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Viruses
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Emerging Concepts in SARS-CoV-2 Biology and Pathology
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Emerging Concepts in SARS-CoV-2 Biology and Pathology

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "SARS-CoV-2 and COVID-19".

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 17732

Special Issue Editor

Dr. Daniele Focosi

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Guest Editor
Pisa University Hospital, 56126 Pisa, Italy
Interests: virology; emerging viruses; pandemics; viral evolution; hematology; immunogenetics; transplant immunology; transfusion medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Much has been learnt about SARS-Co-2 biology, but much also remains to be learned. Despite currently driving pathology mostly in immunocompromised patients, SARS-CoV-2 is still evolving at rates much higher than for other human RNA viruses, with convergence over moving Spike targets, but globally increasing its genetic and serological distance. The source of the pandemic has been redefined as a panzootic disease of placental mammals, leaving room for reverse zoonoses. The virus has also been shown to be able to compartmentalize and persist, even in immunocompetent hosts, where it can cause long-lasting symptoms for which directly acting antivirals are under investigation. Unfortunately, many emergency-use authorized drugs are providing marginal benefits in vaccinated patients, and none of the anti-Spike monoclonal antibodies authorized so far are effective against emerging Omicron variants. Fundamental virology has discovered how SARS-CoV-2 carries miRNA-like molecules able to suppress the immune response and how the genome can integrate. In this Special Issue, we will collect advances in epidemiology and fundamental virology, as well as novel therapeutics.

Dr. Daniele Focosi
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. Viruses 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 2600 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.

Related Special Issue

Published Papers (10 papers)

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Editorial

Jump to: Research, Review, Other

4 pages, 225 KiB  
Editorial
Second-Generation SARS-CoV-2 Recombinants: Lessons from Other Viruses
by Daniele Focosi and Fabrizio Maggi
Viruses 2023, 15(5), 1063; https://doi.org/10.3390/v15051063 - 26 Apr 2023
Cited by 2 | Viewed by 1289
Abstract
RNA viruses have developed notable strategies to evolve and escape host immunity [...] Full article
(This article belongs to the Special Issue Emerging Concepts in SARS-CoV-2 Biology and Pathology)
3 pages, 506 KiB  
Editorial
How SARS-CoV-2 Big Data Are Challenging Viral Taxonomy Rules
by Daniele Focosi and Fabrizio Maggi
Viruses 2023, 15(3), 715; https://doi.org/10.3390/v15030715 - 09 Mar 2023
Cited by 2 | Viewed by 1812
Abstract
SARS-CoV-2 genomic sequencing has peaked to unprecedented compared to other viruses [...] Full article
(This article belongs to the Special Issue Emerging Concepts in SARS-CoV-2 Biology and Pathology)
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Research

