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17 pages, 2339 KiB

Open AccessArticle

SARS-CoV-2 Infects Human ACE2-Negative Endothelial Cells through an α_vβ₃ Integrin-Mediated Endocytosis Even in the Presence of Vaccine-Elicited Neutralizing Antibodies

by Antonella Bugatti, Federica Filippini, Marta Bardelli, Alberto Zani, Paola Chiodelli, Serena Messali, Arnaldo Caruso and Francesca Caccuri

Viruses 2022, 14(4), 705; https://doi.org/10.3390/v14040705 - 29 Mar 2022

Cited by 26 | Viewed by 4698

Abstract

Integrins represent a gateway of entry for many viruses and the Arg-Gly-Asp (RGD) motif is the smallest sequence necessary for proteins to bind integrins. All Severe Acute Respiratory Syndrome Virus type 2 (SARS-CoV-2) lineages own an RGD motif (aa 403–405) in their receptor [...] Read more.

Integrins represent a gateway of entry for many viruses and the Arg-Gly-Asp (RGD) motif is the smallest sequence necessary for proteins to bind integrins. All Severe Acute Respiratory Syndrome Virus type 2 (SARS-CoV-2) lineages own an RGD motif (aa 403–405) in their receptor binding domain (RBD). We recently showed that SARS-CoV-2 gains access into primary human lung microvascular endothelial cells (HL-mECs) lacking Angiotensin-converting enzyme 2 (ACE2) expression through this conserved RGD motif. Following its entry, SARS-CoV-2 remodels cell phenotype and promotes angiogenesis in the absence of productive viral replication. Here, we highlight the α_vβ₃ integrin as the main molecule responsible for SARS-CoV-2 infection of HL-mECs via a clathrin-dependent endocytosis. Indeed, pretreatment of virus with α_vβ₃ integrin or pretreatment of cells with a monoclonal antibody against α_vβ₃ integrin was found to inhibit SARS-CoV-2 entry into HL-mECs. Surprisingly, the anti-Spike antibodies evoked by vaccination were neither able to impair Spike/integrin interaction nor to prevent SARS-CoV-2 entry into HL-mECs. Our data highlight the RGD motif in the Spike protein as a functional constraint aimed to maintain the interaction of the viral envelope with integrins. At the same time, our evidences call for the need of intervention strategies aimed to neutralize the SARS-CoV-2 integrin-mediated infection of ACE2-negative cells in the vaccine era. Full article

(This article belongs to the Special Issue SARS-CoV-2 Host Cell Interactions)

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19 pages, 1568 KiB

Open AccessArticle

Sensitivity of SARS-CoV-2 Life Cycle to IFN Effects and ACE2 Binding Unveiled with a Stochastic Model

by Igor Sazonov, Dmitry Grebennikov, Andreas Meyerhans and Gennady Bocharov

Viruses 2022, 14(2), 403; https://doi.org/10.3390/v14020403 - 15 Feb 2022

Cited by 5 | Viewed by 3525

Abstract

Mathematical modelling of infection processes in cells is of fundamental interest. It helps to understand the SARS-CoV-2 dynamics in detail and can be useful to define the vulnerability steps targeted by antiviral treatments. We previously developed a deterministic mathematical model of the SARS-CoV-2 [...] Read more.

Mathematical modelling of infection processes in cells is of fundamental interest. It helps to understand the SARS-CoV-2 dynamics in detail and can be useful to define the vulnerability steps targeted by antiviral treatments. We previously developed a deterministic mathematical model of the SARS-CoV-2 life cycle in a single cell. Despite answering many questions, it certainly cannot accurately account for the stochastic nature of an infection process caused by natural fluctuation in reaction kinetics and the small abundance of participating components in a single cell. In the present work, this deterministic model is transformed into a stochastic one based on a Markov Chain Monte Carlo (MCMC) method. This model is employed to compute statistical characteristics of the SARS-CoV-2 life cycle including the probability for a non-degenerate infection process. Varying parameters of the model enables us to unveil the inhibitory effects of IFN and the effects of the ACE2 binding affinity. The simulation results show that the type I IFN response has a very strong effect on inhibition of the total viral progeny whereas the effect of a 10-fold variation of the binding rate to ACE2 turns out to be negligible for the probability of infection and viral production. Full article

