scholarly journals Analysis of Indian SARS-CoV-2 Genomes Reveals Prevalence of D614G Mutation in Spike Protein Predicting an Increase in Interaction With TMPRSS2 and Virus Infectivity

2020 ◽  
Vol 11 ◽  
Author(s):  
Sunil Raghav ◽  
Arup Ghosh ◽  
Jyotirmayee Turuk ◽  
Sugandh Kumar ◽  
Atimukta Jha ◽  
...  
Keyword(s):  
Disease Transmission ◽  
Haplotype Network ◽  
Amplicon Sequencing ◽  
Spike Protein ◽  
Virus Infectivity ◽  
Gujarat State ◽  
Docking Analysis ◽  
Virus Shedding ◽  
Global Pandemic ◽  
Molecular Modeling And Docking

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, has emerged as a global pandemic worldwide. In this study, we used ARTIC primers–based amplicon sequencing to profile 225 SARS-CoV-2 genomes from India. Phylogenetic analysis of 202 high-quality assemblies identified the presence of all the five reported clades 19A, 19B, 20A, 20B, and 20C in the population. The analyses revealed Europe and Southeast Asia as two major routes for introduction of the disease in India followed by local transmission. Interestingly, the19B clade was found to be more prevalent in our sequenced genomes (17%) compared to other genomes reported so far from India. Haplotype network analysis showed evolution of 19A and 19B clades in parallel from predominantly Gujarat state in India, suggesting it to be one of the major routes of disease transmission in India during the months of March and April, whereas 20B and 20C appeared to evolve from 20A. At the same time, 20A and 20B clades depicted prevalence of four common mutations 241 C > T in 5′ UTR, P4715L, F942F along with D614G in the Spike protein. D614G mutation has been reported to increase virus shedding and infectivity. Our molecular modeling and docking analysis identified that D614G mutation resulted in enhanced affinity of Spike S1–S2 hinge region with TMPRSS2 protease, possibly the reason for increased shedding of S1 domain in G614 as compared to D614. Moreover, we also observed an increased concordance of G614 mutation with the viral load, as evident from decreased Ct value of Spike and the ORF1ab gene.

scholarly journals SARS-CoV2 genome analysis of Indian isolates and molecular modelling of D614G mutated spike protein with TMPRSS2 depicted its enhanced interaction and virus infectivity

2020 ◽  
Author(s):  
Sunil Raghav ◽  
Arup Ghosh ◽  
Jyotirmayee Turuk ◽  
Sugandh Kumar ◽  
Atimukta Jha ◽  
...  
Keyword(s):  
Molecular Modelling ◽  
Genome Analysis ◽  
Disease Transmission ◽  
Amplicon Sequencing ◽  
Virus Genome ◽  
Host Cells ◽  
Spike Protein ◽  
Disease Spread ◽  
Clinical Samples ◽  
Virus Infectivity

AbstractCOVID-19 that emerged as a global pandemic is caused by SARS-CoV-2 virus. The virus genome analysis during disease spread reveals about its evolution and transmission. We did whole genome sequencing of 225 clinical strains from the state of Odisha in eastern India using ARTIC protocol-based amplicon sequencing. Phylogenetic analysis identified the presence of all five reported clades 19A, 19B, 20A, 20B and 20C in the population. The analyses revealed two major routes for the introduction of the disease in India i.e. Europe and South-east Asia followed by local transmission. Interestingly, 19B clade was found to be much more prevalent in our sequenced genomes (17%) as compared to other genomes reported so far from India. The haplogroup analysis for clades showed evolution of 19A and 19B in parallel whereas the 20B and 20C appeared to evolve from 20A. Majority of the 19A and 19B clades were present in cases that migrated from Gujarat state in India suggesting it to be one of the major initial points of disease transmission in India during month of March and April. We found that with the time 20A and 20B clades evolved drastically that originated from central Europe. At the same time, it has been observed that 20A and 20B clades depicted selection of four common mutations i.e. 241 C>T (5’UTR), P323L in RdRP, F942F in NSP3 and D614G in the spike protein. We found an increase in the concordance of G614 mutation evolution with the viral load in clinical samples as evident from decreased Ct value of spike and Orf1ab gene in qPCR. Molecular modelling and docking analysis identified that D614G mutation enhanced interaction of spike with TMPRSS2 protease, which could impact the shedding of S1 domain and infectivity of the virus in host cells.

