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New Knowledge in the Study of Coronaviruses: Towards One Health...
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New Knowledge in the Study of Coronaviruses: Towards One Health and Whole Genome Sequencing Approaches

A special issue of Microorganisms (ISSN 2076-2607). This special issue belongs to the section "Virology".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 16500

Special Issue Editor

Dr. Simone Peletto

E-Mail Website
Guest Editor
Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d’Aosta, 10154 Torino, Italy
Interests: microbiota; phylogeny; pestivirus; coronavirus; molecular typing
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Coronaviruses, belonging to the order Nidovirales, are enveloped, positive single-stranded RNA viruses that have the largest and most complex genomes among riboviruses. Their name derives from the protrusions (spikes) present in the viral envelope. The Coronaviridae family includes four genera (Alpha-, Beta-, Gamma- and Deltacoronavirus), which include several species of viruses capable of infecting humans, mammals and birds.

The advent of the SARS-CoV-2 pandemic has enormously increased the attention on these viruses, which were previously known in human pathology, especially for SARS-CoV and MERS-CoV. Often, the coronavirus environmental reservoir is represented by different animal species, especially bats; humans are the final hosts of these viruses or become infected due to spillover events. Therefore, given the presence of coronaviruses in animal hosts and their ability to spillover, it is essential to adopt a One Health approach.

Coronaviruses research should be based on molecular approaches—in particular, by adopting Whole Genome Sequencing (WGS) techniques that are needed to characterize these viruses and track possible spillover events, in order to prevent new pandemic events. In fact, if from a diagnostic point of view, it may still be sufficient to adopt classical techniques of the amplification of nucleic acids (NAATs). It is necessary to encourage the research to adopt the full genome approach to constantly increase the available knowledge about these viruses.

For these reasons, this Special Issue was designed to collect works concerning the study of coronaviruses in both humans and animals. We welcome articles that may concern both diagnostic and research aspects, with a particular emphasis on works based on WGS approaches.

Dr. Simone Peletto
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Microorganisms is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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Research