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15 pages, 3310 KiB  
Article
Tetherin Restricts SARS-CoV-2 despite the Presence of Multiple Viral Antagonists
by Elena Hagelauer, Rishikesh Lotke, Dorota Kmiec, Dan Hu, Mirjam Hohner, Sophie Stopper, Rayhane Nchioua, Frank Kirchhoff, Daniel Sauter and Michael Schindler
Viruses 2023, 15(12), 2364; https://doi.org/10.3390/v15122364 - 30 Nov 2023
Cited by 1 | Viewed by 1262
Abstract
Coronavirus infection induces interferon-stimulated genes, one of which encodes Tetherin, a transmembrane protein inhibiting the release of various enveloped viruses from infected cells. Previous studies revealed that SARS-CoV encodes two Tetherin antagonists: the Spike protein (S), inducing lysosomal degradation of Tetherin, and ORF7a, [...] Read more.
Coronavirus infection induces interferon-stimulated genes, one of which encodes Tetherin, a transmembrane protein inhibiting the release of various enveloped viruses from infected cells. Previous studies revealed that SARS-CoV encodes two Tetherin antagonists: the Spike protein (S), inducing lysosomal degradation of Tetherin, and ORF7a, altering its glycosylation. Similarly, SARS-CoV-2 has also been shown to use ORF7a and Spike to enhance virion release in the presence of Tetherin. Here, we directly compare the abilities and mechanisms of these two viral proteins to counteract Tetherin. Therefore, cell surface and total Tetherin levels upon ORF7a or S expression were investigated using flow cytometry and Western blot analysis. SARS-CoV and SARS-CoV-2 S only marginally reduced Tetherin cell surface levels in a cell type-dependent manner. In HEK293T cells, under conditions of high exogenous Tetherin expression, SARS-CoV-2 S and ORF7a reduced total cellular Tetherin levels much more efficiently than the respective counterparts derived from SARS-CoV. Nevertheless, ORF7a from both species was able to alter Tetherin glycosylation. The ability to decrease total protein levels of Tetherin was conserved among S proteins from different SARS-CoV-2 variants (α, γ, δ, ο). While SARS-CoV-2 S and ORF7a both colocalized with Tetherin, only ORF7a directly interacted with the restriction factor in a two-hybrid assay. Despite the presence of multiple Tetherin antagonists, SARS-CoV-2 replication in Caco-2 cells was further enhanced upon Tetherin knockout. Altogether, our data show that endogenous Tetherin restricts SARS-CoV-2 replication and that the antiviral activity of Tetherin is only partially counteracted by viral antagonists with differential and complementary modes of action. Full article
(This article belongs to the Special Issue Emerging Concepts in SARS-CoV-2 Biology and Pathology)
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13 pages, 762 KiB  
Article
Innate Immune Gene Polymorphisms and COVID-19 Prognosis
by Evangelos Bakaros, Ioanna Voulgaridi, Vassiliki Paliatsa, Nikolaos Gatselis, Georgios Germanidis, Evangelia Asvestopoulou, Stamatia Alexiou, Elli Botsfari, Vasiliki Lygoura, Olga Tsachouridou, Iordanis Mimtsoudis, Maria Tseroni, Styliani Sarrou, Varvara A. Mouchtouri, Katerina Dadouli, Fani Kalala, Simeon Metallidis, George Dalekos, Christos Hadjichristodoulou and Matthaios Speletas
Viruses 2023, 15(9), 1784; https://doi.org/10.3390/v15091784 - 22 Aug 2023
Cited by 1 | Viewed by 1123
Abstract
COVID-19 is characterized by a heterogeneous clinical presentation and prognosis. Risk factors contributing to the development of severe disease include old age and the presence of comorbidities. However, the genetic background of the host has also been recognized as an important determinant of [...] Read more.
COVID-19 is characterized by a heterogeneous clinical presentation and prognosis. Risk factors contributing to the development of severe disease include old age and the presence of comorbidities. However, the genetic background of the host has also been recognized as an important determinant of disease prognosis. Considering the pivotal role of innate immunity in the control of SARS-CoV-2 infection, we analyzed the possible contribution of several innate immune gene polymorphisms (including TLR2-rs5743708, TLR4-rs4986790, TLR4-rs4986791, CD14-rs2569190, CARD8-rs1834481, IL18-rs2043211, and CD40-rs1883832) in disease severity and prognosis. A total of 249 individuals were enrolled and further divided into five (5) groups, according to the clinical progression scale provided by the World Health Organization (WHO) (asymptomatic, mild, moderate, severe, and critical). We identified that elderly patients with obesity and/or diabetes mellitus were more susceptible to developing pneumonia and respiratory distress syndrome after SARS-CoV-2 infection, while the IL18-rs1834481 polymorphism was an independent risk factor for developing pneumonia. Moreover, individuals carrying either the TLR2-rs5743708 or the TLR4-rs4986791 polymorphisms exhibited a 3.6- and 2.5-fold increased probability for developing pneumonia and a more severe disease, respectively. Our data support the notion that the host’s genetic background can significantly affect COVID-19 clinical phenotype, also suggesting that the IL18-rs1834481, TLR2-rs5743708, and TLR4-rs4986791 polymorphisms may be used as molecular predictors of COVID-19 clinical phenotype. Full article
(This article belongs to the Special Issue Emerging Concepts in SARS-CoV-2 Biology and Pathology)
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20 pages, 3237 KiB  
Article
Computational Prediction of RNA–RNA Interactions between Small RNA Tracks from Betacoronavirus Nonstructural Protein 3 and Neurotrophin Genes during Infection of an Epithelial Lung Cancer Cell Line: Potential Role of Novel Small Regulatory RNA
by Alexis Felipe Rojas-Cruz and Clara Isabel Bermúdez-Santana
Viruses 2023, 15(8), 1647; https://doi.org/10.3390/v15081647 - 28 Jul 2023
Viewed by 1511
Abstract
Whether RNA–RNA interactions of cytoplasmic RNA viruses, such as Betacoronavirus, might end in the biogenesis of putative virus-derived small RNAs as miRNA-like molecules has been controversial. Even more, whether RNA–RNA interactions of wild animal viruses may act as virus-derived small RNAs is [...] Read more.
