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Molecular and Genetic Aspects of SARS-CoV-2 Infection and COVID-19 Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 66115

Special Issue Editors

Special Issue Information

Dear Colleagues,

More than a year into the SARS-CoV-2 pandemic, the amount of knowledge gathered so far is impressive. This issue aims to summarize what is known about it, from the virus to the host to therapies, including the mechanisms underlying the infection, host response, effects on pathology, and the evolution of the virus and of the pandemic, and which therapeutic strategies should be followed.

It is now clear that SARS-CoV-2 variants contribute to the extent of infection and spread of the virus and may play a role in the immune response, either acquired or induced by vaccination. In addition, host genetics and gene expression regulation have been shown to be key in the response to the infection. Interferon genetics and regulation, levels of the human receptor ACE2 or the protease TMPRSS22, and blood group are examples of how the host’s genetic condition affects the response. The molecular interaction between the S protein and its receptor is another important question in this disease. Besides ACE2, another membrane receptor with high genetic variability, Neuropilin-1, is involved in some aspects of the infection, e.g., the spread of the virus in the olfactory bulb and the central nervous system. For both receptors, it is still unclear how genetic or viral variants affect their interaction and thus the entry of the virus into the cell. Finally, all this knowledge should be translated into the design of therapeutic strategies, through both pharmacologic or epidemiologic interventions.

In this issue, we invite review and original articles that focus on any aspect of SARS-CoV-2 biology, COVID-19 processes, and, in general, any manuscript dealing with related subjects.

Dr. Jordi Pérez-Tur
Guest Editor
Dr. Fernando Cardona Serrate
Co-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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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.

Keywords

  • COVID-19
  • SARS-CoV-2
  • Host genetics
  • Viral genetics
  • Gene expression
  • Molecular interaction
  • Structural biology
  • Genetic variation
  • Genetic epidemiology
  • GWAS
  • Genome sequencing
  • Epigenetics
  • Blood groups
  • Genetic susceptibility
  • Risk factors
  • Molecular intervention
  • Long-covid
  • Drug design
  • SARS-CoV-2, SARS-CoV, MERS-CoV
  • Coronavirus biology
  • Coronavirus variants

Published Papers (8 papers)

