Special Issue "SARS-CoV-2 Host Cell Interactions"

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: 17 December 2021.

Special Issue Editors

Dr. Concetta Castilletti
E-Mail Website
Guest Editor
National Institute for Infectious Diseases INMI-IRCCS, Via Portuense 292, 00149 Rome, Italy
Interests: Emerging/re-emerging viral infections; host-pathogen interactions; innate immunity; mechanisms of IFN induction and regulation of IFN stimulated genes; design and validation of innovative diagnostic methods; molecular epidemiology of viruses; biosafety and field laboratory
Prof. Dr. Luisa Barzon
E-Mail Website
Guest Editor
Department of Molecular Medicine, University of Padova, 35121 Padova, Italy
Interests: surveillance, diagnosis, and pathogenesis of emerging vector-borne viral infections; pathogenesis, diagnosis, and prevention of human papillomavirus-related diseases; investigation of virus–host interactions; development of patient-specific models of human susceptibility to viral infections; application of innovative molecular methods in infectious disease diagnosis
Special Issues, Collections and Topics in MDPI journals
Dr. Francesca Colavita
E-Mail Website
Guest Editor
National Institute for Infectious Diseases "Lazzaro Spallanzani" IRCCS, Via Portuense 292, 00149 Rome, Italy
Interests: Emerging viruses; vector-borne infections; viral haemorrhagic Fevers; antibody response; antiviral innate immunity; virus-host interactions; viral shedding; diagnostic methods; Biosafety

Special Issue Information

Dear Colleagues,

The current coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a global public health problem due to the relatively easy person-to-person transmission and the current lack of effective antiviral therapy. However, the exact molecular mechanisms of SARS-CoV-2 pathogenesis remain largely unknown.

Viruses are obligate intracellular parasites, entirely dependent on host cell machinery for their replication. In fact, they interact with the host machinery and alter cellular pathways to enhance their survival and replication. Part of this process is based on the inhibition of the cellular proteins that play a role in antiviral response and cell duplication. Some viruses directly divert key proteins from these pathways to promote their own replication.

Characterizing how SARS-CoV-2 takes over the operation of host cell machinery while disrupting cellular antiviral response will greatly improve our understanding of the pathophysiology of SARS-CoV-2 infection and will help to identify useful drug targets.

This Special Issue invites articles and expert reviews in the field of virus–host interactions to illustrate the current knowledge about virus–human cell interactome and the related strategies used by SARS-CoV-2 to exploit the host cell machinery and subvert cellular networks. Articles with an emphasis on the mechanisms by which SARS-CoV-2 subverts the antiviral response and triggers cytokine storms, which represent a powerful resource in the pursuit of therapeutic interventions, are particularly welcome.

Dr. Concetta Castilletti
Prof. Dr. Luisa Barzon
Dr. Francesca Colavita
Guest Editors

Manuscript Submission Information

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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 2200 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.

Keywords

  • virus-host cell interactions
  • interactome
  • innate immunity
  • interferon
  • cytokine storm
  • inflammasome

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Published Papers (15 papers)

