Special Issue "The Cell Biology of Coronavirus Infection"

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (15 January 2021).

Special Issue Editor

Prof. Carolyn Machamer
E-Mail Website
Guest Editor
Department of Cell Biology, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, 105 WBSB, Baltimore, MD 21205, USA

Special Issue Information

Dear Colleagues,

Coronaviruses are enveloped positive strand RNA viruses that infect mammals and birds. They have the interesting property of assembling at intracellular membranes. About 20% of common colds in humans are caused by coronaviruses. More severe diseases, including severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), are caused by novel coronaviruses that emerged from animal sources. Another novel coronavirus related to SARS coronavirus (SARS CoV-2) emerged in December 2019 and has spread globally, with significant mortality and economic impact. Much progress has been made in understanding the infectious diseases caused by human coronaviruses since the emergence of SARS and MERS. The animal sources, epidemiology, and types of infections have been well documented. However, there are still no approved vaccines or antiviral therapeutics for any human coronavirus infection.

This lack of treatment is due in part to an incomplete understanding of the basic biology of this family of viruses. Of particular interest is the unknown advantage of intracellular assembly and mechanism of virus egress from infected cells. These characteristics are potential untapped avenues for novel antiviral strategies. In this Special Issue of Cells, coronavirus infection will be examined from a cell biological perspective. Potential topics include virus entry, formation of replication organelles, genome replication and production of viral mRNA, synthesis and targeting of viral proteins, and assembly and budding in the endoplasmic reticulum-Golgi intermediate compartment and virion egress. How cells respond to coronavirus infection is another important potential topic, including how interferon-stimulated genes impact infection.

Prof. Carolyn Machamer
Guest Editor

Manuscript Submission Information

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Keywords

  • coronavirus
  • SARS
  • MERS
  • COVID-19
  • membrane fusion
  • intracellular assembly
  • Golgi complex
  • replication organelle
  • egress
  • host cell response

Published Papers (16 papers)