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Research

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19 pages, 5531 KiB  
Article
Syndecan-4 Is a Key Facilitator of the SARS-CoV-2 Delta Variant’s Superior Transmission
by Anett Hudák, Gábor Veres, Annamária Letoha, László Szilák and Tamás Letoha
Int. J. Mol. Sci. 2022, 23(2), 796; https://doi.org/10.3390/ijms23020796 - 12 Jan 2022
Cited by 10 | Viewed by 6754
Abstract
Emerging SARS-CoV-2 variants pose threats to vaccination campaigns against COVID-19. Being more transmissible than the original virus, the SARS-CoV-2 B.1.617 lineage, named the Delta variant, swept through the world in 2021. The mutations in the Delta’s spike protein shift the protein towards a [...] Read more.
Emerging SARS-CoV-2 variants pose threats to vaccination campaigns against COVID-19. Being more transmissible than the original virus, the SARS-CoV-2 B.1.617 lineage, named the Delta variant, swept through the world in 2021. The mutations in the Delta’s spike protein shift the protein towards a net positive electrostatic potential. To understand the key molecular drivers of the Delta infection, we investigate the cellular uptake of the Delta spike protein and Delta spike-bearing SARS-CoV-2 pseudoviruses. Specific in vitro modification of ACE2 and syndecan expression enabled us to demonstrate that syndecan-4, the syndecan isoform abundant in the lung, enhances the transmission of the Delta variant by attaching its mutated spike glycoprotein and facilitating its cellular entry. Compared to the wild-type spike, the Delta one shows a higher affinity towards heparan sulfate proteoglycans than towards ACE2. In addition to attachment to the polyanionic heparan sulfate chains, the Delta spike’s molecular interactions with syndecan-4 also involve syndecan-4’s cell-binding domain that mediates cell-to-cell adhesion. Regardless of the complexity of these interactions, exogenously added heparin blocks Delta’s cellular entry as efficiently as syndecan-4 knockdown. Therefore, a profound understanding of the molecular mechanisms underlying Delta infections enables the development of molecularly targeted yet simple strategies to reduce the Delta variant’s spread. Full article
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19 pages, 3568 KiB  
Article
Cloning of a Passage-Free SARS-CoV-2 Genome and Mutagenesis Using Red Recombination
by Alexandra Herrmann, Doris Jungnickl, Arne Cordsmeier, Antonia Sophia Peter, Klaus Überla and Armin Ensser
Int. J. Mol. Sci. 2021, 22(19), 10188; https://doi.org/10.3390/ijms221910188 - 22 Sep 2021
Cited by 23 | Viewed by 3322
Abstract
The ongoing pandemic coronavirus (CoV) disease 2019 (COVID-19) by severe acute respiratory syndrome CoV-2 (SARS-CoV-2) has already caused substantial morbidity, mortality, and economic devastation. Reverse genetic approaches to generate recombinant viruses are a powerful tool to characterize and understand newly emerging viruses. To [...] Read more.
The ongoing pandemic coronavirus (CoV) disease 2019 (COVID-19) by severe acute respiratory syndrome CoV-2 (SARS-CoV-2) has already caused substantial morbidity, mortality, and economic devastation. Reverse genetic approaches to generate recombinant viruses are a powerful tool to characterize and understand newly emerging viruses. To contribute to the global efforts for countermeasures to control the spread of SARS-CoV-2, we developed a passage-free SARS-CoV-2 clone based on a bacterial artificial chromosome (BAC). Moreover, using a Lambda-based Red recombination, we successfully generated different reporter and marker viruses, which replicated similar to a clinical isolate in a cell culture. Moreover, we designed a full-length reporter virus encoding an additional artificial open reading frame with wild-type-like replication features. The virus-encoded reporters were successfully applied to ease antiviral testing in cell culture models. Furthermore, we designed a new marker virus encoding 3xFLAG-tagged nucleocapsid that allows the detection of incoming viral particles and, in combination with bio-orthogonal labeling for the visualization of viral RNA synthesis via click chemistry, the spatiotemporal tracking of viral replication on the single-cell level. In summary, by applying BAC-based Red recombination, we developed a powerful, reliable, and convenient platform that will facilitate studies answering numerous questions concerning the biology of SARS-CoV-2. Full article
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10 pages, 2470 KiB  
Article
Imatinib (STI571) Inhibits the Expression of Angiotensin-Converting Enzyme 2 and Cell Entry of the SARS-CoV-2-Derived Pseudotyped Viral Particles
by You-Zhe Lin, Yi-Chun Shen, Wan-Rong Wu, Wei-Jan Wang, Yuan-Liang Wang, Chen-Yuan Lin, Mien-Chie Hung and Shao-Chun Wang
Int. J. Mol. Sci. 2021, 22(13), 6938; https://doi.org/10.3390/ijms22136938 - 28 Jun 2021
Cited by 8 | Viewed by 2844
Abstract
A group of clinically approved cancer therapeutic tyrosine kinase inhibitors was screened to test their effects on the expression of angiotensin-converting enzyme 2 (ACE2), the cell surface receptor for SARS-CoV-2. Here, we show that the receptor tyrosine kinase inhibitor imatinib (also known as [...] Read more.
A group of clinically approved cancer therapeutic tyrosine kinase inhibitors was screened to test their effects on the expression of angiotensin-converting enzyme 2 (ACE2), the cell surface receptor for SARS-CoV-2. Here, we show that the receptor tyrosine kinase inhibitor imatinib (also known as STI571, Gleevec) can inhibit the expression of the endogenous ACE2 gene at both the transcript and protein levels. Treatment with imatinib resulted in inhibition of cell entry of the viral pseudoparticles (Vpps) in cell culture. In FVB mice orally fed imatinib, tissue expression of ACE2 was reduced, specifically in the lungs and renal tubules, but not in the parenchyma of other organs such as the heart and intestine. Our finding suggests that receptor tyrosine kinases play a role in COVID-19 infection and can be therapeutic targets with combined treatments of the best conventional care of COVID-19. Full article
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14 pages, 1915 KiB  
Article
Regulatory Noncoding and Predicted Pathogenic Coding Variants of CCR5 Predispose to Severe COVID-19
by Sueva Cantalupo, Vito Alessandro Lasorsa, Roberta Russo, Immacolata Andolfo, Giuseppe D’Alterio, Barbara Eleni Rosato, Giulia Frisso, Pasquale Abete, Gian Marco Cassese, Giuseppe Servillo, Ivan Gentile, Carmelo Piscopo, Matteo Della Monica, Giuseppe Fiorentino, Giuseppe Russo, Pellegrino Cerino, Carlo Buonerba, Biancamaria Pierri, Massimo Zollo, Achille Iolascon and Mario Capassoadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2021, 22(10), 5372; https://doi.org/10.3390/ijms22105372 - 20 May 2021
Cited by 15 | Viewed by 3157
Abstract
Genome-wide association studies (GWAS) found locus 3p21.31 associated with severe COVID-19. CCR5 resides at the same locus and, given its known biological role in other infection diseases, we investigated if common noncoding and rare coding variants, affecting CCR5, can predispose to severe [...] Read more.
Genome-wide association studies (GWAS) found locus 3p21.31 associated with severe COVID-19. CCR5 resides at the same locus and, given its known biological role in other infection diseases, we investigated if common noncoding and rare coding variants, affecting CCR5, can predispose to severe COVID-19. We combined single nucleotide polymorphisms (SNPs) that met the suggestive significance level (P ≤ 1 × 10−5) at the 3p21.31 locus in public GWAS datasets (6406 COVID-19 hospitalized patients and 902,088 controls) with gene expression data from 208 lung tissues, Hi-C, and Chip-seq data. Through whole exome sequencing (WES), we explored rare coding variants in 147 severe COVID-19 patients. We identified three SNPs (rs9845542, rs12639314, and rs35951367) associated with severe COVID-19 whose risk alleles correlated with low CCR5 expression in lung tissues. The rs35951367 resided in a CTFC binding site that interacts with CCR5 gene in lung tissues and was confirmed to be associated with severe COVID-19 in two independent datasets. We also identified a rare coding variant (rs34418657) associated with the risk of developing severe COVID-19. Our results suggest a biological role of CCR5 in the progression of COVID-19 as common and rare genetic variants can increase the risk of developing severe COVID-19 by affecting the functions of CCR5. Full article
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Review