(This article belongs to the Special Issue SARS-CoV-2 Host Cell Interactions)

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21 pages, 16743 KiB

Open AccessArticle

SARS-CoV-2: Ultrastructural Characterization of Morphogenesis in an In Vitro System

by Debora Ferreira Barreto-Vieira, Marcos Alexandre Nunes da Silva, Ana Luisa Teixeira de Almeida, Arthur da Costa Rasinhas, Maria Eduarda Monteiro, Milene Dias Miranda, Fernando Couto Motta, Marilda M. Siqueira, Wendell Girard-Dias, Bráulio Soares Archanjo, Patricia T. Bozza, Thiago Moreno L. Souza, Suelen Silva Gomes Dias, Vinicius Cardoso Soares and Ortrud Monika Barth

Viruses 2022, 14(2), 201; https://doi.org/10.3390/v14020201 - 20 Jan 2022

Cited by 18 | Viewed by 6324

Abstract

The pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has impacted public health and the world economy and fueled a worldwide race to approve therapeutic and prophylactic agents, but so far there are no specific antiviral drugs. Understanding the biology [...] Read more.

The pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has impacted public health and the world economy and fueled a worldwide race to approve therapeutic and prophylactic agents, but so far there are no specific antiviral drugs. Understanding the biology of the virus is the first step in structuring strategies to combat it, and in this context several studies have been conducted with the aim of understanding the replication mechanism of SARS-CoV-2 in vitro systems. In this work, studies using transmission and scanning electron microscopy and 3D electron microscopy modeling were performed with the goal of characterizing the morphogenesis of SARS-CoV-2 in Vero-E6 cells. Several ultrastructural changes were observed—such as syncytia formation, cytoplasmic membrane projections, lipid droplets accumulation, proliferation of double-membrane vesicles derived from the rough endoplasmic reticulum, and alteration of mitochondria. The entry of the virus into cells occurred through endocytosis. Viral particles were observed attached to the cell membrane and in various cellular compartments, and extrusion of viral progeny took place by exocytosis. These findings allow us to infer that Vero-E6 cells are highly susceptible to SARS-CoV-2 infection as described in the literature and their replication cycle is similar to that described with SARS-CoV and MERS-CoV in vitro models. Full article

(This article belongs to the Special Issue SARS-CoV-2 Host Cell Interactions)

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21 pages, 61592 KiB

Open AccessArticle

Simulation of Molecular Dynamics of SARS-CoV-2 S-Protein in the Presence of Multiple Arbidol Molecules: Interactions and Binding Mode Insights

by Sophia S. Borisevich, Edward M. Khamitov, Maxim A. Gureev, Olga I. Yarovaya, Nadezhda B. Rudometova, Anastasiya V. Zybkina, Ekaterina D. Mordvinova, Dmitriy N. Shcherbakov, Rinat A. Maksyutov and Nariman F. Salakhutdinov

Viruses 2022, 14(1), 119; https://doi.org/10.3390/v14010119 - 10 Jan 2022

Cited by 8 | Viewed by 4043

Abstract

In this work, we evaluated the antiviral activity of Arbidol (Umifenovir) against SARS-CoV-2 using a pseudoviral system with the glycoprotein S of the SARS-CoV-2 virus on its surface. In order to search for binding sites to protein S of the virus, we described [...] Read more.