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15 pages, 5330 KiB  
Article
S-Gene Target Failure as an Effective Tool for Tracking the Emergence of Dominant SARS-CoV-2 Variants in Switzerland and Liechtenstein, Including Alpha, Delta, and Omicron BA.1, BA.2, and BA.4/BA.5
by Dominique Hilti, Faina Wehrli, Sabine Berchtold, Susanna Bigler, Thomas Bodmer, Helena M. B. Seth-Smith, Tim Roloff, Philipp Kohler, Christian R. Kahlert, Laurent Kaiser, Adrian Egli, Lorenz Risch, Martin Risch and Nadia Wohlwend
Microorganisms 2024, 12(2), 321; https://doi.org/10.3390/microorganisms12020321 - 03 Feb 2024
Viewed by 785
Abstract
During the SARS-CoV-2 pandemic, the Dr. Risch medical group employed the multiplex TaqPathTM COVID-19 CE-IVD RT-PCR Kit for large-scale routine diagnostic testing in Switzerland and the principality of Liechtenstein. The TaqPath Kit is a widely used multiplex assay targeting three genes (i.e., [...] Read more.
During the SARS-CoV-2 pandemic, the Dr. Risch medical group employed the multiplex TaqPathTM COVID-19 CE-IVD RT-PCR Kit for large-scale routine diagnostic testing in Switzerland and the principality of Liechtenstein. The TaqPath Kit is a widely used multiplex assay targeting three genes (i.e., ORF1AB, N, S). With emergence of the B.1.1.7 (Alpha) variant, a diagnostic flaw became apparent as the amplification of the S-gene target was absent in these samples due to a deletion (ΔH69/V70) in the Alpha variant genome. This S-gene target failure (SGTF) was the earliest indication of a new variant emerging and was also observed in subsequent variants such as Omicron BA.1 and BA4/BA.5. The Delta variant and Omicron BA.2 did not present with SGTF. From September 2020 to November 2022, we investigated the applicability of the SGTF as a surrogate marker for emerging variants such as B.1.1.7, B.1.617.2 (Delta), and Omicron BA.1, BA.2, and BA.4/BA.5 in samples with cycle threshold (Ct) values < 30. Next to true SGTF-positive and SGTF-negative samples, there were also samples presenting with delayed-type S-gene amplification (higher Ct value for S-gene than ORF1ab gene). Among these, a difference of 3.8 Ct values between the S- and ORF1ab genes was found to best distinguish between “true” SGTF and the cycle threshold variability of the assay. Samples above the cutoff were subsequently termed partial SGTF (pSGTF). Variant confirmation was performed by whole-genome sequencing (Oxford Nanopore Technology, Oxford, UK) or mutation-specific PCR (TIB MOLBIOL). In total, 17,724 (7.4%) samples among 240,896 positives were variant-confirmed, resulting in an overall sensitivity and specificity of 93.2% [92.7%, 93.7%] and 99.3% [99.2%, 99.5%], respectively. Sensitivity was increased to 98.2% [97.9% to 98.4%] and specificity lowered to 98.9% [98.6% to 99.1%] when samples with pSGTF were included. Furthermore, weekly logistic growth rates (α) and sigmoid’s midpoint (t0) were calculated based on SGTF data and did not significantly differ from calculations based on comprehensive data from GISAID. The SGTF therefore allowed for a valid real-time estimate for the introduction of all dominant variants in Switzerland and Liechtenstein. Full article
(This article belongs to the Special Issue New Knowledge in the Study of Coronaviruses: Towards One Health and Whole Genome Sequencing Approaches)
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12 pages, 2375 KiB  
Article
Physics-Based Signal Analysis of Genome Sequences: An Overview of GenomeBits
by Enrique Canessa
Microorganisms 2023, 11(11), 2733; https://doi.org/10.3390/microorganisms11112733 - 09 Nov 2023
Viewed by 840
Abstract
A comprehensive overview of the recent physics-inspired genome analysis tool, GenomeBits, is presented. This is based on traditional signal processing methods such as discrete Fourier transform (DFT). GenomeBits can be used to extract underlying genomics features from the distribution of nucleotides, and can [...] Read more.
A comprehensive overview of the recent physics-inspired genome analysis tool, GenomeBits, is presented. This is based on traditional signal processing methods such as discrete Fourier transform (DFT). GenomeBits can be used to extract underlying genomics features from the distribution of nucleotides, and can be further used to analyze the mutation patterns in viral genomes. Examples of the main GenomeBits findings outlining the intrinsic signal organization of genomics sequences for different SARS-CoV-2 variants along the pandemic years 2020–2022 and Monkeypox cases in 2021 are presented to show the usefulness of GenomeBits. GenomeBits results for DFT of SARS-CoV-2 genomes in different geographical regions are discussed, together with the GenomeBits analysis of complete genome sequences for the first coronavirus variants reported: Alpha, Beta, Gamma, Epsilon and Eta. Interesting features of the Delta and Omicron variants in the form of a unique ‘order–disorder’ transition are uncovered from these samples, as well as from their cumulative distribution function and scatter plots. This class of transitions might reveal the cumulative outcome of mutations on the spike protein. A salient feature of GenomeBits is the mapping of the nucleotide bases (A,T,C,G) into an alternating spin-like numerical sequence via a series having binary (0,1) indicators for each A,T,C,G. This leads to the derivation of a set of statistical distribution curves. Furthermore, the quantum-based extension of the GenomeBits model to an analogous probability measure is shown to identify properties of genome sequences as wavefunctions via a superposition of states. An association of the integral of the GenomeBits coding and a binding-like energy can, in principle, also be established. The relevance of these different results in bioinformatics is analyzed. Full article
(This article belongs to the Special Issue New Knowledge in the Study of Coronaviruses: Towards One Health and Whole Genome Sequencing Approaches)
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14 pages, 1906 KiB  
Article
Sequencing of SARS-CoV-2 RNA Fragments in Wastewater Detects the Spread of New Variants during Major Events
by Damir Zhakparov, Yves Quirin, Yi Xiao, Nicole Battaglia, Michael Holzer, Martin Bühler, Walter Kistler, Doortje Engel, Jon Paulin Zumthor, Alexa Caduff and Katja Baerenfaller
Microorganisms 2023, 11(11), 2660; https://doi.org/10.3390/microorganisms11112660 - 30 Oct 2023
Cited by 1 | Viewed by 1134
Abstract
The sequencing of SARS-CoV-2 RNA in wastewater is an unbiased method to detect the spread of emerging variants and to track regional infection dynamics, which is especially useful in case of limited testing and clinical sequencing. To test how major international events influence [...] Read more.