Whether RNA–RNA interactions of cytoplasmic RNA viruses, such as Betacoronavirus, might end in the biogenesis of putative virus-derived small RNAs as miRNA-like molecules has been controversial. Even more, whether RNA–RNA interactions of wild animal viruses may act as virus-derived small RNAs is unknown. Here, we address these issues in four ways. First, we use conserved RNA structures undergoing negative selection in the genomes of SARS-CoV, MERS-CoV, and SARS-CoV-2 circulating in different bat species, intermediate animals, and human hosts. Second, a systematic literature review was conducted to identify Betacoronavirus-targeting hsa-miRNAs involved in lung cell infection. Third, we employed sophisticated long-range RNA–RNA interactions to refine the seed sequence homology of hsa-miRNAs with conserved RNA structures. Fourth, we used high-throughput RNA sequencing of a Betacoronavirus-infected epithelial lung cancer cell line (Calu-3) to validate the results. We proposed nine potential virus-derived small RNAs: two vsRNAs in SARS-CoV (Bats: SB-vsRNA-ORF1a-3p; SB-vsRNA-S-5p), one vsRNA in MERS-CoV (Bats: MB-vsRNA-ORF1b-3p), and six vsRNAs in SARS-CoV-2 (Bats: S2B-vsRNA-ORF1a-5p; intermediate animals: S2I-vsRNA-ORF1a-5p; and humans: S2H-vsRNA-ORF1a-5p, S2H-vsRNA-ORF1a-3p, S2H-vsRNA-ORF1b-3p, S2H-vsRNA-ORF3a-3p), mainly encoded by nonstructural protein 3. Notably, Betacoronavirus-derived small RNAs targeted 74 differentially expressed genes in infected human cells, of which 55 upregulate the molecular mechanisms underlying acute respiratory distress syndrome (ARDS), and the 19 downregulated genes might be implicated in neurotrophin signaling impairment. These results reveal a novel small RNA-based regulatory mechanism involved in neuropathogenesis that must be further studied to validate its therapeutic use. Full article
(This article belongs to the Special Issue Emerging Concepts in SARS-CoV-2 Biology and Pathology)
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14 pages, 2728 KiB  
Article
SARS-CoV-2 Structural Proteins Modulated Blood-Testis Barrier-Related Proteins through Autophagy in the Primary Sertoli Cells
by Kai Kang, Yao-Dan Ma, Si-Qi Liu, Ri-Wei Huang, Jin-Jun Chen, Li-Long An and Jiang Wu
Viruses 2023, 15(6), 1272; https://doi.org/10.3390/v15061272 - 29 May 2023
Cited by 2 | Viewed by 1601
Abstract
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) disrupts the blood-testis barrier (BTB), resulting in alterations in spermatogenesis. However, whether BTB-related proteins (such as ZO-1, claudin11, N-cadherin, and CX43) are targeted by SARS-CoV-2 remains to be clarified. BTB is a physical barrier between the [...] Read more.
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) disrupts the blood-testis barrier (BTB), resulting in alterations in spermatogenesis. However, whether BTB-related proteins (such as ZO-1, claudin11, N-cadherin, and CX43) are targeted by SARS-CoV-2 remains to be clarified. BTB is a physical barrier between the blood vessels and the seminiferous tubules of the animal testis, and it is one of the tightest blood-tissue barriers in the mammalian body. In this study, we investigated the effects of viral proteins, via ectopic expression of individual viral proteins, on BTB-related proteins, the secretion of immune factors, and the formation and degradation of autophagosomes in human primary Sertoli cells. Our study demonstrated that ectopic expression of viral E (envelope protein) and M (membrane protein) induced the expressions of ZO-1 and claudin11, promoted the formation of autophagosomes, and inhibited autophagy flux. S (spike protein) reduced the expression of ZO-1, N-cadherin, and CX43, induced the expression of claudin11, and inhibited the formation and degradation of autophagosomes. N (nucleocapsid protein) reduced the expression of ZO-1, claudin11, and N-cadherin. All the structural proteins (SPs) E, M, N, and S increased the expression of the FasL gene, and the E protein promoted the expression and secretion of FasL and TGF-β proteins and the expression of IL-1. Blockage of autophagy by specific inhibitors resulted in the suppression of BTB-related proteins by the SPs. Our results indicated that SARS-CoV-2 SPs (E, M, and S) regulate BTB-related proteins through autophagy. Full article
(This article belongs to the Special Issue Emerging Concepts in SARS-CoV-2 Biology and Pathology)
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16 pages, 1592 KiB  
Article
Transcription Factor Driven Gene Regulation in COVID-19 Patients
by Daniele Santoni, Nimisha Ghosh, Carlo Derelitto and Indrajit Saha
Viruses 2023, 15(5), 1188; https://doi.org/10.3390/v15051188 - 18 May 2023
Cited by 1 | Viewed by 1300
Abstract
SARS-CoV-2 and its many variants have caused a worldwide emergency. Host cells colonised by SARS-CoV-2 present a significantly different gene expression landscape. As expected, this is particularly true for genes that directly interact with virus proteins. Thus, understanding the role that transcription factors [...] Read more.
SARS-CoV-2 and its many variants have caused a worldwide emergency. Host cells colonised by SARS-CoV-2 present a significantly different gene expression landscape. As expected, this is particularly true for genes that directly interact with virus proteins. Thus, understanding the role that transcription factors can play in driving differential regulation in patients affected by COVID-19 is a focal point to unveil virus infection. In this regard, we have identified 19 transcription factors which are predicted to target human proteins interacting with Spike glycoprotein of SARS-CoV-2. Transcriptomics RNA-Seq data derived from 13 human organs are used to analyse expression correlation between identified transcription factors and related target genes in both COVID-19 patients and healthy individuals. This resulted in the identification of transcription factors showing the most relevant impact in terms of most evident differential correlation between COVID-19 patients and healthy individuals. This analysis has also identified five organs such as the blood, heart, lung, nasopharynx and respiratory tract in which a major effect of differential regulation mediated by transcription factors is observed. These organs are also known to be affected by COVID-19, thereby providing consistency to our analysis. Furthermore, 31 key human genes differentially regulated by the transcription factors in the five organs are identified and the corresponding KEGG pathways and GO enrichment are also reported. Finally, the drugs targeting those 31 genes are also put forth. This in silico study explores the effects of transcription factors on human genes interacting with Spike glycoprotein of SARS-CoV-2 and intends to provide new insights to inhibit the virus infection. Full article
(This article belongs to the Special Issue Emerging Concepts in SARS-CoV-2 Biology and Pathology)
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Review