In this work, we evaluated the antiviral activity of Arbidol (Umifenovir) against SARS-CoV-2 using a pseudoviral system with the glycoprotein S of the SARS-CoV-2 virus on its surface. In order to search for binding sites to protein S of the virus, we described alternative binding sites of Arbidol in RBD and in the ACE-2-RBD complex. As a result of our molecular dynamics simulations combined with molecular docking data, we note the following fact: wherever the molecules of Arbidol bind, the interaction of the latter affects the structural flexibility of the protein. This interaction may result both in a change in the shape of the domain–enzyme binding interface and simply in a change in the structural flexibility of the domain, which can subsequently affect its affinity to the enzyme. In addition, we examined the possibility of Arbidol binding in the stem part of the surface protein. The possibility of Arbidol binding in different parts of the protein is not excluded. This may explain the antiviral activity of Arbidol. Our results could be useful for researchers searching for effective SARS-CoV-2 virus inhibitors targeting the viral entry stage. Full article

(This article belongs to the Special Issue SARS-CoV-2 Host Cell Interactions)

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14 pages, 1923 KiB

Open AccessArticle

Evaluation of Clinical and Immune Responses in Recovered Children with Mild COVID-19

by Xiaodong Tian, Zhihua Bai, Ying Cao, Haizhou Liu, Di Liu, Wenjun Liu and Jing Li

Viruses 2022, 14(1), 85; https://doi.org/10.3390/v14010085 - 4 Jan 2022

Cited by 10 | Viewed by 2697

Abstract

The coronavirus disease 2019 (COVID-19) has spread globally and variants continue to emerge, with children are accounting for a growing share of COVID-19 cases. However, the establishment of immune memory and the long-term health consequences in asymptomatic or mildly symptomatic children after severe [...] Read more.

The coronavirus disease 2019 (COVID-19) has spread globally and variants continue to emerge, with children are accounting for a growing share of COVID-19 cases. However, the establishment of immune memory and the long-term health consequences in asymptomatic or mildly symptomatic children after severe acute respiratory syndrome coronavirus 2 infection are not fully understood. We collected clinical data and whole blood samples from discharged children for 6–8 months after symptom onset among 0-to-14-year-old children. Representative inflammation signs returned to normal in all age ranges. The infants and young children (0–4 years old) had lung lesions that persisted for 6–8 months and were less responsive for antigen-specific IgG secretion. In the 5-to-14-year-old group, lung imaging abnormalities gradually recovered, and the IgG-specific antibody response was strongest. In addition, we found a robust IgM⁺ memory B cell response in all age. Memory T cells specific for the spike or nucleocapsid protein were generated, with no significant difference in IFN-γ response among all ages. Our study highlights that although lung lesions caused by COVID-19 can last for at least 6–8 months in infants and young children, most children have detectable residual neutralizing antibodies and specific cellular immune responses at this stage. Full article

(This article belongs to the Special Issue SARS-CoV-2 Host Cell Interactions)

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14 pages, 38285 KiB

Open AccessArticle

RBD Double Mutations of SARS-CoV-2 Strains Increase Transmissibility through Enhanced Interaction between RBD and ACE2 Receptor

by Siddharth Sinha, Benjamin Tam and San Ming Wang

Viruses 2022, 14(1), 1; https://doi.org/10.3390/v14010001 - 21 Dec 2021

Cited by 12 | Viewed by 3901

Abstract

The COVID-19 pandemic, caused by SARS-CoV-2, has led to catastrophic damage for global human health. The initial step of SARS-CoV-2 infection is the binding of the receptor-binding domain (RBD) in its spike protein to the ACE2 receptor in the host cell membrane. Constant [...] Read more.