The sequencing of SARS-CoV-2 RNA in wastewater is an unbiased method to detect the spread of emerging variants and to track regional infection dynamics, which is especially useful in case of limited testing and clinical sequencing. To test how major international events influence the spread of new variants we have sequenced SARS-CoV-2 RNA in the wastewater samples of Davos, Landquart, Lostallo, and St. Moritz in the Swiss canton of Grisons in the time around the international sports competitions in Davos and St. Moritz in December 2021, and additionally in May 2022 and January 2023 in Davos and St. Moritz during the World Economic Forum (WEF) in Davos. The prevalence of the variants identified from the wastewater sequencing data showed that the Omicron variant BA.1 had spread in Davos and St. Moritz during the international sporting events hosted there in December 2021. This spread was associated with an increase in case numbers, while it was not observed in Landquart and Lostallo. Another instance of new variant spread occurred during the WEF in January 2023, when the Omicron variant BA.2.75 arrived in Davos but not in St. Moritz. We can therefore conclude that major international events promote the spread of new variants in the respective host region, which has important implications for the protective measures that should be taken. Full article
(This article belongs to the Special Issue New Knowledge in the Study of Coronaviruses: Towards One Health and Whole Genome Sequencing Approaches)
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13 pages, 438 KiB  
Article
Tracking the Selective Pressure Profile and Gene Flow of SARS-CoV-2 Delta Variant in Italy from April to October 2021 and Frequencies of Key Mutations from Three Representative Italian Regions
by Alessandra Lo Presti, Angela Di Martino, Luigina Ambrosio, Luca De Sabato, Arnold Knijn, Gabriele Vaccari, Ilaria Di Bartolo, Stefano Morabito, Calogero Terregino, Alice Fusaro, Isabella Monne, Edoardo Giussani, Fabio Tramuto, Carmelo Massimo Maida, Walter Mazzucco, Claudio Costantino, Martina Rueca, Emanuela Giombini, Cesare Ernesto Maria Gruber, Maria Rosaria Capobianchi, Anna Teresa Palamara, Paola Stefanelli and on behalf of the Italian Genomic Laboratory Networkadd Show full author list remove Hide full author list
Microorganisms 2023, 11(11), 2644; https://doi.org/10.3390/microorganisms11112644 - 27 Oct 2023
Cited by 1 | Viewed by 879
Abstract
The SARS-CoV-2 Delta variant of concern (VOC) was often associated with serious clinical course of the COVID-19 disease. Herein, we investigated the selective pressure, gene flow and evaluation on the frequencies of mutations causing amino acid substitutions in the Delta variant in three [...] Read more.
The SARS-CoV-2 Delta variant of concern (VOC) was often associated with serious clinical course of the COVID-19 disease. Herein, we investigated the selective pressure, gene flow and evaluation on the frequencies of mutations causing amino acid substitutions in the Delta variant in three Italian regions. A total of 1500 SARS-CoV-2 Delta genomes, collected in Italy from April to October 2021 were investigated, including a subset of 596 from three Italian regions. The selective pressure and the frequency of amino acid substitutions and the prediction of their possible impact on the stability of the proteins were investigated. Delta variant dataset, in this study, identified 68 sites under positive selection: 16 in the spike (23.5%), 11 in nsp2 (16.2%) and 10 in nsp12 (14.7%) genes. Three of the positive sites in the spike were located in the receptor-binding domain (RBD). In Delta genomes from the three regions, 6 changes were identified as very common (>83.7%), 4 as common (>64.0%), 21 at low frequency (2.1%–25.0%) and 29 rare (≤2.0%). The detection of positive selection on key mutations may represent a model to identify recurrent signature mutations of the virus. Full article
(This article belongs to the Special Issue New Knowledge in the Study of Coronaviruses: Towards One Health and Whole Genome Sequencing Approaches)
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13 pages, 4003 KiB  
Article
Prevalence of SARS-CoV-2 Omicron Sublineages and Spike Protein Mutations Conferring Resistance against Monoclonal Antibodies in a Swedish Cohort during 2022–2023
by Jonathan Haars, Navaneethan Palanisamy, Frans Wallin, Paula Mölling, Johan Lindh, Martin Sundqvist, Patrik Ellström, René Kaden and Johan Lennerstrand
Microorganisms 2023, 11(10), 2417; https://doi.org/10.3390/microorganisms11102417 - 27 Sep 2023
Viewed by 1559
Abstract
Monoclonal antibodies (mAbs) are an important treatment option for COVID-19 caused by SARS-CoV-2, especially in immunosuppressed patients. However, this treatment option can become ineffective due to mutations in the SARS-CoV-2 genome, mainly in the receptor binding domain (RBD) of the spike (S) protein. [...] Read more.
Monoclonal antibodies (mAbs) are an important treatment option for COVID-19 caused by SARS-CoV-2, especially in immunosuppressed patients. However, this treatment option can become ineffective due to mutations in the SARS-CoV-2 genome, mainly in the receptor binding domain (RBD) of the spike (S) protein. In the present study, 7950 SARS-CoV-2 positive samples from the Uppsala and Örebro regions of central Sweden, collected between March 2022 and May 2023, were whole-genome sequenced using amplicon-based sequencing methods on Oxford Nanopore GridION, Illumina MiSeq, Illumina HiSeq, or MGI DNBSEQ-G400 instruments. Pango lineages were determined and all single nucleotide polymorphism (SNP) mutations that occurred in these samples were identified. We found that the dominant sublineages changed over time, and mutations conferring resistance to currently available mAbs became common. Notable ones are R346T and K444T mutations in the RBD that confer significant resistance against tixagevimab and cilgavimab mAbs. Further, mutations conferring a high-fold resistance to bebtelovimab, such as the K444T and V445P mutations, were also observed in the samples. This study highlights that resistance mutations have over time rendered currently available mAbs ineffective against SARS-CoV-2 in most patients. Therefore, there is a need for continued surveillance of resistance mutations and the development of new mAbs that target more conserved regions of the RBD. Full article
(This article belongs to the Special Issue New Knowledge in the Study of Coronaviruses: Towards One Health and Whole Genome Sequencing Approaches)