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18 pages, 1345 KiB  
Review
Unraveling the Molecular and Cellular Pathogenesis of COVID-19-Associated Liver Injury
by Hikmet Akkiz
Viruses 2023, 15(6), 1287; https://doi.org/10.3390/v15061287 - 30 May 2023
Cited by 6 | Viewed by 1935
Abstract
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) continues to cause substantial morbidity and mortality. Most infections are mild; however, some patients experience severe and potentially fatal systemic inflammation, tissue damage, cytokine storm, and acute respiratory distress [...] Read more.
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) continues to cause substantial morbidity and mortality. Most infections are mild; however, some patients experience severe and potentially fatal systemic inflammation, tissue damage, cytokine storm, and acute respiratory distress syndrome. Patients with chronic liver disease have been frequently affected, experiencing high morbidity and mortality. In addition, elevated liver enzymes may be a risk factor for disease progression, even in the absence of underlying liver disease. While the respiratory tract is a primary target of SARS-CoV-2, it has become evident that COVID-19 is a multisystemic infectious disease. The hepatobiliary system might be influenced during COVID-19 infection, ranging from a mild elevation of aminotransferases to the development of autoimmune hepatitis and secondary sclerosing cholangitis. Furthermore, the virus can promote existing chronic liver diseases to liver failure and activate the autoimmune liver disease. Whether the direct cytopathic effects of the virus, host reaction, hypoxia, drugs, vaccination, or all these risk factors cause liver injury has not been clarified to a large extent in COVID-19. This review article discussed the molecular and cellular mechanisms involved in the pathogenesis of SARS-CoV-2 virus-associated liver injury and highlighted the emerging role of liver sinusoidal epithelial cells (LSECs) in virus-related liver damage. Full article
(This article belongs to the Special Issue Emerging Concepts in SARS-CoV-2 Biology and Pathology)
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22 pages, 4624 KiB  
Review
Understanding Mutations in Human SARS-CoV-2 Spike Glycoprotein: A Systematic Review & Meta-Analysis
by Reetesh Kumar, Yogesh Srivastava, Pandiyan Muthuramalingam, Sunil Kumar Singh, Geetika Verma, Savitri Tiwari, Nikunj Tandel, Samir Kumar Beura, Abhishek Ramachandra Panigrahi, Somnath Maji, Prakriti Sharma, Pankaj Kumar Rai, Dinesh Kumar Prajapati, Hyunsuk Shin and Rajeev K. Tyagi
Viruses 2023, 15(4), 856; https://doi.org/10.3390/v15040856 - 27 Mar 2023
Cited by 9 | Viewed by 3942
Abstract
Genetic variant(s) of concern (VoC) of SARS-CoV-2 have been emerging worldwide due to mutations in the gene encoding spike glycoprotein. We performed comprehensive analyses of spike protein mutations in the significant variant clade of SARS-CoV-2, using the data available on the Nextstrain server. [...] Read more.
Genetic variant(s) of concern (VoC) of SARS-CoV-2 have been emerging worldwide due to mutations in the gene encoding spike glycoprotein. We performed comprehensive analyses of spike protein mutations in the significant variant clade of SARS-CoV-2, using the data available on the Nextstrain server. We selected various mutations, namely, A222V, N439K, N501Y, L452R, Y453F, E484K, K417N, T478K, L981F, L212I, N856K, T547K, G496S, and Y369C for this study. These mutations were chosen based on their global entropic score, emergence, spread, transmission, and their location in the spike receptor binding domain (RBD). The relative abundance of these mutations was mapped with global mutation D614G as a reference. Our analyses suggest the rapid emergence of newer global mutations alongside D614G, as reported during the recent waves of COVID-19 in various parts of the world. These mutations could be instrumentally imperative for the transmission, infectivity, virulence, and host immune system’s evasion of SARS-CoV-2. The probable impact of these mutations on vaccine effectiveness, antigenic diversity, antibody interactions, protein stability, RBD flexibility, and accessibility to human cell receptor ACE2 was studied in silico. Overall, the present study can help researchers to design the next generation of vaccines and biotherapeutics to combat COVID-19 infection. Full article
(This article belongs to the Special Issue Emerging Concepts in SARS-CoV-2 Biology and Pathology)
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Other

