scholarly journals Epistatic models predict mutable sites in SARS-CoV-2 proteins and epitopes

2022 ◽  
Vol 119 (4) ◽  
pp. e2113118119
Author(s):  
Juan Rodriguez-Rivas ◽  
Giancarlo Croce ◽  
Maureen Muscat ◽  
Martin Weigt
Keyword(s):  
Statistical Models ◽  
Operating Characteristic ◽  
Sequence Data ◽  
Viral Evolution ◽  
Therapeutic Interventions ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Potential Impact ◽  
Over Time ◽  
Amino Acid Conservation

The emergence of new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major concern given their potential impact on the transmissibility and pathogenicity of the virus as well as the efficacy of therapeutic interventions. Here, we predict the mutability of all positions in SARS-CoV-2 protein domains to forecast the appearance of unseen variants. Using sequence data from other coronaviruses, preexisting to SARS-CoV-2, we build statistical models that not only capture amino acid conservation but also more complex patterns resulting from epistasis. We show that these models are notably superior to conservation profiles in estimating the already observable SARS-CoV-2 variability. In the receptor binding domain of the spike protein, we observe that the predicted mutability correlates well with experimental measures of protein stability and that both are reliable mutability predictors (receiver operating characteristic areas under the curve ∼0.8). Most interestingly, we observe an increasing agreement between our model and the observed variability as more data become available over time, proving the anticipatory capacity of our model. When combined with data concerning the immune response, our approach identifies positions where current variants of concern are highly overrepresented. These results could assist studies on viral evolution and future viral outbreaks and, in particular, guide the exploration and anticipation of potentially harmful future SARS-CoV-2 variants.

scholarly journals Epistatic models predict mutable sites in SARS-CoV-2 proteins and epitopes

2021 ◽  
Author(s):  
Juan Rodriguez-Rivas ◽  
Giancarlo Croce ◽  
Maureen Muscat ◽  
Martin Weigt
Keyword(s):  
Immune Response ◽  
Statistical Models ◽  
Sequence Data ◽  
Viral Evolution ◽  
Therapeutic Interventions ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Potential Impact ◽  
Over Time ◽  
Amino Acid Conservation

The emergence of new variants of SARS-CoV-2 is a major concern given their potential impact on the transmissibility and pathogenicity of the virus as well as the efficacy of therapeutic interventions. Here, we predict the mutability of all positions in SARS-CoV-2 protein domains to forecast the appearance of unseen variants. Using sequence data from other coronaviruses, pre-existing to SARS-CoV-2, we build statistical models that do not only capture amino-acid conservation but more complex patterns resulting from epistasis. We show that these models are notably superior to conservation profiles in estimating the already observable SARS-CoV-2 variability. In the receptor binding domain of the spike protein, we observe that the predicted mutability correlates well with experimental measures of protein stability and that both are reliable mutability predictors (ROC AUC ~0.8). Most interestingly, we observe an increasing agreement between our model and the observed variability as more data become available over time, proving the anticipatory capacity of our model. When combined with data concerning the immune response, our approach identifies positions where current variants of concern are highly overrepresented. These results could assist studies on viral evolution, future viral outbreaks and, in particular, guide the exploration and anticipation of potentially harmful future SARS-CoV-2 variants.

scholarly journals Persistent SARS-CoV-2 Infection in Immunocompromised Host Displaying Treatment Induced Viral Evolution

2021 ◽  
Author(s):  
Ida Monrad ◽  
Signe Risgaard Sahlertz ◽  
Stine Sofie Frank Nielsen ◽  
Louise Ørnskov Pedersen ◽  
Mikkel Steen Petersen ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Plasma Treatment ◽  
Immunocompromised Patient ◽  
Viral Evolution ◽  
Immunocompromised Host ◽  
Lymphocytic Leukemia ◽  
Spike Protein ◽  
Viral Sequencing ◽  
Over Time

Abstract We report a COVID-19 case with SARS-CoV-2 persisting beyond 333 days in an immunocompromised patient with chronic lymphocytic leukemia, asymptomatically carrying infectious SARS-CoV-2 at day 197 post diagnosis. Additionally, viral sequencing indicates major changes in the spike protein over time, temporally associated with convalescent plasma treatment.

scholarly journals Adaptation, spread and transmission of SARS-CoV-2 in farmed minks and related humans in the Netherlands