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8 pages, 2991 KiB  
Communication
Early Detection of the Recombinant SARS-CoV-2 XAN Variant in Bulgaria: Initial Genomic Insights into Yet Another Piece of the Growing Puzzle of Recombinant Clades
by Ivailo Alexiev, Ivan Ivanov, Marta Giovanetti, Eleonora Cella, Ivan Stoikov, Deyan Donchev, Lyubomira Grigorova, Anna Gancheva, Reneta Dimitrova, Fabio Scarpa, Neli Korsun, Ivelina Trifonova, Veselin Dobrinov, Todor Kantardjiev, Iva Christova and Massimo Ciccozzi
Microorganisms 2023, 11(8), 2041; https://doi.org/10.3390/microorganisms11082041 - 09 Aug 2023
Cited by 1 | Viewed by 1099
Abstract
The first recombinant SARS-CoV-2 variants were identified in 2022, causing public health concerns. The importance of recombinant variants has increased especially since the WHO designated the recombinant variant XBB and its lineages as subvariants that require monitoring on 20 November 2022. In this [...] Read more.
The first recombinant SARS-CoV-2 variants were identified in 2022, causing public health concerns. The importance of recombinant variants has increased especially since the WHO designated the recombinant variant XBB and its lineages as subvariants that require monitoring on 20 November 2022. In this study, we provide the first insights into the new SARS-CoV-2 variant named XAN, a recombinant composed of Omicron sub-lineages BA.2 and BA.5. To our knowledge, this is the first report on the recombinant SARS-CoV-2 XAN variant identified in Bulgaria. Full article
(This article belongs to the Special Issue New Knowledge in the Study of Coronaviruses: Towards One Health and Whole Genome Sequencing Approaches)
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14 pages, 2952 KiB  
Article
SARS-CoV-2 Recombinants: Genomic Comparison between XBF and Its Parental Lineages
by Fabio Scarpa, Chiara Locci, Ilenia Azzena, Marco Casu, Pier Luigi Fiori, Alessandra Ciccozzi, Marta Giovanetti, Miriana Quaranta, Giancarlo Ceccarelli, Stefano Pascarella, Massimo Ciccozzi and Daria Sanna
Microorganisms 2023, 11(7), 1824; https://doi.org/10.3390/microorganisms11071824 - 17 Jul 2023
Cited by 3 | Viewed by 2928
Abstract
Recombination events are very common and represent one of the primary drivers of RNA virus evolution. The XBF SARS-CoV-2 lineage is one of the most recently generated recombinants during the COVID-19 pandemic. It is a recombinant of BA.5.2.3 and BA.2.75.3, both descendants of [...] Read more.
Recombination events are very common and represent one of the primary drivers of RNA virus evolution. The XBF SARS-CoV-2 lineage is one of the most recently generated recombinants during the COVID-19 pandemic. It is a recombinant of BA.5.2.3 and BA.2.75.3, both descendants of lineages that caused many concerns (BA.5 and BA.2.75, respectively). Here, we performed a genomic survey focused on comparing the recombinant XBF with its parental lineages to provide a comprehensive assessment of the evolutionary potential, epidemiological trajectory, and potential risks. Genetic analyses indicated that although XBF initially showed the typical expansion depicted by a steep curve, causing several concerns, currently there is no indication of significant expansion potential or a contagion rate surpassing that of other currently active or previously prevalent lineages. BSP indicated that the peak has been reached around 19 October 2022 and then the genetic variability suffered slight oscillations until early 5 March 2023 when the population size reduced for the last time starting its last plateau that is still lasting. Structural analyses confirmed its reduced potential, also indicating that properties of NTDs and RBDs of XBF and its parental lineages present no significant difference. Of course, cautionary measures must still be taken and genome-based monitoring remains the best tool for detecting any important changes in viral genome composition. Full article
(This article belongs to the Special Issue New Knowledge in the Study of Coronaviruses: Towards One Health and Whole Genome Sequencing Approaches)
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13 pages, 2204 KiB  
Article
Molecular In-Depth on the Epidemiological Expansion of SARS-CoV-2 XBB.1.5
by Fabio Scarpa, Ilenia Azzena, Chiara Locci, Marco Casu, Pier Luigi Fiori, Alessandra Ciccozzi, Silvia Angeletti, Elena Imperia, Marta Giovanetti, Antonello Maruotti, Alessandra Borsetti, Roberto Cauda, Antonio Cassone, Allegra Via, Stefano Pascarella, Daria Sanna and Massimo Ciccozzi
Microorganisms 2023, 11(4), 912; https://doi.org/10.3390/microorganisms11040912 - 31 Mar 2023
Cited by 10 | Viewed by 2236
Abstract
Since the beginning of the pandemic, the generation of new variants periodically recurs. The XBB.1.5 SARS-CoV-2 variant is one of the most recent. This research was aimed at verifying the potential hazard of this new subvariant. To achieve this objective, we performed a [...] Read more.
Since the beginning of the pandemic, the generation of new variants periodically recurs. The XBB.1.5 SARS-CoV-2 variant is one of the most recent. This research was aimed at verifying the potential hazard of this new subvariant. To achieve this objective, we performed a genome-based integrative approach, integrating results from genetic variability/phylodynamics with structural and immunoinformatic analyses to obtain as comprehensive a viewpoint as possible. The Bayesian Skyline Plot (BSP) shows that the viral population size reached the plateau phase on 24 November 2022, and the number of lineages peaked at the same time. The evolutionary rate is relatively low, amounting to 6.9 × 10−4 subs/sites/years. The NTD domain is identical for XBB.1 and XBB.1.5 whereas their RBDs only differ for the mutations at position 486, where the Phe (in the original Wuhan) is replaced by a Ser in XBB and XBB.1, and by a Pro in XBB.1.5. The variant XBB.1.5 seems to spread more slowly than sub-variants that have caused concerns in 2022. The multidisciplinary molecular in-depth analyses on XBB.1.5 performed here does not provide evidence for a particularly high risk of viral expansion. Results indicate that XBB.1.5 does not possess features to become a new, global, public health threat. As of now, in its current molecular make-up, XBB.1.5 does not represent the most dangerous variant. Full article
(This article belongs to the Special Issue New Knowledge in the Study of Coronaviruses: Towards One Health and Whole Genome Sequencing Approaches)
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Review