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Research

Article
SARS–CoV–2 Spike Impairs DNA Damage Repair and Inhibits V(D)J Recombination In Vitro
Viruses 2021, 13(10), 2056; https://0-doi-org.brum.beds.ac.uk/10.3390/v13102056 - 13 Oct 2021
Viewed by 425
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS–CoV–2) has led to the coronavirus disease 2019 (COVID–19) pandemic, severely affecting public health and the global economy. Adaptive immunity plays a crucial role in fighting against SARS–CoV–2 infection and directly influences the clinical outcomes of patients. [...] Read more.
Severe acute respiratory syndrome coronavirus 2 (SARS–CoV–2) has led to the coronavirus disease 2019 (COVID–19) pandemic, severely affecting public health and the global economy. Adaptive immunity plays a crucial role in fighting against SARS–CoV–2 infection and directly influences the clinical outcomes of patients. Clinical studies have indicated that patients with severe COVID–19 exhibit delayed and weak adaptive immune responses; however, the mechanism by which SARS–CoV–2 impedes adaptive immunity remains unclear. Here, by using an in vitro cell line, we report that the SARS–CoV–2 spike protein significantly inhibits DNA damage repair, which is required for effective V(D)J recombination in adaptive immunity. Mechanistically, we found that the spike protein localizes in the nucleus and inhibits DNA damage repair by impeding key DNA repair protein BRCA1 and 53BP1 recruitment to the damage site. Our findings reveal a potential molecular mechanism by which the spike protein might impede adaptive immunity and underscore the potential side effects of full-length spike-based vaccines. Full article
(This article belongs to the Special Issue SARS-CoV-2 Host Cell Interactions)
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Article
Robust Neutralizing Antibody Levels Detected after Either SARS-CoV-2 Vaccination or One Year after Infection
Viruses 2021, 13(10), 2003; https://0-doi-org.brum.beds.ac.uk/10.3390/v13102003 - 05 Oct 2021
Viewed by 1438
Abstract
Humoral immunity after infection or after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been attributed a key part in mitigating the further transmission of the virus. In this study, we used a commercial anti-Spike immunoglobulin G (S-IgG) assay and developed [...] Read more.
Humoral immunity after infection or after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been attributed a key part in mitigating the further transmission of the virus. In this study, we used a commercial anti-Spike immunoglobulin G (S-IgG) assay and developed a cell culture-based neutralization assay to understand the longitudinal course of neutralizing antibodies in both SARS-CoV2 infected or vaccinated individuals. We show that even more than one year after infection, about 78% of observed study participants remained seropositive concerning S-IgG antibodies. In addition, the serum of the individuals had stable neutralization capacity in a neutralization assay against a SARS-CoV-2 patient isolate from March 2020. We also examined volunteers after either homologous BNT162b2 prime-boost vaccination or heterologous AZD1222 prime/mRNA-based booster vaccination. Both the heterologous and the homologous vaccination regimens induced higher levels of neutralizing antibodies in healthy subjects when compared to subjects after a mild infection, showing the high effectiveness of available vaccines. In addition, we could demonstrate the reliability of S-IgG levels in predicting neutralization capacity, with 94.8% of seropositive samples showing a neutralization titer of ≥10, making it a viable yet cheap and easy-to-determine surrogate parameter for neutralization capacity. Full article
(This article belongs to the Special Issue SARS-CoV-2 Host Cell Interactions)
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Article
Enrichment of SARS-CoV-2 Entry Factors and Interacting Intracellular Genes in Tissue and Circulating Immune Cells
Viruses 2021, 13(9), 1757; https://0-doi-org.brum.beds.ac.uk/10.3390/v13091757 - 02 Sep 2021
Viewed by 739
Abstract
SARS-CoV-2 uses ACE2 and TMPRSS2 to gain entry into the cell. However, recent studies have shown that SARS-CoV-2 may use additional host factors that are required for the viral lifecycle. Here we used publicly available datasets, CoV-associated genes, and machine learning algorithms to [...] Read more.