scholarly journals Experimental Models to Study COVID-19 Effect in Stem Cells

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 91
Author(s):  
Rishi Man Chugh ◽  
Payel Bhanja ◽  
Andrew Norris ◽  
Subhrajit Saha
Keyword(s):  
Stem Cells ◽  
Ex Vivo ◽  
Drug Efficacy ◽  
Cell Loss ◽  
Experimental Models ◽  
Model Systems ◽  
Virus Infectivity ◽  
Ex Vivo Model ◽  
Global Pandemic ◽  
The Impact

The new strain of coronavirus (severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)) emerged in 2019 and hence is often referred to as coronavirus disease 2019 (COVID-19). This disease causes hypoxic respiratory failure and acute respiratory distress syndrome (ARDS), and is considered as the cause of a global pandemic. Very limited reports in addition to ex vivo model systems are available to understand the mechanism of action of this virus, which can be used for testing of any drug efficacy against virus infectivity. COVID-19 induces tissue stem cell loss, resulting inhibition of epithelial repair followed by inflammatory fibrotic consequences. Development of clinically relevant models is important to examine the impact of the COVID-19 virus in tissue stem cells among different organs. In this review, we discuss ex vivo experimental models available to study the effect of COVID-19 on tissue stem cells.

scholarly journals Conformational Flexibility and Local Frustration in the Functional States of the SARS-CoV-2 Spike B.1.1.7 and B.1.351 Variants: Mutation-Induced Allosteric Modulation Mechanism of Functional Dynamics and Protein Stability

2021 ◽  
Author(s):  
Gennady Verkhivker
Keyword(s):  
Protein Stability ◽  
Cell Receptor ◽  
Spike Protein ◽  
Coarse Grained ◽  
Virus Infectivity ◽  
Functional Changes ◽  
Conformational Substates ◽  
Functional Relationships ◽  
Functional Dynamics ◽  
Open States

The experimental and computational studies of the SARS-CoV-2 spike protein variants revealed an important role of the D614G mutation that is shared across variants of concern(VOCs), linking the effect of this mutation with the enhanced virus infectivity and transmissibility. The recent structural and biophysical studies characterized the closed and open states of the B.1.1.7 (B.1.1.7) and B.1.351 (Beta) spike variants allowing for a more detailed atomistic characterization of the conformational landscapes and functional changes. In this study, we employed coarse-grained simulations of the SARS-CoV-2 spike variant trimers together with the ensemble-based mutational frustration analysis to characterize the dynamics signatures of the conformational landscapes. By combining the local frustration analysis of the conformational ensembles with collective dynamics and residue-based mutational scanning of protein stability, we determine protein stability hotspots and identify potential energetic drivers favoring the receptor-accessible open spike states for the B.1.1.7 and B.1.351 spike variants. Through mutational scanning of protein stability changes we quantify mutational adaptability of the S-G614, S-B.1.1.7 and S-B.1.351 variants in different functional forms. Using this analysis, we found a significant conformational and mutational plasticity of the open states for all studied variants. The results of this study suggest that modulation of the energetic frustration at the inter-protomer interfaces can serve as a mechanism for allosteric couplings between mutational sites, the inter-protomer hinges of functional motions and motions of the receptor-binding domain required for binding of the host cell receptor. The proposed mechanism of mutation-induced energetic frustration may result in the greater adaptability and the emergence of multiple conformational substates in the open form. This study also suggested functional relationships between mutation-induced modulation of protein dynamics, local frustration and allosteric regulation of the SARS-CoV-2 spike protein.