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10 pages, 805 KiB  
Review
A One Health Perspective on Canine Coronavirus: A Wolf in Sheep’s Clothing?
by Alessio Buonavoglia, Francesco Pellegrini, Nicola Decaro, Michela Galgano and Annamaria Pratelli
Microorganisms 2023, 11(4), 921; https://doi.org/10.3390/microorganisms11040921 - 02 Apr 2023
Viewed by 2092
Abstract
Canine coronavirus (CCoV) is a positive-strand RNA virus generally responsible for mild-to-severe gastroenteritis in dogs. In recent years, new CCoVs with acquired pathogenic characteristics have emerged, turning the spotlight on the evolutionary potential of CCoVs. To date, two genotypes are known, CCoV type [...] Read more.
Canine coronavirus (CCoV) is a positive-strand RNA virus generally responsible for mild-to-severe gastroenteritis in dogs. In recent years, new CCoVs with acquired pathogenic characteristics have emerged, turning the spotlight on the evolutionary potential of CCoVs. To date, two genotypes are known, CCoV type I and CCoV type II, sharing up to 96% nucleotide identity in the genome but highly divergent in the spike gene. In 2009, the detection of a novel CCoV type II, which likely originated from a double recombination event with transmissible gastroenteritis virus (TGEV), led to the proposal of a new classification: CCoV type IIa, including classical CCoVs and CCoV type IIb, including TGEV-like CCoV. Recently, a virus strictly correlated to CCoV was isolated from children with pneumonia in Malaysia. The HuPn-2018 strain, classified as a novel canine–feline-like recombinant virus, is supposed to have jumped from dogs into people. A novel CoV of canine origin, HuCCoV_Z19Haiti, closely related to the Malaysian strain was also detected in a man with fever after travel to Haiti, suggesting that infection with Malaysian-like strains may occur. These data and the emergence of highly pathogenic CoVs in humans underscore the significant threat that CoV spillovers pose to humans and how we should mitigate this hazard. Full article
(This article belongs to the Special Issue New Knowledge in the Study of Coronaviruses: Towards One Health and Whole Genome Sequencing Approaches)
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Other

