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1.
PLoS One ; 17(2): e0264198, 2022.
Article in English | MEDLINE | ID: covidwho-1703502

ABSTRACT

We consider whether one can forecast the emergence of variants of concern in the SARS-CoV-2 outbreak and similar pandemics. We explore methods of population genetics and identify key relevant principles in both deterministic and stochastic models of spread of infectious disease. Finally, we demonstrate that fitness variation, defined as a trait for which an increase in its value is associated with an increase in net Darwinian fitness if the value of other traits are held constant, is a strong indicator of imminent transition in the viral population.


Subject(s)
COVID-19/epidemiology , Forecasting/methods , SARS-CoV-2/genetics , COVID-19/transmission , Genetic Fitness/genetics , Genetics, Population/methods , Humans , Pandemics , SARS-CoV-2/pathogenicity
2.
Cell Rep ; 38(6): 110344, 2022 02 08.
Article in English | MEDLINE | ID: covidwho-1639571

ABSTRACT

SARS-CoV-2 has a broad mammalian species tropism infecting humans, cats, dogs, and farmed mink. Since the start of the 2019 pandemic, several reverse zoonotic outbreaks of SARS-CoV-2 have occurred in mink, one of which reinfected humans and caused a cluster of infections in Denmark. Here we investigate the molecular basis of mink and ferret adaptation and demonstrate the spike mutations Y453F, F486L, and N501T all specifically adapt SARS-CoV-2 to use mustelid ACE2. Furthermore, we risk assess these mutations and conclude mink-adapted viruses are unlikely to pose an increased threat to humans, as Y453F attenuates the virus replication in human cells and all three mink adaptations have minimal antigenic impact. Finally, we show that certain SARS-CoV-2 variants emerging from circulation in humans may naturally have a greater propensity to infect mustelid hosts and therefore these species should continue to be surveyed for reverse zoonotic infections.


Subject(s)
Adaptation, Biological/immunology , SARS-CoV-2/genetics , Viral Zoonoses/genetics , Animals , COVID-19 , Ferrets/immunology , Genetic Fitness/genetics , Humans , Mink/immunology , Mutation , Pandemics , Respiratory System/virology , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/immunology
3.
mBio ; 12(4): e0058721, 2021 08 31.
Article in English | MEDLINE | ID: covidwho-1327613

ABSTRACT

Since the D614G substitution in the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged, the variant strain has undergone a rapid expansion to become the most abundant strain worldwide. Therefore, this substitution may provide an advantage for viral spreading. To explore the mechanism, we analyzed 18 viral isolates containing S proteins with either G614 or D614 (S-G614 and S-D614, respectively). The plaque assay showed a significantly higher virus titer in S-G614 than in S-D614 isolates. We further found increased cleavage of the S protein at the furin substrate site, a key event that promotes syncytium formation, in S-G614 isolates. The enhancement of the D614G substitution in the cleavage of the S protein and in syncytium formation has been validated in cells expressing S protein. The effect on the syncytium was abolished by furin inhibitor treatment and mutation of the furin cleavage site, suggesting its dependence on cleavage by furin. Our study pointed to the impact of the D614G substitution on syncytium formation through enhanced furin-mediated S cleavage, which might increase the transmissibility and infectivity of SARS-CoV-2 strains containing S-G614. IMPORTANCE Analysis of viral genomes and monitoring of the evolutionary trajectory of SARS-CoV-2 over time has identified the D614G substitution in spike (S) as the most prevalent expanding variant worldwide, which might confer a selective advantage in transmission. Several studies showed that the D614G variant replicates and transmits more efficiently than the wild-type virus, but the mechanism is unclear. By comparing 18 virus isolates containing S with either D614 or G614, we found significantly higher virus titers in association with higher furin protease-mediated cleavage of S, an event that promotes syncytium formation and virus infectivity, in the S-G614 viruses. The effect of the D614G substitution on furin-mediated S cleavage and the resulting enhancement of the syncytium phenotype has been validated in S-expressing cells. This study suggests a possible effect of the D614G substitution on S of SARS-CoV-2; the antiviral effect through targeting furin protease is worthy of being investigated in proper animal models.