Virtual Screening of Phyto Chemicals Against SARS-CoV-2 Targets

2021 ◽  
Vol 6 (3) ◽  
pp. 61-76
Author(s):  
Shahanas Naisam ◽  
Vidhya V. S. ◽  
Suvanish Kumar ◽  
Nidhin Sreekumar
Keyword(s):  
Dynamics Simulation ◽  
Spike Protein ◽  
Ligand Interaction ◽  
Docking Analysis ◽  
Drug Molecules ◽  
In Vivo Analysis ◽  
Protein Ligand Interaction ◽  
The Stability ◽  
3Cl Protease

The COVID-19 pandemic wave has recommenced and is spreading like wildfire across the globe. The well-reported antiviral potency of phyto compounds could offer potential drug molecules for the current predicament. The present study analyses the molecular interaction of selected phyto compounds and SARS-CoV-2 molecular target proteins, namely spike protein, RNA-dependent RNA polymerase, 3C-like proteases, and papain-like protease. Ten newly modeled ligands were also considered for the study. Molecular docking analysis was carried out independently using MOE, AutoDock Vina, Schrodinger-Glide, and the stability of protein-ligand interaction was validated through molecular dynamics simulation. Petunidin interacts with spike protein resulting in a good Gscore, binding energy, and H-bond interaction. Also, alions, letestuianin-A, (+)-pinitol show better interaction with RdRp, 3CL-protease, and papain-like protease, respectively. The presented work screens through 2314 ligands to yield top-ranked molecules which could be taken up to develop potential lead molecules via in-vivo analysis.

scholarly journals Whole-Genome Sequence of SARS-CoV-2 Isolate Siena-1/2020

2020 ◽  
Vol 9 (39) ◽  
Author(s):  
Maria Grazia Cusi ◽  
David Pinzauti ◽  
Claudia Gandolfo ◽  
Gabriele Anichini ◽  
Gianni Pozzi ◽  
...  
Keyword(s):  
Amino Acid ◽  
Severe Acute Respiratory Syndrome ◽  
Genome Sequence ◽  
Amino Acid Change ◽  
Amplicon Sequencing ◽  
Spike Protein ◽  
Whole Genome Sequence ◽  
Whole Genome ◽  
Nanopore Sequencing ◽  
Protein Coding

ABSTRACT The complete genome sequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) isolate Siena-1/2020 was obtained by Nanopore sequencing, combining the direct RNA sequencing and amplicon sequencing approaches. The isolate belongs to the B1.1 lineage, which is prevalent in Europe, and contains a mutation in the spike protein coding sequence leading to the D614G amino acid change.

scholarly journals Patients’ case scenario as well as approaches and strategies adopted to manage COVID-19 pandemic at Aligarh Muslim University, Aligarh, India

2020 ◽  
Author(s):  
Syed Ziaur Rahman ◽  
Saif Khan
Keyword(s):  
Health Care Professionals ◽  
Disease Transmission ◽  
Recovery Rate ◽  
Tertiary Care ◽  
Medical Science ◽  
Transmission Curve ◽  
Corona Virus ◽  
Global Pandemic ◽  
Severe Acute Respiratory Infection ◽  
The University

Corona virus Disease 2019 (COVID-19) is a severe acute respiratory infection caused by corona virus-2 (SARS-CoV-2). It originated from Wuhan city of China in December 2019 and spread like a wild fire to the entire globe and was declared as global pandemic by WHO on March 11, 2020. With no available cure and vaccine, this disease has taken a mammoth toll on the human life; therefore, SMS (‘Social Distancing’, use of ‘Mask’ and regular hand washing with ‘Soap’) has emerged as a sole tool to prevent its spread. The Indian government declared the first lockdown from March 25th 2020 with subsequent second, third and fourth lockdowns up to 31st March 2020 to decrease the disease transmission and flatten the disease transmission curve. Aligarh Muslim University is one of the prestigious central and residential universities in India. It is located in Aligarh district adjoining national capital region. The university has an attached tertiary care ‘Jawaharlal Nehru Medical College Hospital’. This narrative review discusses the various steps and procedures taken up by the university and hospital administration, other functionaries, faculty members and doctors in tackling the serious pandemic until 22nd June 2020. The proactive role of administration, dedication and hard work of health care professionals and innovation of some academicians has given a new vista of opportunities to tackle this global health pandemic. The recovery rate of coronavirus patients at AMU hospital is recorded as 71.9%, which is much higher than national average recovery rate (56%). Thus, AMU model gives some positive insights to fight the current global pandemic. Bangladesh Journal of Medical Science Vol.19(0) 2020 p. S 28-S 35

scholarly journals Incorporating the mutational landscape of SARS-COV-2 variants and case-dependent vaccination rates into epidemic models