2021 ◽  
Author(s):  
Lu Lu ◽  
Reina S. Sikkema ◽  
Francisca C. Velkers ◽  
David F. Nieuwenhuijse ◽  
Egil A.J. Fischer ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Genetic Information ◽  
Human Population ◽  
Sequence Data ◽  
Spike Protein ◽  
Genomic Sequencing ◽  
Receptor Binding Domain ◽  
Human Interface ◽  
Protein Position ◽  
Epidemiological Information

In the first wave of the COVID-19 pandemic (April 2020), SARS-CoV-2 was detected in farmed minks and genomic sequencing was performed on mink farms and farm personnel. Here, we describe the outbreak and use sequence data with Bayesian phylodynamic methods to explore SARS-CoV-2 transmission in minks and related humans on farms. High number of farm infections (68/126) in minks and farm related personnel (>50% of farms) were detected, with limited spread to the general human population. Three of five initial introductions of SARS-CoV-2 lead to subsequent spread between mink farms until November 2020. The largest cluster acquired a mutation in the receptor binding domain of the Spike protein (position 486), evolved faster and spread more widely and longer. Movement of people and distance between farms were statistically significant predictors of virus dispersal between farms. Our study provides novel insights into SARS-CoV-2 transmission between mink farms and highlights the importance of combing genetic information with epidemiological information at the animal-human interface.

Predicting Variant-Driven Multi-Wave Pattern of COVID-19 via a Machine Learning Analysis of Spike Protein Mutations

2021 ◽  
Author(s):  
Adele de Hoffer ◽  
Shahram Vatani ◽  
Corentin Cot ◽  
Giacomo Cacciapaglia ◽  
Maria Luisa Chiusano ◽  
...  
Keyword(s):  
Machine Learning ◽  
Learning Algorithm ◽  
Sequence Data ◽  
Epidemiological Data ◽  
Wave Pattern ◽  
Host Cells ◽  
Spike Protein ◽  
Levenshtein Distance ◽  
Current Case ◽  
Over Time

Abstract Never before such a vast amount of data, including genome sequencing, has been collected for any viral pandemic than for the current case of COVID-19. This offers the possibility to trace the virus evolution and to assess the role mutations play in its spread within the population, in real time. To this end, we focused on the Spike protein for its central role in mediating viral outbreak and replication in host cells. Employing the Levenshtein distance on the Spike protein sequences, we designed a machine learning algorithm yielding a temporal clustering of the available dataset. From this, we were able to identify and define emerging persistent variants that are in agreement with known evidences. Our novel algorithm allowed us to define persistent variants as chains that remain stable over time and to highlight emerging variants of epidemiological interest as branching events that occur over time. Hence, we determined the relationship and temporal connection between variants of interest and the ensuing passage to dominance of the current variants of concern. Remarkably, the analysis and the relevant tools introduced in our work serve as an early warning for the emergence of new persistent variants once the associated cluster reaches 1% of the time-binned sequence data. We validated our approach and its effectiveness on the onset of the Alpha variant of concern. We further predict that the recently identified lineage AY.4.2 (‘Delta plus’) is causing a new emerging variant. Comparing our findings with the epidemiological data we demonstrated that each new wave is dominated by a new emerging variant, thus confirming the hypothesis of the existence of a strong correlation between the birth of variants and the pandemic multi-wave temporal pattern. The above allows us to introduce the epidemiology of variants that we described via the Mutation epidemiological Renormalisation Group (MeRG) framework.

scholarly journals A collection of designed peptides to target SARS-Cov-2 – ACE2 interaction: PepI-Covid19 database

2020 ◽  
Author(s):  
Ruben Molina ◽  
Baldo Oliva ◽  
Narcis Fernandez-Fuentes
Keyword(s):  
Scientific Community ◽  
Therapeutic Agents ◽  
Spike Protein ◽  
Structural Basis ◽  
Cellular Receptor ◽  
Receptor Binding Domain ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Potential Impact ◽  
Novel Therapeutic