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13 pages, 1061 KiB  
Review
Omicron BA.2 Lineage, the “Stealth” Variant: Is It Truly a Silent Epidemic? A Literature Review
by Giorgio Tiecco, Samuele Storti, Stefania Arsuffi, Melania Degli Antoni, Emanuele Focà, Francesco Castelli and Eugenia Quiros-Roldan
Int. J. Mol. Sci. 2022, 23(13), 7315; https://doi.org/10.3390/ijms23137315 - 30 Jun 2022
Cited by 18 | Viewed by 2224
Abstract
The epidemic curve of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is silently rising again. Worldwide, the dominant SARS-CoV-2 variant of concern (VOC) is Omicron, and its virological characteristics, such as transmissibility, pathogenicity, and resistance to both vaccine- and infection-induced immunity as well [...] Read more.
The epidemic curve of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is silently rising again. Worldwide, the dominant SARS-CoV-2 variant of concern (VOC) is Omicron, and its virological characteristics, such as transmissibility, pathogenicity, and resistance to both vaccine- and infection-induced immunity as well as antiviral drugs, are an urgent public health concern. The Omicron variant has five major sub-lineages; as of February 2022, the BA.2 lineage has been detected in several European and Asian countries, becoming the predominant variant and the real antagonist of the ongoing surge. Hence, although global attention is currently focused on dramatic, historically significant events and the multi-country monkeypox outbreak, this new epidemic is unlikely to fade away in silence. Many aspects of this lineage are still unclear and controversial, but its apparent replication advantage and higher transmissibility, as well as its ability to escape neutralizing antibodies induced by vaccination and previous infection, are rising global concerns. Herein, we review the latest publications and the most recent available literature on the BA.2 lineage of the Omicron variant. Full article
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15 pages, 1334 KiB  
Review
Omicron Genetic and Clinical Peculiarities That May Overturn SARS-CoV-2 Pandemic: A Literature Review
by Giorgio Tiecco, Samuele Storti, Melania Degli Antoni, Emanuele Focà, Francesco Castelli and Eugenia Quiros-Roldan
Int. J. Mol. Sci. 2022, 23(4), 1987; https://doi.org/10.3390/ijms23041987 - 11 Feb 2022
Cited by 38 | Viewed by 4601
Abstract
The Coronavirus disease 2019 (COVID-19) pandemic poses a great threat to global public health. The original wild-type strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has genetically evolved, and several variants of concern (VOC) have emerged. On 26 November 2021, a new [...] Read more.
The Coronavirus disease 2019 (COVID-19) pandemic poses a great threat to global public health. The original wild-type strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has genetically evolved, and several variants of concern (VOC) have emerged. On 26 November 2021, a new variant named Omicron (B.1.1.529) was designated as the fifth VOC, revealing that SARS-CoV-2 has the potential to go beyond the available therapies. The high number of mutations harboured on the spike protein make Omicron highly transmissible, less responsive to several of the currently used drugs, as well as potentially able to escape immune protection elicited by both vaccines and previous infection. We reviewed the latest publication and the most recent available literature on the Omicron variant, enlightening both reasons for concern and high hopes for new therapeutic strategies. Full article
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Other