SARS-CoV-2 uses ACE2 and TMPRSS2 to gain entry into the cell. However, recent studies have shown that SARS-CoV-2 may use additional host factors that are required for the viral lifecycle. Here we used publicly available datasets, CoV-associated genes, and machine learning algorithms to explore the SARS-CoV-2 interaction landscape in different tissues. We found that in general a small fraction of cells express ACE2 in the different tissues, including nasal, bronchi, and lungs. We show that a small fraction of immune cells (including T cells, macrophages, dendritic cells) found in tissues also express ACE2. We show that healthy circulating immune cells do not express ACE2 and TMPRSS2. However, a small fraction of circulating immune cells (including dendritic cells, monocytes, T cells) in the PBMC of COVID-19 patients express ACE2 and TMPRSS2. Additionally, we found that a large spectrum of cells (in tissues and circulation) in both healthy and COVID-19-positive patients were significantly enriched for SARS-CoV-2 factors, such as those associated with RHOA and RAB GTPases, mRNA translation proteins, COPI- and COPII-mediated transport, and integrins. Thus, we propose that further research is needed to explore if SARS-CoV-2 can directly infect tissue and circulating immune cells to better understand the virus’ mechanism of action. Full article
(This article belongs to the Special Issue SARS-CoV-2 Host Cell Interactions)
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Article
SARS-CoV-2 Infection Modulates ACE2 Function and Subsequent Inflammatory Responses in Swabs and Plasma of COVID-19 Patients
Viruses 2021, 13(9), 1715; https://0-doi-org.brum.beds.ac.uk/10.3390/v13091715 - 28 Aug 2021
Viewed by 796
Abstract
Angiotensin converting enzyme 2 (ACE2) is a host ectopeptidase and the receptor for the SARS-CoV-2 virus, albeit virus-ACE2 interaction goes far beyond viral entry into target cells. Controversial data exists linking viral infection to changes in ACE2 expression and function, which might influence [...] Read more.
Angiotensin converting enzyme 2 (ACE2) is a host ectopeptidase and the receptor for the SARS-CoV-2 virus, albeit virus-ACE2 interaction goes far beyond viral entry into target cells. Controversial data exists linking viral infection to changes in ACE2 expression and function, which might influence the subsequent induction of an inflammatory response. Here, we tested the significance of soluble ACE2 enzymatic activity longitudinally in nasopharyngeal swabs and plasma samples of SARS-CoV-2 infected patients, along with the induction of inflammatory cytokines. Release of soluble functional ACE2 increases upon SARS-CoV-2 infection in swabs and plasma of infected patients, albeit rapidly decreasing during infection course in parallel with ACE2 gene expression. Similarly, SARS-CoV-2 infection also induced the expression of inflammatory cytokines. These changes positively correlated with the viral load. Overall, our results demonstrate the existence of mechanisms by which SARS-CoV-2 modulates ACE2 expression and function, intracellular viral sensing and subsequent inflammatory response, offering new insights into ACE2 dynamics in the human upper respiratory tract and pointing towards soluble ACE2 levels as a putative early biomarker of infection severity. Full article
(This article belongs to the Special Issue SARS-CoV-2 Host Cell Interactions)
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Article
Characterization of the SARS-CoV-2 Host Response in Primary Human Airway Epithelial Cells from Aged Individuals
Viruses 2021, 13(8), 1603; https://0-doi-org.brum.beds.ac.uk/10.3390/v13081603 - 12 Aug 2021
Viewed by 915
Abstract
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), a global pandemic characterized by an exaggerated immune response and respiratory illness. Age (>60 years) is a significant risk factor for developing severe COVID-19. To better understand [...] Read more.
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), a global pandemic characterized by an exaggerated immune response and respiratory illness. Age (>60 years) is a significant risk factor for developing severe COVID-19. To better understand the host response of the aged airway epithelium to SARS-CoV-2 infection, we performed an in vitro study using primary human bronchial epithelial cells from donors >67 years of age differentiated on an air–liquid interface culture. We demonstrate that SARS-CoV-2 infection leads to early induction of a proinflammatory response and a delayed interferon response. In addition, we observed changes in the genes and pathways associated with cell death and senescence throughout infection. In summary, our study provides new and important insights into the temporal kinetics of the airway epithelial innate immune response to SARS-CoV-2 in older individuals. Full article
(This article belongs to the Special Issue SARS-CoV-2 Host Cell Interactions)
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Article
SARS-CoV-2 N Protein Targets TRIM25-Mediated RIG-I Activation to Suppress Innate Immunity
Viruses 2021, 13(8), 1439; https://0-doi-org.brum.beds.ac.uk/10.3390/v13081439 - 23 Jul 2021
Viewed by 787
Abstract
A weak production of INF-β along with an exacerbated release of pro-inflammatory cytokines have been reported during infection by the novel SARS-CoV-2 virus. SARS-CoV-2 encodes several proteins able to counteract the host immune system, which is believed to be one of the most [...] Read more.