AbstractThe angiotensin-converting enzyme 2 is the cellular receptor used by SARS coronavirus SARS-CoV and SARS-CoV-2 to enter the cell. Both coronavirus use the receptor-binding domain (RBD) of their viral spike protein to interact with ACE2. The structural basis of these interactions are already known, forming a dimer of ACE2 with a trimer of the spike protein, opening the door to target them to prevent the infection. Here we present PepI-Cov19 database, a repository of peptides designed to target the interaction between the RDB of SARS-CoV-2 and ACE2 as well as the dimerization of ACE2 monomers. The peptides were modelled using our method PiPreD that uses native elements of the interaction between the targeted protein and cognate partner that are subsequently included in the designed peptides. These peptides recapitulate stretches of residues present in the native interface plus novel and highly diverse conformations that preserve the key interactions on the interface. PepI-Covid19 database provides an easy and convenient access to this wealth of information to the scientific community with the view of maximizing its potential impact in the development of novel therapeutic agents.

scholarly journals Increased Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7 to Antibody Neutralization

2021 ◽  
Author(s):  
David Ho ◽  
Pengfei Wang ◽  
Lihong Liu ◽  
Sho Iketani ◽  
Yang Luo ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Protective Efficacy ◽  
Viral Evolution ◽  
Spike Protein ◽  
Binding Motif ◽  
Receptor Binding Domain ◽  
Effective Interventions ◽  
Recent Emergence ◽  
New Challenges ◽  
The Uk

Abstract The Covid-19 pandemic has ravaged the globe, and its causative agent, SARS-CoV-2, continues to rage. Prospects of ending this pandemic rest on the development of effective interventions. Two monoclonal antibody (mAb) therapeutics have received emergency use authorization, and more are in the pipeline. Furthermore, multiple vaccine constructs have shown promise, including two with ~95% protective efficacy against Covid-19. However, these interventions were directed toward the initial SARS-CoV-2 that emerged in 2019. Considerable viral evolution has occurred since, including variants with a D614G mutation that have become dominant. Viruses with this mutation alone do not appear to be antigenically distinct, however. Recent emergence of new SARS-CoV-2 variants B.1.1.7 in the UK and B.1.351 in South Africa is of concern because of their purported ease of transmission and extensive mutations in the spike protein. We now report that B.1.1.7 is refractory to neutralization by most mAbs to the N-terminal domain (NTD) of spike and relatively resistant to a number of mAbs to the receptor-binding domain (RBD). It is modestly more resistant to convalescent plasma (~3 fold) and vaccinee sera (~2 fold). Findings on B.1.351 are more worrisome in that this variant is not only refractory to neutralization by most NTD mAbs but also by multiple potent mAbs to the receptor-binding motif on RBD, largely due to an E484K mutation. Moreover, B.1.351 is markedly more resistant to neutralization by convalescent plasma (~11-33 fold) and vaccinee sera (~6.5-8.6 fold). B.1.351 and emergent variants with similar spike mutations present new challenges for mAb therapy and threaten the protective efficacy of current vaccines.

scholarly journals Analysis of SARS-CoV-2 Mutations Over Time Reveals Increasing Prevalence of Variants in the Spike Protein and RNA-Dependent RNA Polymerase

2021 ◽  
Author(s):  
William M Showers ◽  
Sonia M Leach ◽  
Katerina Kechris ◽  
Michael Strong
Keyword(s):  
Rna Polymerase ◽  
High Frequency ◽  
Drug Targets ◽  
Spike Protein ◽  
Structural Level ◽  
Receptor Binding Domain ◽  
Rna Dependent Rna Polymerase ◽  
Public Health Strategies ◽  
Further Development ◽  
Over Time

Amid the ongoing COVID-19 pandemic, it has become increasingly important to monitor the mutations that arise in the SARS-CoV-2 virus, to prepare public health strategies and guide the further development of vaccines and therapeutics. The spike (S) protein and the proteins comprising the RNA-Dependent RNA Polymerase (RdRP) are key vaccine and drug targets, respectively, making mutation surveillance of these proteins of great importance. Full protein sequences for the spike proteins and RNA-dependent RNA polymerase proteins were downloaded from the GISAID database, aligned, and the variants identified. Polymorphisms in the protein sequence were investigated at the protein structural level and examined longitudinally in order to identify sequence and strain variants that are emerging over time. Our analysis revealed a group of variants in the spike protein and the polymerase complex that appeared in August, and account for around five percent of the genomes analyzed up to the last week of October. A structural analysis also facilitated investigation of several unique variants in the receptor binding domain and the N-terminal domain of the spike protein, with high-frequency mutations occurring more commonly in these regions. The identification of new variants emphasizes the need for further study on the effects of these mutations and the implications of their increased prevalence, particularly as these mutations may impact vaccine or therapeutic efficacy.