The COVID-19 pandemic, caused by SARS-CoV-2, has led to catastrophic damage for global human health. The initial step of SARS-CoV-2 infection is the binding of the receptor-binding domain (RBD) in its spike protein to the ACE2 receptor in the host cell membrane. Constant evolution of SARS-CoV-2 generates new mutations across its genome including the coding region for the RBD in the spike protein. In addition to the well-known single mutation in the RBD, the recent new mutation strains with an RBD “double mutation” are causing new outbreaks globally, as represented by the delta strain containing RBD L452R/T478K. Although it is considered that the increased transmissibility of double-mutated strains could be attributed to the altered interaction between the RBD and ACE2 receptor, the molecular details remain to be elucidated. Using the methods of molecular dynamics simulation, superimposed structural comparison, free binding energy estimation, and antibody escaping, we investigated the relationship between the ACE2 receptor and the RBD double mutants of L452R/T478K (delta), L452R/E484Q (kappa), and E484K/N501Y (beta, gamma). The results demonstrated that each of the three RBD double mutants altered the RBD structure and enhanced the binding of the mutated RBD to ACE2 receptor. Together with the mutations in other parts of the virus genome, the double mutations increase the transmissibility of SARS-CoV-2 to host cells. Full article

(This article belongs to the Special Issue SARS-CoV-2 Host Cell Interactions)

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16 pages, 3729 KiB

Open AccessArticle

Macrophages and Monocytes: “Trojan Horses” in COVID-19

by Elena Percivalle, Josè Camilla Sammartino, Irene Cassaniti, Eloisa Arbustini, Mario Urtis, Alexandra Smirnova, Monica Concardi, Cristina Belgiovine, Alessandro Ferrari, Daniele Lilleri, Antonio Piralla and Fausto Baldanti

Viruses 2021, 13(11), 2178; https://doi.org/10.3390/v13112178 - 28 Oct 2021

Cited by 19 | Viewed by 4464

Abstract

We aimed to explore whether variants of SARS-CoV-2 (Chinese-derived strain (D614, lineage A), Italian strain PV10734 (D614G, lineage B.1.1) and Alpha strain (lineage B.1.1.7)) were able to infect monocytes (MN) and monocyte-derived macrophages (MDM) and whether these infected cells may, in turn, be [...] Read more.

We aimed to explore whether variants of SARS-CoV-2 (Chinese-derived strain (D614, lineage A), Italian strain PV10734 (D614G, lineage B.1.1) and Alpha strain (lineage B.1.1.7)) were able to infect monocytes (MN) and monocyte-derived macrophages (MDM) and whether these infected cells may, in turn, be vectors of infection. For this purpose, we designed an in vitro study following the evolution of MN and MDM infection at different time points in order to confirm whether these cells were permissive for SARS-CoV-2 replication. Finally, we investigated whether, regardless of viral replication, the persistent virus can be transferred to non-infected cells permissive for viral replication. Thus, we co-cultured the infected MN/MDM with permissive VERO E6 cells verifying the viral transmission. This is a further in vitro demonstration of the important role of MN and MDM in the dissemination of SARS-CoV-2 and evolution of the COVID-19 disease. Full article

(This article belongs to the Special Issue SARS-CoV-2 Host Cell Interactions)

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10 pages, 2351 KiB

Open AccessArticle

RETRACTED: SARS–CoV–2 Spike Impairs DNA Damage Repair and Inhibits V(D)J Recombination In Vitro

by Hui Jiang and Ya-Fang Mei

Viruses 2021, 13(10), 2056; https://doi.org/10.3390/v13102056 - 13 Oct 2021

Cited by 28 | Viewed by 1261904 | Retraction

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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12 pages, 1864 KiB

Open AccessArticle

Robust Neutralizing Antibody Levels Detected after Either SARS-CoV-2 Vaccination or One Year after Infection

by Stefan Glöckner, Franziska Hornung, Michael Baier, Sebastian Weis, Mathias W. Pletz, Stefanie Deinhardt-Emmer, Bettina Löffler and the CoNAN Study Group

Viruses 2021, 13(10), 2003; https://doi.org/10.3390/v13102003 - 5 Oct 2021

Cited by 15 | Viewed by 8353

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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17 pages, 4071 KiB

Open AccessArticle

Enrichment of SARS-CoV-2 Entry Factors and Interacting Intracellular Genes in Tissue and Circulating Immune Cells

by Abhinandan Devaprasad and Aridaman Pandit

Viruses 2021, 13(9), 1757; https://doi.org/10.3390/v13091757 - 2 Sep 2021

Cited by 3 | Viewed by 3010

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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11 pages, 588 KiB