A weak production of INF-β along with an exacerbated release of pro-inflammatory cytokines have been reported during infection by the novel SARS-CoV-2 virus. SARS-CoV-2 encodes several proteins able to counteract the host immune system, which is believed to be one of the most important features contributing to the viral pathogenesis and development of a severe clinical picture. Previous reports have demonstrated that SARS-CoV-2 N protein, along with some non-structural and accessory proteins, efficiently suppresses INF-β production by interacting with RIG-I, an important pattern recognition receptor (PRR) involved in the recognition of pathogen-derived molecules. In the present study, we better characterized the mechanism by which the SARS-CoV-2 N counteracts INF-β secretion and affects RIG-I signaling pathways. In detail, when the N protein was ectopically expressed, we noted a marked decrease in TRIM25-mediated RIG-I activation. The capability of the N protein to bind to, and probably mask, TRIM25 could be the consequence of its antagonistic activity. Furthermore, this interaction occurred at the SPRY domain of TRIM25, harboring the RNA-binding activity necessary for TRIM25 self-activation. Here, we describe new findings regarding the interplay between SARS-CoV-2 and the IFN system, filling some gaps for a better understanding of the molecular mechanisms affecting the innate immune response in COVID-19. Full article
(This article belongs to the Special Issue SARS-CoV-2 Host Cell Interactions)
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Article
Resveratrol and Pterostilbene Inhibit SARS-CoV-2 Replication in Air–Liquid Interface Cultured Human Primary Bronchial Epithelial Cells
Viruses 2021, 13(7), 1335; https://0-doi-org.brum.beds.ac.uk/10.3390/v13071335 - 10 Jul 2021
Cited by 1 | Viewed by 1661
Abstract
The current COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has an enormous impact on human health and economy. In search for therapeutic options, researchers have proposed resveratrol, a food supplement with known antiviral, anti-inflammatory, and antioxidant properties [...] Read more.
The current COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has an enormous impact on human health and economy. In search for therapeutic options, researchers have proposed resveratrol, a food supplement with known antiviral, anti-inflammatory, and antioxidant properties as an advantageous antiviral therapy for SARS-CoV-2 infection. Here, we provide evidence that both resveratrol and its metabolically more stable structural analog, pterostilbene, exhibit potent antiviral properties against SARS-CoV-2 in vitro. First, we show that resveratrol and pterostilbene antiviral activity in African green monkey kidney cells. Both compounds actively inhibit virus replication within infected cells as reduced virus progeny production was observed when the compound was added at post-inoculation conditions. Without replenishment of the compound, antiviral activity was observed up to roughly five rounds of replication, demonstrating the long-lasting effect of these compounds. Second, as the upper respiratory tract represents the initial site of SARS-CoV-2 replication, we also assessed antiviral activity in air–liquid interface (ALI) cultured human primary bronchial epithelial cells, isolated from healthy volunteers. Resveratrol and pterostilbene showed a strong antiviral effect in these cells up to 48 h post-infection. Collectively, our data indicate that resveratrol and pterostilbene are promising antiviral compounds to inhibit SARS-CoV-2 infection. Because these results represent laboratory findings in cells, we advocate evaluation of these compounds in clinical trials before statements are made whether these drugs are advantageous for COVID-19 treatment. Full article
(This article belongs to the Special Issue SARS-CoV-2 Host Cell Interactions)
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Article
Rationale and Criteria for a COVID-19 Model Framework
Viruses 2021, 13(7), 1309; https://0-doi-org.brum.beds.ac.uk/10.3390/v13071309 - 06 Jul 2021
Cited by 2 | Viewed by 1058 | Retraction
Abstract
Complex systems are inherently multilevel and multiscale systems. The infectious disease system is considered a complex system resulting from the interaction between three sub-systems (host, pathogen, and environment) organized into a hierarchical structure, ranging from the cellular to the macro-ecosystem level, with multiscales. [...] Read more.