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9 pages, 879 KiB  
Case Report
Transient SARS-CoV-2 RNA-Dependent RNA Polymerase Mutations after Remdesivir Treatment for Chronic COVID-19 in Two Transplant Recipients: Case Report and Intra-Host Viral Genomic Investigation
by Shangxin Yang, Ashrit Multani, Jacob M. Garrigues, Michael S. Oh, Peera Hemarajata, Taylor Burleson, Nicole M. Green, Caspian Oliai, Pryce T. Gaynor, Omer E. Beaird, Drew J. Winston, Christopher S. Seet and Joanna M. Schaenman
Microorganisms 2023, 11(8), 2096; https://doi.org/10.3390/microorganisms11082096 - 16 Aug 2023
Cited by 2 | Viewed by 2032
Abstract
Remdesivir is the first FDA-approved drug for treating severe SARS-CoV-2 infection and targets RNA-dependent RNA polymerase (RdRp) that is required for viral replication. To monitor for the development of mutations that may result in remdesivir resistance during prolonged treatment, we sequenced SARS-CoV-2 specimens [...] Read more.
Remdesivir is the first FDA-approved drug for treating severe SARS-CoV-2 infection and targets RNA-dependent RNA polymerase (RdRp) that is required for viral replication. To monitor for the development of mutations that may result in remdesivir resistance during prolonged treatment, we sequenced SARS-CoV-2 specimens collected at different treatment time points in two transplant patients with severe COVID-19. In the first patient, an allogeneic hematopoietic stem cell transplant recipient, a transient RdRp catalytic subunit mutation (nsp12:A449V) was observed that has not previously been associated with remdesivir resistance. As no in vitro study had been conducted to elucidate the phenotypic effect of nsp12:A449V, its clinical significance is unclear. In the second patient, two other transient RdRp mutations were detected: one in the catalytic subunit (nsp12:V166A) and the other in an accessory subunit important for processivity (nsp7:D67N). This is the first case report for a potential link between the nsp12:V166A mutation and remdesivir resistance in vivo, which had only been previously described by in vitro studies. The nsp7:D67N mutation has not previously been associated with remdesivir resistance, and whether it has a phenotypic effect is unknown. Our study revealed SARS-CoV-2 genetic dynamics during remdesivir treatment in transplant recipients that involved mutations in the RdRp complex (nsp7 and nsp12), which may be the result of selective pressure. These results suggest that close monitoring for potential resistance during the course of remdesivir treatment in highly vulnerable patient populations may be beneficial. Development and utilization of diagnostic RdRp genotyping tests may be a future direction for improving the management of chronic COVID-19. Full article
(This article belongs to the Special Issue New Knowledge in the Study of Coronaviruses: Towards One Health and Whole Genome Sequencing Approaches)
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