Open AccessArticle

SARS-CoV-2 Infection Modulates ACE2 Function and Subsequent Inflammatory Responses in Swabs and Plasma of COVID-19 Patients

by Lucía Gutiérrez-Chamorro, Eva Riveira-Muñoz, Clara Barrios, Vanesa Palau, Maria Nevot, Sònia Pedreño-López, Jordi Senserrich, Marta Massanella, Bonaventura Clotet, Cecilia Cabrera, Oriol Mitjà, Marta Crespo, Julio Pascual, Marta Riera and Ester Ballana

Viruses 2021, 13(9), 1715; https://doi.org/10.3390/v13091715 - 28 Aug 2021

Cited by 16 | Viewed by 3043

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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17 pages, 3523 KiB

Open AccessArticle

Characterization of the SARS-CoV-2 Host Response in Primary Human Airway Epithelial Cells from Aged Individuals

by Bharathiraja Subramaniyan, Jason L. Larabee, Manish Bodas, Andrew R. Moore, Anthony W. G. Burgett, Dean A. Myers, Constantin Georgescu, Jonathan D. Wren, James F. Papin and Matthew S. Walters

Viruses 2021, 13(8), 1603; https://doi.org/10.3390/v13081603 - 12 Aug 2021

Cited by 10 | Viewed by 3856

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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14 pages, 567 KiB

Open AccessArticle

SARS-CoV-2 N Protein Targets TRIM25-Mediated RIG-I Activation to Suppress Innate Immunity

by Gianni Gori Savellini, Gabriele Anichini, Claudia Gandolfo and Maria Grazia Cusi

Viruses 2021, 13(8), 1439; https://doi.org/10.3390/v13081439 - 23 Jul 2021

Cited by 45 | Viewed by 5074

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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17 pages, 4329 KiB

Open AccessArticle

Resveratrol and Pterostilbene Inhibit SARS-CoV-2 Replication in Air–Liquid Interface Cultured Human Primary Bronchial Epithelial Cells

by Bram M. ter Ellen, Nilima Dinesh Kumar, Ellen M. Bouma, Berit Troost, Denise P.I. van de Pol, Heidi H. van der Ende-Metselaar, Leonie Apperloo, Djoke van Gosliga, Maarten van den Berge, Martijn C. Nawijn, Peter H.J. van der Voort, Jill Moser, Izabela A. Rodenhuis-Zybert and Jolanda M. Smit

Viruses 2021, 13(7), 1335; https://doi.org/10.3390/v13071335 - 10 Jul 2021

Cited by 50 | Viewed by 6587

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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17 pages, 1384 KiB

Open AccessArticle

RETRACTED: Rationale and Criteria for a COVID-19 Model Framework

by Francesco Messina, Chiara Montaldo, Isabella Abbate, Manuela Antonioli, Veronica Bordoni, Giulia Matusali, Alessandra Sacchi, Emanuela Giombini, Gian Maria Fimia, Mauro Piacentini, Maria Rosaria Capobianchi, Francesco Nicola Lauria, Giuseppe Ippolito and on behalf of COVID-19 Scoping Review Working Group

Viruses 2021, 13(7), 1309; https://doi.org/10.3390/v13071309 - 6 Jul 2021

Cited by 3 | Viewed by 3816 | 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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15 pages, 1537 KiB

Open AccessArticle

Modeling within-Host SARS-CoV-2 Infection Dynamics and Potential Treatments

by Mehrshad Sadria and Anita T. Layton

Viruses 2021, 13(6), 1141; https://doi.org/10.3390/v13061141 - 14 Jun 2021

Cited by 53 | Viewed by 6391

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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18 pages, 2015 KiB

