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1.
Microb Genom ; 9(4)2023 04.
Article in English | MEDLINE | ID: covidwho-2298278

ABSTRACT

While the world is still recovering from the Covid-19 pandemic, monkeypox virus (MPXV) awaits to cause another global outbreak as a challenge to all of mankind. However, the Covid-19 pandemic has taught us a lesson to speed up the pace of viral genomic research for the implementation of preventive and treatment strategies. One of the important aspects of MPXV that needs immediate insight is its evolutionary lineage based on genomic studies. Utilizing high-quality isolates from the GISAID (Global Initiative on Sharing All Influenza Data) database, primarily sourced from Europe and North America, we employed a SNP-based whole-genome phylogeny method and identified four major clusters among 628 MPXV isolates. Our findings indicate a distinct evolutionary lineage for the first MPXV isolate, and a complex epidemiology and evolution of MPXV strains across various countries. Further analysis of the host-pathogen interaction network revealed key viral proteins, such as E3, SPI-2, K7 and CrmB, that play a significant role in regulating the network and inhibiting the host's cellular innate immune system. Our structural analysis of proteins E3 and CrmB revealed potential disruption of stability due to certain mutations. While this study identified a large number of mutations within the new outbreak clade, it also reflected that we need to move fast with the genomic analysis of newly detected strains from around the world to develop better prevention and treatment methods.


Subject(s)
COVID-19 , Monkeypox , Humans , Monkeypox virus/genetics , Phylogeny , Pandemics , Mutation
2.
Nature ; 599(7883): 114-119, 2021 11.
Article in English | MEDLINE | ID: covidwho-2114880

ABSTRACT

The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha)1. In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era.


Subject(s)
Immune Evasion , SARS-CoV-2/growth & development , SARS-CoV-2/immunology , Virus Replication/immunology , Antibodies, Neutralizing/immunology , COVID-19 Vaccines/immunology , Cell Fusion , Cell Line , Female , Health Personnel , Humans , India , Kinetics , Male , Spike Glycoprotein, Coronavirus/metabolism , Vaccination
3.
Nucleic Acids Res ; 50(3): 1551-1561, 2022 02 22.
Article in English | MEDLINE | ID: covidwho-1636373

ABSTRACT

During the course of the COVID-19 pandemic, large-scale genome sequencing of SARS-CoV-2 has been useful in tracking its spread and in identifying variants of concern (VOC). Viral and host factors could contribute to variability within a host that can be captured in next-generation sequencing reads as intra-host single nucleotide variations (iSNVs). Analysing 1347 samples collected till June 2020, we recorded 16 410 iSNV sites throughout the SARS-CoV-2 genome. We found ∼42% of the iSNV sites to be reported as SNVs by 30 September 2020 in consensus sequences submitted to GISAID, which increased to ∼80% by 30th June 2021. Following this, analysis of another set of 1774 samples sequenced in India between November 2020 and May 2021 revealed that majority of the Delta (B.1.617.2) and Kappa (B.1.617.1) lineage-defining variations appeared as iSNVs before getting fixed in the population. Besides, mutations in RdRp as well as RNA-editing by APOBEC and ADAR deaminases seem to contribute to the differential prevalence of iSNVs in hosts. We also observe hyper-variability at functionally critical residues in Spike protein that could alter the antigenicity and may contribute to immune escape. Thus, tracking and functional annotation of iSNVs in ongoing genome surveillance programs could be important for early identification of potential variants of concern and actionable interventions.


Subject(s)
Evolution, Molecular , Genetic Variation/genetics , Genome, Viral/genetics , Host-Pathogen Interactions/genetics , SARS-CoV-2/genetics , APOBEC-1 Deaminase/genetics , Adenosine Deaminase/genetics , Animals , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19/virology , Chlorocebus aethiops , Coronavirus RNA-Dependent RNA Polymerase/genetics , Databases, Genetic , Immune Evasion/genetics , India/epidemiology , Phylogeny , RNA-Binding Proteins/genetics , SARS-CoV-2/classification , SARS-CoV-2/growth & development , Spike Glycoprotein, Coronavirus/genetics , Vero Cells
4.
J Cell Biochem ; 123(3): 673-690, 2022 03.
Article in English | MEDLINE | ID: covidwho-1626208

ABSTRACT

COVID-19 is a sneaking deadly disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The rapid increase in the number of infected patients worldwide enhances the exigency for medicines. However, precise therapeutic drugs are not available for COVID-19; thus, exhaustive research is critically required to unscramble the pathogenic tools and probable therapeutic targets for the development of effective therapy. This study utilizes a chemogenomics strategy, including computational tools for the identification of viral-associated differentially expressed genes (DEGs), and molecular docking of potential chemical compounds available in antiviral, anticancer, and natural product-based libraries against these DEGs. We scrutinized the messenger RNA expression profile of SARS-CoV-2 patients, publicly available on the National Center for Biotechnology Information-Gene Expression Omnibus database, stratified them into different groups based on the severity of infection, superseded by identification of overlapping mild and severe infectious (MSI)-DEGs. The profoundly expressed MSI-DEGs were then subjected to trait-linked weighted co-expression network construction and hub module detection. The hub module MSI-DEGs were then exposed to enrichment (gene ontology + pathway) and protein-protein interaction network analyses where Rho guanine nucleotide exchange factor 1 (ARHGEF1) gene conjectured in all groups and could be a probable target of therapy. Finally, we used the molecular docking and molecular dynamics method to identify inherent hits against the ARHGEF1 gene from antiviral, anticancer, and natural product-based libraries. Although the study has an identified significant association of the ARHGEF1 gene in COVID19; and probable compounds targeting it, using in silico methods, these targets need to be validated by both in vitro and in vivo methods to effectively determine their therapeutic efficacy against the devastating virus.


Subject(s)
COVID-19 Drug Treatment , COVID-19 , COVID-19/genetics , Gene Ontology , Humans , Molecular Docking Simulation , Rho Guanine Nucleotide Exchange Factors , SARS-CoV-2/genetics
5.
Science ; 374(6570): 995-999, 2021 Nov 19.
Article in English | MEDLINE | ID: covidwho-1526449

ABSTRACT

Delhi, the national capital of India, experienced multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreaks in 2020 and reached population seropositivity of >50% by 2021. During April 2021, the city became overwhelmed by COVID-19 cases and fatalities, as a new variant, B.1.617.2 (Delta), replaced B.1.1.7 (Alpha). A Bayesian model explains the growth advantage of Delta through a combination of increased transmissibility and reduced sensitivity to immune responses generated against earlier variants (median estimates: 1.5-fold greater transmissibility and 20% reduction in sensitivity). Seropositivity of an employee and family cohort increased from 42% to 87.5% between March and July 2021, with 27% reinfections, as judged by increased antibody concentration after a previous decline. The likely high transmissibility and partial evasion of immunity by the Delta variant contributed to an overwhelming surge in Delhi.


Subject(s)
COVID-19/epidemiology , COVID-19/virology , Genome, Viral , Adolescent , Adult , COVID-19/immunology , COVID-19/transmission , Child , Humans , Immune Evasion , India/epidemiology , Molecular Epidemiology , Phylogeny , Reinfection , Seroepidemiologic Studies , Young Adult
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