Complex systems are inherently multilevel and multiscale systems. The infectious disease system is considered a complex system resulting from the interaction between three sub-systems (host, pathogen, and environment) organized into a hierarchical structure, ranging from the cellular to the macro-ecosystem level, with multiscales. Therefore, to describe infectious disease phenomena that change through time and space and at different scales, we built a model framework where infectious disease must be considered the set of biological responses of human hosts to pathogens, with biological pathways shared with other pathologies in an ecological interaction context. In this paper, we aimed to design a framework for building a disease model for COVID-19 based on current literature evidence. The model was set up by identifying the molecular pathophysiology related to the COVID-19 phenotypes, collecting the mechanistic knowledge scattered across scientific literature and bioinformatic databases, and integrating it using a logical/conceptual model systems biology. The model framework building process began from the results of a domain-based literature review regarding a multiomics approach to COVID-19. This evidence allowed us to define a framework of COVID-19 conceptual model and to report all concepts in a multilevel and multiscale structure. The same interdisciplinary working groups that carried out the scoping review were involved. The conclusive result is a conceptual method to design multiscale models of infectious diseases. The methodology, applied in this paper, is a set of partially ordered research and development activities that result in a COVID-19 multiscale model. Full article
(This article belongs to the Special Issue SARS-CoV-2 Host Cell Interactions)
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Article
Modeling within-Host SARS-CoV-2 Infection Dynamics and Potential Treatments
Viruses 2021, 13(6), 1141; https://0-doi-org.brum.beds.ac.uk/10.3390/v13061141 - 14 Jun 2021
Cited by 1 | Viewed by 1831
Abstract
The goal of this study was to develop a mathematical model to simulate the actions of drugs that target SARS-CoV-2 virus infection. To accomplish that goal, we have developed a mathematical model that describes the control of a SARS-CoV-2 infection by the innate [...] Read more.
The goal of this study was to develop a mathematical model to simulate the actions of drugs that target SARS-CoV-2 virus infection. To accomplish that goal, we have developed a mathematical model that describes the control of a SARS-CoV-2 infection by the innate and adaptive immune components. Invasion of the virus triggers the innate immunity, whereby interferon renders some of the target cells resistant to infection, and infected cells are removed by effector cells. The adaptive immune response is represented by plasma cells and virus-specific antibodies. The model is parameterized and then validated against viral load measurements collected in COVID-19 patients. We apply the model to simulate three potential anti-SARS-CoV-2 therapies: (1) Remdesivir, a repurposed drug that has been shown to inhibit the transcription of SARS-CoV-2, (2) an alternative (hypothetical) therapy that inhibits the virus’ entry into host cells, and (3) convalescent plasma transfusion therapy. Simulation results point to the importance of early intervention, i.e., for any of the three therapies to be effective, it must be administered sufficiently early, not more than a day or two after the onset of symptoms. The model can serve as a key component in integrative platforms for rapid in silico testing of potential COVID-19 therapies and vaccines. Full article
(This article belongs to the Special Issue SARS-CoV-2 Host Cell Interactions)
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Article
The Pro-Inflammatory Chemokines CXCL9, CXCL10 and CXCL11 Are Upregulated Following SARS-CoV-2 Infection in an AKT-Dependent Manner
Viruses 2021, 13(6), 1062; https://0-doi-org.brum.beds.ac.uk/10.3390/v13061062 - 03 Jun 2021
Cited by 1 | Viewed by 1255
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible RNA virus that is the causative agent of the Coronavirus disease 2019 (COVID-19) pandemic. Patients with severe COVID-19 may develop acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) and require [...] Read more.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible RNA virus that is the causative agent of the Coronavirus disease 2019 (COVID-19) pandemic. Patients with severe COVID-19 may develop acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) and require mechanical ventilation. Key features of SARS-CoV-2 induced pulmonary complications include an overexpression of pro-inflammatory chemokines and cytokines that contribute to a ‘cytokine storm.’ In the current study an inflammatory state in Calu-3 human lung epithelial cells was characterized in which significantly elevated transcripts of the immunostimulatory chemokines CXCL9, CXCL10, and CXCL11 were present. Additionally, an increase in gene expression of the cytokines IL-6, TNFα, and IFN-γ was observed. The transcription of CXCL9, CXCL10, IL-6, and IFN-γ was also induced in the lungs of human transgenic angiotensin converting enzyme 2 (ACE2) mice infected with SARS-CoV-2. To elucidate cell signaling pathways responsible for chemokine upregulation in SARS-CoV-2 infected cells, small molecule inhibitors targeting key signaling kinases were used. The induction of CXCL9, CXCL10, and CXCL11 gene expression in response to SARS-CoV-2 infection was markedly reduced by treatment with the AKT inhibitor GSK690693. Samples from COVID-19 positive individuals also displayed marked increases in CXCL9, CXCL10, and CXCL11 transcripts as well as transcripts in the AKT pathway. The current study elucidates potential pathway specific targets for reducing the induction of chemokines that may be contributing to SARS-CoV-2 pathogenesis via hyperinflammation. Full article