Subject(s)
COVID-19/transmission , Furin/metabolism , Giant Cells/virology , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Amino Acid Substitution/genetics , Animals , COVID-19/pathology , Cell Line , Chlorocebus aethiops , Furin/antagonists & inhibitors , Genetic Fitness/genetics , Genome, Viral/genetics , HEK293 Cells , Humans , SARS-CoV-2/isolation & purification , Vero Cells , Viral Load/genetics , Virus Replication/genetics
4.
mBio ; 12(4): e0085021, 2021 08 31.
Article in English | MEDLINE | ID: covidwho-1297961

ABSTRACT

Since its emergence in 2019, circulating populations of the new coronavirus (CoV) continuously acquired genetic diversity. At the end of 2020, a variant named 20I/501Y.V1 (lineage B.1.1.7) emerged and replaced other circulating strains in several regions. This phenomenon has been poorly associated with biological evidence that this variant and the original strain exhibit different phenotypic characteristics. Here, we analyze the replication ability of this new variant in different cellular models using for comparison an ancestral D614G European strain (lineage B1). Results from comparative replication kinetics experiments in vitro and in a human reconstituted bronchial epithelium showed no difference. However, when both viruses were put in competition in human reconstituted bronchial epithelium, the 20I/501Y.V1 variant outcompeted the ancestral strain. All together, these findings demonstrate that this new variant replicates more efficiently and may contribute to a better understanding of the progressive replacement of circulating strains by the severe acute respiratory CoV-2 (SARS-CoV-2) 20I/501Y.V1 variant. IMPORTANCE The emergence of several SARS-CoV-2 variants raised numerous questions concerning the future course of the pandemic. We are currently observing a replacement of the circulating viruses by the variant from the United Kingdom known as 20I/501Y.V1, from the B.1.1.7 lineage, but there is little biological evidence that this new variant exhibits a different phenotype. In the present study, we used different cellular models to assess the replication ability of the 20I/501Y.V1 variant. Our results showed that this variant replicates more efficiently in human reconstituted bronchial epithelium, which may explain why it spreads so rapidly in human populations.


Subject(s)
COVID-19/transmission , Genetic Fitness/genetics , SARS-CoV-2/growth & development , SARS-CoV-2/genetics , Virus Replication/genetics , Animals , COVID-19/pathology , Caco-2 Cells , Cell Line , Chlorocebus aethiops , Humans , Respiratory Mucosa/virology , Vero Cells , Viral Load
5.
Viruses ; 13(5)2021 05 18.
Article in English | MEDLINE | ID: covidwho-1234834

ABSTRACT

The understanding of the molecular mechanisms driving the fitness of the SARS-CoV-2 virus and its mutational evolution is still a critical issue. We built a simplified computational model, called SpikePro, to predict the SARS-CoV-2 fitness from the amino acid sequence and structure of the spike protein. It contains three contributions: the inter-human transmissibility of the virus predicted from the stability of the spike protein, the infectivity computed in terms of the affinity of the spike protein for the ACE2 receptor, and the ability of the virus to escape from the human immune response based on the binding affinity of the spike protein for a set of neutralizing antibodies. Our model reproduces well the available experimental, epidemiological and clinical data on the impact of variants on the biophysical characteristics of the virus. For example, it is able to identify circulating viral strains that, by increasing their fitness, recently became dominant at the population level. SpikePro is a useful, freely available instrument which predicts rapidly and with good accuracy the dangerousness of new viral strains. It can be integrated and play a fundamental role in the genomic surveillance programs of the SARS-CoV-2 virus that, despite all the efforts, remain time-consuming and expensive.


Subject(s)
Computational Biology/methods , Genetic Fitness/genetics , SARS-CoV-2/genetics , Amino Acid Sequence/genetics , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/genetics , COVID-19/metabolism , Humans , Models, Theoretical , Mutation/genetics , Protein Binding/genetics , Receptors, Virus/metabolism , SARS-CoV-2/pathogenicity , Software , Spike Glycoprotein, Coronavirus/genetics
6.
mSphere ; 6(2)2021 03 31.
Article in English | MEDLINE | ID: covidwho-1166378

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) carrying the D614G mutation on the spike protein is the predominant circulating variant and is associated with enhanced infectivity. However, whether this dominant variant can potentially spread through the cold chain and whether the spike protein affects virus stability after cold storage remain unclear. To compare the infectivity of two SARS-CoV-2 variants, namely, SARS-CoV-2 variants with spike protein with the D614 mutation (S-D614) and G614 mutation (S-G614), after different periods of refrigeration (4°C) and freezing (-20°C). We also determined the integrity of the viral RNA and the ability of the spike protein to bind angiotensin-converting enzyme 2 (ACE2) after storage at these conditions. The results showed that SARS-CoV-2 was more stable and infectious after storage at -20°C than at 4°C. Particularly, the S-G614 variant was found to be more stable than the S-D614 variant. The spike protein of the S-G614 variant had better binding ability with the ACE2 receptor than that of the S-D614 variant after storage at -20°C for up to 30 days. Our findings revealed that SARS-CoV-2 remains stable and infectious after refrigeration or freezing, and their stability and infectivity up to 30 days depends on the spike variant. Stability and infectivity are related to each other, and the higher stability of S-G614 compared to that of S-D614 may contribute to rapid viral spread of the S-G614 variant.IMPORTANCE It has been observed that variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are more stable and infectious after storage at -20°C than at 4°C. A SARS-CoV-2 S-D614G variant is currently the most dominant variant in circulation and is associated with enhanced infectivity. We compared the stability of two SARS-CoV-2 variants: the early S-D614 variant carrying the D614 spike protein and the new S-G614 variant carrying the G614 spike protein, stored at both 4°C and -20°C for different periods. We observed that SARS-CoV-2 remains stable and infectious after refrigeration or freezing, which further depends on the spike variant, that is, the ability of the spike protein to bind with the ACE2 receptor with higher efficiency. The high stability of the S-G614 variant also explains its rapid spread and infectivity. Therefore, precautions should be taken during and after handling food preserved under cold conditions.