2021 ◽  
Author(s):  
Mohammad Mihrab Chowdhury ◽  
Md Rafiul Islam ◽  
Md Sakhawat Hossain ◽  
Nusrat Tabassum ◽  
Angela Peace
Keyword(s):  
Disease Transmission ◽  
Vaccine Development ◽  
Vaccination Rate ◽  
Time Varying ◽  
Vaccination Rates ◽  
Mutational Landscape ◽  
Global Pandemic ◽  
Effective Manner ◽  
Short Period ◽  
People’S Attitudes

Coronavirus Disease (COVID-19), which began as a small outbreak in Wuhan, China in December 2019, became a global pandemic within months due to its high transmissibility. In the absence of pharmaceutical treatment, various non-pharmaceutical interventions (NPIs) to contain the spread of COVID-19 brought the entire world to a halt. After almost a year of seemingly returning to normalcy with the world's quickest vaccine development, the advent of more infectious and vaccine-resistant coronavirus variants is bringing the situation back to where it was a year ago. In the light of this new situation, we conducted a study to portray the possible scenarios based on the three key factors: impact of interventions (pharmaceutical and NPIs), vaccination rate, and vaccine efficacy. In our study, we assessed two of the most crucial factors, transmissibility and vaccination rate, in order to reduce the spreading of COVID in a simple but effective manner. In order to incorporate the time-varying mutational landscape of COVID-19 variants, we estimated weighted transmissibility composed of the proportion of existing strains that naturally vary over time. Additionally, we consider time-varying vaccination rates based on the number of daily new cases. Our method for calculating the vaccination rate from past active cases is an effective approach in forecasting probable future scenarios as it actively tracks people's attitudes toward immunization as active cases change. Our simulations show that if a large number of individuals cannot be vaccinated in a short period of time, adopting NPIs is the best approach to manage disease transmission with the emergence of new vaccine breakthrough variants and more infectious variants.

scholarly journals Conserved in 186 countries the RBD fraction of SARS CoV-2 S-protein with in-silicoT500S mutation strongly blocks ACE2 rejecting the viral spike; A Molecular-docking analysis.

2021 ◽  
Author(s):  
Amrita Banerjee ◽  
Mehak Kanwar ◽  
Dipannita Santra ◽  
Smarajit Maiti
Keyword(s):  
Crystal Structure ◽  
Molecular Docking ◽  
Receptor Binding ◽  
Structural Alignment ◽  
Receptor Binding Domain ◽  
Wild Type ◽  
Docking Analysis ◽  
Global Pandemic ◽  
Complete Rejection ◽  
Molecular Docking Analysis

SARS-CoV-2 developed global-pandemic with millions of infections/deaths. Blocker/inhibitor of ACE2 and viral-spikes Receptor-Binding-Domain RBD-blockers are helpful. Here, conserved RBD (CUTs) from 186-countries were compared with WUHAN-Hu-1 wild-type by CLUSTAL-X2 and Structural-alignment using Pymol. The RBD of ACE2-bound nCOV2 crystal-structure (2.68)6VW1 was analyzed by Haddock-PatchDock. Extensive structural study/trial to introduce point/double/triple mutations in the following locations (Y489S/Y453S/T500S/T500Y)/(Y489S,Y453S/Y489S,T500S/Y489S,T500Y/Y453S,T500S/Y453S,T500Y)/ (Y489S,Y453S,T500S/Y489S,Y453S,T500Y) of CUT4 (most-effective) were tested with Swiss-Model-Expacy. Blind-docking of mutated-CUTs to ACE2 (6VW1) by Haddock-Hawkdock was performed and optimally complete-rejection of nCOV2 to ACE2 was noticed. Further, competitive-docking/binding-analyses were done by PRODIGY. Present results suggest that compared to the wild-spike, CUT4 showed extra LYS31-PHE490/GLN42-GLN498 bonding and lack of TYR41-THR500 interaction (in wild H-bond:2.639) with ACE2 RBD. Mutated-CUT4 strongly binds with the ACE2-RBD, promoting TYR41-T500S (H-bond: 2.0 and 1.8)/T500Y (H-bond:2.6) interaction and complete inhibition of ACE2 RBD-nCOV2. Mutant combinations T500S,Y489S,T500S and Y489S,Y453S,T500Y mostly blocked ACE2. Conclusively, CUT4-mutant rejects whole glycosylated-nCoV2 pre-dock/post-dock/competitive-docking conditions.