(This article belongs to the Special Issue SARS-CoV-2 Host Cell Interactions)
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Article
Identification of Novel Candidate CD8+ T Cell Epitopes of the SARS-CoV2 with Homology to Other Seasonal Coronaviruses
Viruses 2021, 13(6), 972; https://0-doi-org.brum.beds.ac.uk/10.3390/v13060972 - 24 May 2021
Viewed by 1243
Abstract
Cross-reactive T cell immunity to seasonal coronaviruses (HCoVs) may lead to immunopathology or protection during SARS-CoV2 infection. To understand the influence of cross-reactive T cell responses, we used IEDB (Immune epitope database) and NetMHCpan (ver. 4.1) to identify candidate CD8+ T cell [...] Read more.
Cross-reactive T cell immunity to seasonal coronaviruses (HCoVs) may lead to immunopathology or protection during SARS-CoV2 infection. To understand the influence of cross-reactive T cell responses, we used IEDB (Immune epitope database) and NetMHCpan (ver. 4.1) to identify candidate CD8+ T cell epitopes, restricted through HLA-A and B alleles. Conservation analysis was carried out for these epitopes with HCoVs, OC43, HKU1, and NL63. 12/18 the candidate CD8+ T cell epitopes (binding score of ≥0.90), which had a high degree of homology (>75%) with the other three HCoVs were within the NSP12 and NSP13 proteins. They were predicted to be restricted through HLA-A*2402, HLA-A*201, HLA-A*206, and HLA-B alleles B*3501. Thirty-one candidate CD8+ T cell epitopes that were specific to SARS-CoV2 virus (<25% homology with other HCoVs) were predominantly identified within the structural proteins (spike, envelop, membrane, and nucleocapsid) and the NSP1, NSP2, and NSP3. They were predominantly restricted through HLA-B*3501 (6/31), HLA-B*4001 (6/31), HLA-B*4403 (7/31), and HLA-A*2402 (8/31). It would be crucial to understand T cell responses that associate with protection, and the differences in the functionality and phenotype of epitope specific T cell responses, presented through different HLA alleles common in different geographical groups, to understand disease pathogenesis. Full article
(This article belongs to the Special Issue SARS-CoV-2 Host Cell Interactions)
Article
Profiles of Peripheral Immune Cells of Uncomplicated COVID-19 Cases with Distinct Viral RNA Shedding Periods
Viruses 2021, 13(3), 514; https://0-doi-org.brum.beds.ac.uk/10.3390/v13030514 - 19 Mar 2021
Viewed by 653
Abstract
The heterogeneity of immune response to COVID-19 has been reported to correlate with disease severity and prognosis. While so, how the immune response progress along the period of viral RNA-shedding (VRS), which determines the infectiousness of disease, is yet to be elucidated. We [...] Read more.
The heterogeneity of immune response to COVID-19 has been reported to correlate with disease severity and prognosis. While so, how the immune response progress along the period of viral RNA-shedding (VRS), which determines the infectiousness of disease, is yet to be elucidated. We aim to exhaustively evaluate the peripheral immune cells to expose the interplay of the immune system in uncomplicated COVID-19 cases with different VRS periods and dynamic changes of the immune cell profile in the prolonged cases. We prospectively recruited four uncomplicated COVID-19 patients and four healthy controls (HCs) and evaluated the immune cell profile throughout the disease course. Peripheral blood mononuclear cells (PBMCs) were collected and submitted to a multi-panel flowcytometric assay. CD19+-B cells were upregulated, while CD4, CD8, and NK cells were downregulated in prolonged VRS patients. Additionally, the pro-inflammatory-Th1 population showed downregulation, followed by improvement along the disease course, while the immunoregulatory cells showed upregulation with subsequent decline. COVID-19 patients with longer VRS expressed an immune profile comparable to those with severe disease, although they remained clinically stable. Further studies of immune signature in a larger cohort are warranted. Full article
(This article belongs to the Special Issue SARS-CoV-2 Host Cell Interactions)
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Article
mRNA-lncRNA Co-Expression Network Analysis Reveals the Role of lncRNAs in Immune Dysfunction during Severe SARS-CoV-2 Infection
Viruses 2021, 13(3), 402; https://0-doi-org.brum.beds.ac.uk/10.3390/v13030402 - 03 Mar 2021
Cited by 3 | Viewed by 2052
Abstract
The recently emerged SARS-CoV-2 virus is responsible for the ongoing COVID-19 pandemic that has rapidly developed into a global public health threat. Patients severely affected with COVID-19 present distinct clinical features, including acute respiratory disorder, neutrophilia, cytokine storm, and sepsis. In addition, multiple [...] Read more.