Subject(s)
COVID-19 , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Cold Temperature , Genetic Fitness/genetics , Humans , Mutation , Protein Stability
7.
Biochem Biophys Res Commun ; 555: 147-153, 2021 05 28.
Article in English | MEDLINE | ID: covidwho-1157143

ABSTRACT

Several existing drugs are currently being tested worldwide to treat COVID-19 patients. Recent data indicate that SARS-CoV-2 is rapidly evolving into more transmissible variants. It is therefore highly possible that SARS-CoV-2 can accumulate adaptive mutations modulating drug susceptibility and hampering viral antigenicity. Thus, it is vital to predict potential non-synonymous mutation sites and predict the evolution of protein structural modifications leading to drug tolerance. As two FDA-approved anti-hepatitis C virus (HCV) drugs, boceprevir, and telaprevir, have been shown to effectively inhibit SARS-CoV-2 by targeting the main protease (Mpro), here we used a high-throughput interface-based protein design strategy to identify mutational hotspots and potential signatures of adaptation in these drug binding sites of Mpro. Several mutants exhibited reduced binding affinity to these drugs, out of which hotspot residues having a strong tendency to undergo positive selection were identified. The data further indicated that these anti-HCV drugs have larger footprints in the mutational landscape of Mpro and hence encompass the highest potential for positive selection and adaptation. These findings are crucial in understanding the potential structural modifications in the drug binding sites of Mpro and thus its signatures of adaptation. Furthermore, the data could provide systemic strategies for robust antiviral design and discovery against COVID-19 in the future.


Subject(s)
Adaptation, Physiological/genetics , Antiviral Agents/chemistry , Coronavirus 3C Proteases/chemistry , Drug Design , Drug Resistance, Viral/genetics , Mutation , SARS-CoV-2/enzymology , SARS-CoV-2/genetics , Amino Acid Sequence , Antiviral Agents/pharmacology , Binding Sites/drug effects , Binding Sites/genetics , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/genetics , Coronavirus 3C Proteases/metabolism , Genetic Fitness/genetics , Hepacivirus/drug effects , Hepacivirus/enzymology , Ligands , Models, Molecular , Oligopeptides/chemistry , Oligopeptides/pharmacology , Proline/analogs & derivatives , Proline/chemistry , Proline/pharmacology , Reproducibility of Results , SARS-CoV-2/drug effects , Selection, Genetic/genetics , Structure-Activity Relationship
8.
Science ; 370(6523): 1464-1468, 2020 12 18.
Article in English | MEDLINE | ID: covidwho-922513

ABSTRACT

The spike aspartic acid-614 to glycine (D614G) substitution is prevalent in global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains, but its effects on viral pathogenesis and transmissibility remain unclear. We engineered a SARS-CoV-2 variant containing this substitution. The variant exhibits more efficient infection, replication, and competitive fitness in primary human airway epithelial cells but maintains similar morphology and in vitro neutralization properties, compared with the ancestral wild-type virus. Infection of human angiotensin-converting enzyme 2 (ACE2) transgenic mice and Syrian hamsters with both viruses resulted in similar viral titers in respiratory tissues and pulmonary disease. However, the D614G variant transmits significantly faster and displayed increased competitive fitness than the wild-type virus in hamsters. These data show that the D614G substitution enhances SARS-CoV-2 infectivity, competitive fitness, and transmission in primary human cells and animal models.


Subject(s)
COVID-19/transmission , COVID-19/virology , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Amino Acid Substitution , Angiotensin-Converting Enzyme 2/genetics , Animals , Asparagine/genetics , Cricetinae , Genetic Fitness/genetics , Glycine/genetics , Humans , Mesocricetus , Mice , Mice, Transgenic , Respiratory Mucosa/virology , Virulence/genetics , Virus Replication/genetics
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