Open AccessArticle

The Pro-Inflammatory Chemokines CXCL9, CXCL10 and CXCL11 Are Upregulated Following SARS-CoV-2 Infection in an AKT-Dependent Manner

by Victoria Callahan, Seth Hawks, Matthew A. Crawford, Caitlin W. Lehman, Holly A. Morrison, Hannah M. Ivester, Ivan Akhrymuk, Niloufar Boghdeh, Rafaela Flor, Carla V. Finkielstein, Irving Coy Allen, James Weger-Lucarelli, Nisha Duggal, Molly A. Hughes and Kylene Kehn-Hall

Viruses 2021, 13(6), 1062; https://doi.org/10.3390/v13061062 - 3 Jun 2021

Cited by 81 | Viewed by 6988

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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16 pages, 233 KiB

Open AccessArticle

Identification of Novel Candidate CD8⁺ T Cell Epitopes of the SARS-CoV2 with Homology to Other Seasonal Coronaviruses

by Pradeep Darshana Pushpakumara, Deshan Madhusanka, Saubhagya Dhanasekara, Chandima Jeewandara, Graham S. Ogg and Gathsaurie Neelika Malavige

Viruses 2021, 13(6), 972; https://doi.org/10.3390/v13060972 - 24 May 2021

Cited by 4 | Viewed by 3511

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)

9 pages, 2092 KiB

Open AccessArticle

Profiles of Peripheral Immune Cells of Uncomplicated COVID-19 Cases with Distinct Viral RNA Shedding Periods

by Denise Utami Putri, Cheng-Hui Wang, Po-Chun Tseng, Wen-Sen Lee, Fu-Lun Chen, Han-Pin Kuo, Chih-Hsin Lee and Chiou-Feng Lin

Viruses 2021, 13(3), 514; https://doi.org/10.3390/v13030514 - 19 Mar 2021

Cited by 1 | Viewed by 2749

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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13 pages, 3134 KiB

Open AccessArticle

mRNA-lncRNA Co-Expression Network Analysis Reveals the Role of lncRNAs in Immune Dysfunction during Severe SARS-CoV-2 Infection

by Sumit Mukherjee, Bodhisattwa Banerjee, David Karasik and Milana Frenkel-Morgenstern

Viruses 2021, 13(3), 402; https://doi.org/10.3390/v13030402 - 3 Mar 2021

Cited by 32 | Viewed by 5687

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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11 pages, 2455 KiB

Open AccessArticle

The Mutation Profile of SARS-CoV-2 Is Primarily Shaped by the Host Antiviral Defense

by Cem Azgari, Zeynep Kilinc, Berk Turhan, Defne Circi and Ogun Adebali

Viruses 2021, 13(3), 394; https://doi.org/10.3390/v13030394 - 2 Mar 2021

Cited by 31 | Viewed by 5754

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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9 pages, 1539 KiB

Open AccessCommunication

TMPRSS11D and TMPRSS13 Activate the SARS-CoV-2 Spike Protein

by Mai Kishimoto, Kentaro Uemura, Takao Sanaki, Akihiko Sato, William W. Hall, Hiroaki Kariwa, Yasuko Orba, Hirofumi Sawa and Michihito Sasaki

Viruses 2021, 13(3), 384; https://doi.org/10.3390/v13030384 - 28 Feb 2021

Cited by 48 | Viewed by 6068

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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1 pages, 155 KiB

Open AccessExpression of Concern

Expression of Concern: Jiang, H.; Mei, Y.-F. SARS-CoV-2 Spike Impairs DNA Damage Repair and Inhibits V(D)J Recombination In Vitro. Viruses 2021, 13, 2056

by Eric O. Freed and Oliver Schildgen

Viruses 2022, 14(1), 12; https://doi.org/10.3390/v14010012 - 22 Dec 2021

Cited by 1 | Viewed by 26594

Abstract

We are issuing this expression of concern in consultation with the publisher to fulfil their reporting obligation regarding the publication [...] Full article

(This article belongs to the Special Issue SARS-CoV-2 Host Cell Interactions)

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