The recently emerged SARS-CoV-2 virus is responsible for the ongoing COVID-19 pandemic that has rapidly developed into a global public health threat. Patients severely affected with COVID-19 present distinct clinical features, including acute respiratory disorder, neutrophilia, cytokine storm, and sepsis. In addition, multiple pro-inflammatory cytokines are found in the plasma of such patients. Transcriptome sequencing of different specimens obtained from patients suffering from severe episodes of COVID-19 shows dynamics in terms of their immune responses. However, those host factors required for SARS-CoV-2 propagation and the underlying molecular mechanisms responsible for dysfunctional immune responses during COVID-19 infection remain elusive. In the present study, we analyzed the mRNA-long non-coding RNA (lncRNA) co-expression network derived from publicly available SARS-CoV-2-infected transcriptome data of human lung epithelial cell lines and bronchoalveolar lavage fluid (BALF) from COVID-19 patients. Through co-expression network analysis, we identified four differentially expressed lncRNAs strongly correlated with genes involved in various immune-related pathways crucial for cytokine signaling. Our findings suggest that the aberrant expression of these four lncRNAs can be associated with cytokine storms and anti-viral responses during severe SARS-CoV-2 infection of the lungs. Thus, the present study uncovers molecular interactions behind the cytokine storm activation potentially responsible for hyper-inflammatory responses in critical COVID-19 patients. Full article
(This article belongs to the Special Issue SARS-CoV-2 Host Cell Interactions)
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Article
The Mutation Profile of SARS-CoV-2 Is Primarily Shaped by the Host Antiviral Defense
Viruses 2021, 13(3), 394; https://0-doi-org.brum.beds.ac.uk/10.3390/v13030394 - 02 Mar 2021
Cited by 4 | Viewed by 1295
Abstract
Understanding SARS-CoV-2 evolution is a fundamental effort in coping with the COVID-19 pandemic. The virus genomes have been broadly evolving due to the high number of infected hosts world-wide. Mutagenesis and selection are two inter-dependent mechanisms of virus diversification. However, which mechanisms contribute [...] Read more.
Understanding SARS-CoV-2 evolution is a fundamental effort in coping with the COVID-19 pandemic. The virus genomes have been broadly evolving due to the high number of infected hosts world-wide. Mutagenesis and selection are two inter-dependent mechanisms of virus diversification. However, which mechanisms contribute to the mutation profiles of SARS-CoV-2 remain under-explored. Here, we delineate the contribution of mutagenesis and selection to the genome diversity of SARS-CoV-2 isolates. We generated a comprehensive phylogenetic tree with representative genomes. Instead of counting mutations relative to the reference genome, we identified each mutation event at the nodes of the phylogenetic tree. With this approach, we obtained the mutation events that are independent of each other and generated the mutation profile of SARS-CoV-2 genomes. The results suggest that the heterogeneous mutation patterns are mainly reflections of host (i) antiviral mechanisms that are achieved through APOBEC, ADAR, and ZAP proteins, and (ii) probable adaptation against reactive oxygen species. Full article
(This article belongs to the Special Issue SARS-CoV-2 Host Cell Interactions)
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Communication
TMPRSS11D and TMPRSS13 Activate the SARS-CoV-2 Spike Protein
Viruses 2021, 13(3), 384; https://0-doi-org.brum.beds.ac.uk/10.3390/v13030384 - 28 Feb 2021
Cited by 9 | Viewed by 1498
Abstract
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) utilizes host proteases, including a plasma membrane-associated transmembrane protease, serine 2 (TMPRSS2) to cleave and activate the virus spike protein to facilitate cellular entry. Although TMPRSS2 is a well-characterized type II transmembrane serine protease (TTSP), the role [...] Read more.
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) utilizes host proteases, including a plasma membrane-associated transmembrane protease, serine 2 (TMPRSS2) to cleave and activate the virus spike protein to facilitate cellular entry. Although TMPRSS2 is a well-characterized type II transmembrane serine protease (TTSP), the role of other TTSPs on the replication of SARS-CoV-2 remains to be elucidated. Here, we have screened 12 TTSPs using human angiotensin-converting enzyme 2-expressing HEK293T (293T-ACE2) cells and Vero E6 cells and demonstrated that exogenous expression of TMPRSS11D and TMPRSS13 enhanced cellular uptake and subsequent replication of SARS-CoV-2. In addition, SARS-CoV-1 and SARS-CoV-2 share the same TTSPs in the viral entry process. Our study demonstrates the impact of host TTSPs on infection of SARS-CoV-2, which may have implications for cell and tissue tropism, for pathogenicity, and potentially for vaccine development. Full article
(This article belongs to the Special Issue SARS-CoV-2 Host Cell Interactions)
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