scholarly journals Dissecting genetic and sex-specific sources of host heterogeneity in pathogen shedding and spread

2021 ◽  
Vol 17 (1) ◽  
pp. e1009196
Author(s):  
Jonathon A. Siva-Jothy ◽  
Pedro F. Vale
Keyword(s):  
Viral Load ◽  
Individual Variation ◽  
Disease Transmission ◽  
Genetic Background ◽  
Pathogen Transmission ◽  
Published Data ◽  
Virus Shedding ◽  
Transmission Potential ◽  
Sources Of Variation ◽  
Host Heterogeneity

Host heterogeneity in disease transmission is widespread but precisely how different host traits drive this heterogeneity remains poorly understood. Part of the difficulty in linking individual variation to population-scale outcomes is that individual hosts can differ on multiple behavioral, physiological and immunological axes, which will together impact their transmission potential. Moreover, we lack well-characterized, empirical systems that enable the quantification of individual variation in key host traits, while also characterizing genetic or sex-based sources of such variation. Here we used Drosophila melanogaster and Drosophila C Virus as a host-pathogen model system to dissect the genetic and sex-specific sources of variation in multiple host traits that are central to pathogen transmission. Our findings show complex interactions between genetic background, sex, and female mating status accounting for a substantial proportion of variance in lifespan following infection, viral load, virus shedding, and viral load at death. Two notable findings include the interaction between genetic background and sex accounting for nearly 20% of the variance in viral load, and genetic background alone accounting for ~10% of the variance in viral shedding and in lifespan following infection. To understand how variation in these traits could generate heterogeneity in individual pathogen transmission potential, we combined measures of lifespan following infection, virus shedding, and previously published data on fly social aggregation. We found that the interaction between genetic background and sex explained ~12% of the variance in individual transmission potential. Our results highlight the importance of characterising the sources of variation in multiple host traits to understand the drivers of heterogeneity in disease transmission.

scholarly journals Cell-Mimicking Nanodecoys Protect Lung Cells by Neutralization of SARS-CoV-2 Spike Proteins

2020 ◽  
Author(s):  
Zhenhua Li ◽  
Phuong-Uyen C. Dinh ◽  
Kristen D. Popowski ◽  
Halle Lutz ◽  
Zhenzhen Wang ◽  
...  
Keyword(s):  
Viral Entry ◽  
Human Lung ◽  
Spike Protein ◽  
Inhalation Therapy ◽  
Viral Receptor ◽  
Angiotensin Converting Enzyme 2 ◽  
Non Invasive ◽  
Global Pandemic ◽  
Integral Role

Abstract Coronavirus disease of 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has grown into a global pandemic, with no specific antiviral treatments or vaccines are yet approved. The viral receptor, angiotensin-converting enzyme 2 (ACE2), has been demonstrated to play an integral role in the pathogenesis of SARS-CoV-2, necessary for host cell viral entry. Inspired by this, we synthesized ACE2 nanodecoys from human lung spheroid cells (LSCs) capable of binding the Spike protein as a potential neutralization agent for SARS-CoV-2. Our results show LSC-nanodecoys has a high affinity and neutralization efficiency to both spike protein and chemically synthesized SARS-CoV-2 mimics. In addition, non-invasive inhalation therapy in mice showed successful delivery of the nanodecoy to the lungs, as well as in-vivo retention of the nanodecoys over 72 hours after a single administration. Furthermore, inhalation of nanodecoy accelerated the clearance of SARS-CoV-2 mimics from the lung and did not cause toxicity.

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