5 pages, 883 KiB  
Protocol
A Web Tool to Estimate Baseline Anti-Spike Monoclonal Antibody Efficacy Based on Regional Genomic Surveillance
by Daniele Focosi
Viruses 2023, 15(5), 1048; https://doi.org/10.3390/v15051048 - 25 Apr 2023
Cited by 2 | Viewed by 1171
Abstract
Drug appropriateness is a pillar of modern evidence-based medicine, but the turnaround times of genomic sequencing are not compatible with the urgent need to deliver treatments against microorganisms. Massive worldwide genomic surveillance has created an unprecedented landscape for exploiting viral sequencing for therapeutic [...] Read more.
Drug appropriateness is a pillar of modern evidence-based medicine, but the turnaround times of genomic sequencing are not compatible with the urgent need to deliver treatments against microorganisms. Massive worldwide genomic surveillance has created an unprecedented landscape for exploiting viral sequencing for therapeutic purposes. When it comes to therapeutic antiviral antibodies, using IC50 against specific polymorphisms of the target antigen can be calculated in vitro, and a list of mutations leading to drug resistance (immune escape) can be compiled. The author encountered this type of knowledge (available from the Stanford University Coronavirus Antiviral Resistance Database,) in a publicly accessible repository of SARS-CoV-2 sequences. The author used a custom function of the CoV-Spectrum.org web portal to deliver up-to-date, regional prevalence estimates of baseline efficacy for each authorized anti-spike mAb across all co-circulating SARS-CoV-2 sublineages at a given time point. This publicly accessible tool can inform therapeutic choices that would otherwise be blind. Full article
(This article belongs to the Special Issue Emerging Concepts in SARS-CoV-2 Biology and Pathology)
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