat hosts. The closest bat virus to SARS-CoV-2, RmYN02 (sharing an ancestor about 1976), is a recombinant with a structure that includes differential CpG content in Spike; clear evidence of coinfection and evolution in bats without involvement of other species. While an undiscovered "facilitating" intermediate species cannot be discounted, collectively, our results support the progenitor of SARS-CoV-2 being capable of efficient human-human transmission as a consequence of its adaptive evolutionary history in bats, not humans, which created a relatively generalist virus.


Subject(s)
COVID-19/virology , Chiroptera/virology , SARS-CoV-2/genetics , Viral Zoonoses/virology , Animals , COVID-19/epidemiology , COVID-19/transmission , Evolution, Molecular , Genome, Viral , Host Specificity , Humans , Pandemics , Phylogeny , Receptors, Virus/genetics , SARS-CoV-2/pathogenicity , Selection, Genetic , Viral Zoonoses/genetics , Viral Zoonoses/transmission
10.
Cell ; 184(5): 1171-1187.e20, 2021 03 04.
Article in English | MEDLINE | ID: covidwho-1051523

ABSTRACT

SARS-CoV-2 can mutate and evade immunity, with consequences for efficacy of emerging vaccines and antibody therapeutics. Here, we demonstrate that the immunodominant SARS-CoV-2 spike (S) receptor binding motif (RBM) is a highly variable region of S and provide epidemiological, clinical, and molecular characterization of a prevalent, sentinel RBM mutation, N439K. We demonstrate N439K S protein has enhanced binding affinity to the hACE2 receptor, and N439K viruses have similar in vitro replication fitness and cause infections with similar clinical outcomes as compared to wild type. We show the N439K mutation confers resistance against several neutralizing monoclonal antibodies, including one authorized for emergency use by the US Food and Drug Administration (FDA), and reduces the activity of some polyclonal sera from persons recovered from infection. Immune evasion mutations that maintain virulence and fitness such as N439K can emerge within SARS-CoV-2 S, highlighting the need for ongoing molecular surveillance to guide development and usage of vaccines and therapeutics.


Subject(s)
COVID-19/immunology , Genetic Fitness , Immune Evasion , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Angiotensin-Converting Enzyme 2/chemistry , Antibodies, Neutralizing/genetics , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/virology , Humans , Mutation , Phylogeny , SARS-CoV-2/chemistry , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/chemistry , Virulence
11.
Mol Biol Evol ; 37(9): 2706-2710, 2020 09 01.
Article in English | MEDLINE | ID: covidwho-641314

ABSTRACT

Due to the scope and impact of the COVID-19 pandemic there exists a strong desire to understand where the SARS-CoV-2 virus came from and how it jumped species boundaries to humans. Molecular evolutionary analyses can trace viral origins by establishing relatedness and divergence times of viruses and identifying past selective pressures. However, we must uphold rigorous standards of inference and interpretation on this topic because of the ramifications of being wrong. Here, we dispute the conclusions of Xia (2020. Extreme genomic CpG deficiency in SARS-CoV-2 and evasion of host antiviral defense. Mol Biol Evol. doi:10.1093/molbev/masa095) that dogs are a likely intermediate host of a SARS-CoV-2 ancestor. We highlight major flaws in Xia's inference process and his analysis of CpG deficiencies, and conclude that there is no direct evidence for the role of dogs as intermediate hosts. Bats and pangolins currently have the greatest support as ancestral hosts of SARS-CoV-2, with the strong caveat that sampling of wildlife species for coronaviruses has been limited.


Subject(s)
Alphacoronavirus/genetics , Betacoronavirus/genetics , Coronavirus Infections/epidemiology , Genome, Viral , Pandemics , Pneumonia, Viral/epidemiology , Reassortant Viruses/genetics , Alphacoronavirus/classification , Alphacoronavirus/pathogenicity , Animals , Betacoronavirus/classification , Betacoronavirus/pathogenicity , Biological Evolution , COVID-19 , Chiroptera/virology , Coronavirus Infections/immunology , Coronavirus Infections/transmission , Coronavirus Infections/virology , CpG Islands , Dogs , Eutheria/virology , Humans , Immune Evasion/genetics , Pneumonia, Viral/immunology , Pneumonia, Viral/transmission , Pneumonia, Viral/virology , Protein Binding , RNA, Viral/genetics , RNA, Viral/metabolism , RNA-Binding Proteins/genetics , RNA-Binding Proteins/immunology , RNA-Binding Proteins/metabolism , Reassortant Viruses/classification , Reassortant Viruses/pathogenicity , SARS-CoV-2 , Virus Replication
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