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13 pages, 2328 KiB  
Case Report
Successful Treatment of Persistent SARS-CoV-2 Infection in a B-Cell Depleted Patient with Activated Cytotoxic T and NK Cells: A Case Report
by Jacek Jassem, Natalia Maria Marek-Trzonkowska, Tomasz Smiatacz, Łukasz Arcimowicz, Ines Papak, Ewa Jassem and Jan Maciej Zaucha
Int. J. Mol. Sci. 2021, 22(20), 10934; https://doi.org/10.3390/ijms222010934 - 10 Oct 2021
Cited by 6 | Viewed by 3595
Abstract
We report a lymphoma patient with profound B-cell deficiency after chemotherapy combined with anti-CD20 antibody successfully treated with remdesivir and convalescent plasma for prolonged SARS-CoV-2 infection. Viral clearance was likely attributed to the robust expansion and activation of TCR Vβ2 CD8+ cytotoxic T [...] Read more.
We report a lymphoma patient with profound B-cell deficiency after chemotherapy combined with anti-CD20 antibody successfully treated with remdesivir and convalescent plasma for prolonged SARS-CoV-2 infection. Viral clearance was likely attributed to the robust expansion and activation of TCR Vβ2 CD8+ cytotoxic T cells and CD16 + CD56- NK cells. This is the first presentation of TCR-specific T cell oligoclonal response in COVID-19. Our study suggests that B-cell depleted patients may effectively respond to anti-SARS-CoV-2 treatment when NK and antigen-specific Tc cell response is induced. Full article
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14 pages, 1818 KiB  
Hypothesis
Evidence for Biological Age Acceleration and Telomere Shortening in COVID-19 Survivors
by Alessia Mongelli, Veronica Barbi, Michela Gottardi Zamperla, Sandra Atlante, Luana Forleo, Marialisa Nesta, Massimo Massetti, Alfredo Pontecorvi, Simona Nanni, Antonella Farsetti, Oronzo Catalano, Maurizio Bussotti, Laura Adelaide Dalla Vecchia, Tiziana Bachetti, Fabio Martelli, Maria Teresa La Rovere and Carlo Gaetano
Int. J. Mol. Sci. 2021, 22(11), 6151; https://doi.org/10.3390/ijms22116151 - 07 Jun 2021
Cited by 53 | Viewed by 37654
Abstract
The SARS-CoV-2 infection determines the COVID-19 syndrome characterized, in the worst cases, by severe respiratory distress, pulmonary and cardiac fibrosis, inflammatory cytokine release, and immunosuppression. This condition has led to the death of about 2.15% of the total infected world population so far. [...] Read more.
The SARS-CoV-2 infection determines the COVID-19 syndrome characterized, in the worst cases, by severe respiratory distress, pulmonary and cardiac fibrosis, inflammatory cytokine release, and immunosuppression. This condition has led to the death of about 2.15% of the total infected world population so far. Among survivors, the presence of the so-called persistent post-COVID-19 syndrome (PPCS) is a common finding. In COVID-19 survivors, PPCS presents one or more symptoms: fatigue, dyspnea, memory loss, sleep disorders, and difficulty concentrating. In this study, a cohort of 117 COVID-19 survivors (post-COVID-19) and 144 non-infected volunteers (COVID-19-free) was analyzed using pyrosequencing of defined CpG islands previously identified as suitable for biological age determination. The results show a consistent biological age increase in the post-COVID-19 population, determining a DeltaAge acceleration of 10.45 ± 7.29 years (+5.25 years above the range of normality) compared with 3.68 ± 8.17 years for the COVID-19-free population (p < 0.0001). A significant telomere shortening parallels this finding in the post-COVID-19 cohort compared with COVID-19-free subjects (p < 0.0001). Additionally, ACE2 expression was decreased in post-COVID-19 patients, compared with the COVID-19-free population, while DPP-4 did not change. In light of these observations, we hypothesize that some epigenetic alterations are associated with the post-COVID-19 condition, particularly in younger patients (< 60 years). Full article
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