scholarly journals Novel Mutations in the S1 domain of COVID 19 Spike Protein of Isolate from Gujarat Origin, Western India

2020 ◽  
Author(s):  
Arup Kumar Banerjee ◽  
Feroza Begum ◽  
Dluya Thagriki ◽  
Prem Prakash Tripathi ◽  
Upasana Ray
Keyword(s):  
Receptor Binding ◽  
Virus Genome ◽  
Binding Domain ◽  
Therapeutic Interventions ◽  
Spike Protein ◽  
Western India ◽  
Receptor Binding Domain ◽  
Genome Sequences ◽  
Novel Mutations ◽  
Receptor Interactions

Till date there are three full length COVID 19 virus genome sequences available from India. The earlier two were reported from Kerala, Southern India and the more recent one has been reported from Gujarat, western part of India. In this paper we report two novel mutations in the Spike protein sequence of Gujarat’s isolate. These mutations are based on comparison with the original Wuhan sequence. The two mutations have been found to be located just upstream and downstream of the receptor binding domain (RBD). Out of these two one has also been found to affect the secondary structure of the S1 domain. Since both of these mutations lie near the receptor binding domain, they might influence the spike receptor interactions by changing the conformation of the spike protein S1 domain. These mutations are uniquely placed and might be important in the context of vaccine engineering and therapeutic interventions.

scholarly journals Genomic Evidence of a Sars-Cov-2 Reinfection Case With E484K Spike Mutation in Brazil

2021 ◽  
Author(s):  
Carolina Kymie Vasques Nonaka ◽  
Marília Miranda Franco ◽  
Tiago Gräf ◽  
Ana Verena Almeida Mendes ◽  
Renato Santana de Aguiar ◽  
...  
Keyword(s):  
South Africa ◽  
Immune Responses ◽  
Neutralizing Antibodies ◽  
Immune Escape ◽  
Viral Evolution ◽  
First Episode ◽  
Receptor Binding Domain ◽  
First Case ◽  
Potential Impact ◽  
The Uk

To date, uncertainty remains about how long the protective immune responses against SARS-CoV-2 persists and the first reports of suspected reinfection began to be described in recovered patients months after the first episode. Viral evolution may favor reinfections, and the recently described spike mutations, particularly in the receptor binding domain (RBD) in SARS-CoV-2 lineages circulating in the UK, South Africa, and most recently in Brazil, have raised concern on their potential impact in infectivity and immune escape. We report the first case of reinfection from genetically distinct SARS-CoV-2 lineage presenting the E484K spike mutation in Brazil, a variant associated with escape from neutralizing antibodies.

scholarly journals Adaptation, spread and transmission of SARS-CoV-2 in farmed minks and associated humans in the Netherlands

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lu Lu ◽  
Reina S. Sikkema ◽  
Francisca C. Velkers ◽  
David F. Nieuwenhuijse ◽  
Egil A. J. Fischer ◽  
...  
Keyword(s):  
Amino Acid ◽  
Genetic Information ◽  
Sequence Data ◽  
Farm Workers ◽  
Spike Protein ◽  
Genomic Sequencing ◽  
Receptor Binding Domain ◽  
Human Interface ◽  
Protein Position ◽  
Epidemiological Information

AbstractIn the first wave of the COVID-19 pandemic (April 2020), SARS-CoV-2 was detected in farmed minks and genomic sequencing was performed on mink farms and farm personnel. Here, we describe the outbreak and use sequence data with Bayesian phylodynamic methods to explore SARS-CoV-2 transmission in minks and humans on farms. High number of farm infections (68/126) in minks and farm workers (>50% of farms) were detected, with limited community spread. Three of five initial introductions of SARS-CoV-2 led to subsequent spread between mink farms until November 2020. Viruses belonging to the largest cluster acquired an amino acid substitution in the receptor binding domain of the Spike protein (position 486), evolved faster and spread longer and more widely. Movement of people and distance between farms were statistically significant predictors of virus dispersal between farms. Our study provides novel insights into SARS-CoV-2 transmission between mink farms and highlights the importance of combining genetic information with epidemiological information when investigating outbreaks at the animal-human interface.

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