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Research

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Article
Assembly and Entry of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2): Evaluation Using Virus-Like Particles
Cells 2021, 10(4), 853; https://doi.org/10.3390/cells10040853 - 09 Apr 2021
Cited by 8 | Viewed by 1659
Abstract
Research on infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is currently restricted to BSL-3 laboratories. SARS-CoV2 virus-like particles (VLPs) offer a BSL-1, replication-incompetent system that can be used to evaluate virus assembly and virus-cell entry processes in tractable cell culture conditions. Here, [...] Read more.
Research on infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is currently restricted to BSL-3 laboratories. SARS-CoV2 virus-like particles (VLPs) offer a BSL-1, replication-incompetent system that can be used to evaluate virus assembly and virus-cell entry processes in tractable cell culture conditions. Here, we describe a SARS-CoV2 VLP system that utilizes nanoluciferase (Nluc) fragment complementation to track assembly and entry. We utilized the system in two ways. Firstly, we investigated the requirements for VLP assembly. VLPs were produced by concomitant synthesis of three viral membrane proteins, spike (S), envelope (E), and matrix (M), along with the cytoplasmic nucleocapsid (N). We discovered that VLP production and secretion were highly dependent on N proteins. N proteins from related betacoronaviruses variably substituted for the homologous SARS-CoV2 N, and chimeric betacoronavirus N proteins effectively supported VLP production if they contained SARS-CoV2 N carboxy-terminal domains (CTD). This established the CTDs as critical features of virus particle assembly. Secondly, we utilized the system by investigating virus-cell entry. VLPs were produced with Nluc peptide fragments appended to E, M, or N proteins, with each subsequently inoculated into target cells expressing complementary Nluc fragments. Complementation into functional Nluc was used to assess virus-cell entry. We discovered that each of the VLPs were effective at monitoring virus-cell entry, to various extents, in ways that depended on host cell susceptibility factors. Overall, we have developed and utilized a VLP system that has proven useful in identifying SARS-CoV2 assembly and entry features. Full article
(This article belongs to the Special Issue The Cell Biology of Coronavirus Infection)
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Article
SARS-CoV-2 Nucleocapsid Protein Targets RIG-I-Like Receptor Pathways to Inhibit the Induction of Interferon Response
Cells 2021, 10(3), 530; https://doi.org/10.3390/cells10030530 - 02 Mar 2021
Cited by 15 | Viewed by 1803
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the coronavirus disease 2019 (COVID-19) that has resulted in the current pandemic. The lack of highly efficacious antiviral drugs that can manage this ongoing global emergency gives urgency to establishing a [...] Read more.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the coronavirus disease 2019 (COVID-19) that has resulted in the current pandemic. The lack of highly efficacious antiviral drugs that can manage this ongoing global emergency gives urgency to establishing a comprehensive understanding of the molecular pathogenesis of SARS-CoV-2. We characterized the role of the nucleocapsid protein (N) of SARS-CoV-2 in modulating antiviral immunity. Overexpression of SARS-CoV-2 N resulted in the attenuation of retinoic acid inducible gene-I (RIG-I)-like receptor-mediated interferon (IFN) production and IFN-induced gene expression. Similar to the SARS-CoV-1 N protein, SARS-CoV-2 N suppressed the interaction between tripartate motif protein 25 (TRIM25) and RIG-I. Furthermore, SARS-CoV-2 N inhibited polyinosinic: polycytidylic acid [poly(I:C)]-mediated IFN signaling at the level of Tank-binding kinase 1 (TBK1) and interfered with the association between TBK1 and interferon regulatory factor 3 (IRF3), subsequently preventing the nuclear translocation of IRF3. We further found that both type I and III IFN production induced by either the influenza virus lacking the nonstructural protein 1 or the Zika virus were suppressed by the SARS-CoV-2 N protein. Our findings provide insights into the molecular function of the SARS-CoV-2 N protein with respect to counteracting the host antiviral immune response. Full article
(This article belongs to the Special Issue The Cell Biology of Coronavirus Infection)
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Article
Molecular Insights into the Thrombotic and Microvascular Injury in Placental Endothelium of Women with Mild or Severe COVID-19
Cells 2021, 10(2), 364; https://doi.org/10.3390/cells10020364 - 10 Feb 2021
Cited by 11 | Viewed by 3264
Abstract
Clinical manifestations of coronavirus disease 2019 (COVID-19) in pregnant women are diverse, and little is known of the impact of the disease on placental physiology. Severe acute respiratory syndrome coronavirus (SARS-CoV-2) has been detected in the human placenta, and its binding receptor ACE2 [...] Read more.
Clinical manifestations of coronavirus disease 2019 (COVID-19) in pregnant women are diverse, and little is known of the impact of the disease on placental physiology. Severe acute respiratory syndrome coronavirus (SARS-CoV-2) has been detected in the human placenta, and its binding receptor ACE2 is present in a variety of placental cells, including endothelium. Here, we analyze the impact of COVID-19 in placental endothelium, studying by immunofluorescence the expression of von Willebrand factor (vWf), claudin-5, and vascular endothelial (VE) cadherin in the decidua and chorionic villi of placentas from women with mild and severe COVID-19 in comparison to healthy controls. Our results indicate that: (1) vWf expression increases in the endothelium of decidua and chorionic villi of placentas derived from women with COVID-19, being higher in severe cases; (2) Claudin-5 and VE-cadherin expression decrease in the decidua and chorionic villus of placentas from women with severe COVID-19 but not in those with mild disease. Placental histological analysis reveals thrombosis, infarcts, and vascular wall remodeling, confirming the deleterious effect of COVID-19 on placental vessels. Together, these results suggest that placentas from women with COVID-19 have a condition of leaky endothelium and thrombosis, which is sensitive to disease severity. Full article
(This article belongs to the Special Issue The Cell Biology of Coronavirus Infection)
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Article
Usefulness of the New Hematological Parameter: Reactive Lymphocytes RE-LYMP with Flow Cytometry Markers of Inflammation in COVID-19
Cells 2021, 10(1), 82; https://doi.org/10.3390/cells10010082 - 06 Jan 2021
Cited by 4 | Viewed by 1280
Abstract
Identification of patients with activation of the immune system which indicates the presence of infection is essential, especially in the times of the global coronavirus 2019 (COVID-19) pandemic. The aim of the present study was to evaluate the reactive lymphocytes (RE-LYMP) parameter in [...] Read more.
Identification of patients with activation of the immune system which indicates the presence of infection is essential, especially in the times of the global coronavirus 2019 (COVID-19) pandemic. The aim of the present study was to evaluate the reactive lymphocytes (RE-LYMP) parameter in COVID-19 and to correlate it with activation lymphocytes markers by flow cytometry. The study group consisted of 40 patients: with COVID-19 infection (n = 20) and with others virus infections without COVID-19 (COVID-19(−) virus (n = 20)) and 20 healthy donors (HC). Blood count and flow cytometry were performed. The COVID-19(+) group had significantly lower RE-LYMP parameter than the COVID-19(−) virus group (5.45 vs. 11.05, p < 0.05). We observed higher proportion of plasmablasts in the COVID-19(+) and COVID-19(−) virus groups than HC (8.8 vs. 11.1 vs. 2.7, p < 0.05). In the COVID-19(+) there was a lower proportion of CD4+ CD38+ cells than in the other groups (significant differences between COVID-19(+) and COVID-19(−) virus groups). RE-LYMP correlated with activated T lymphocytes CD38+ and HLA-DR+ in the COVID-19(−) virus group, however in the COVID-19(+) group correlations with T lymphocytes CD25+ and CD45RO+ were observed. In summary the analysis of the RE-LYMP together with flow cytometric activation markers can be helpful in identifying and distinguishing patients with COVID-19(+) from other viruses and HC. Full article
(This article belongs to the Special Issue The Cell Biology of Coronavirus Infection)
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Article
Maturation of T and B Lymphocytes in the Assessment of the Immune Status in COVID-19 Patients
Cells 2020, 9(12), 2615; https://doi.org/10.3390/cells9122615 - 05 Dec 2020
Cited by 5 | Viewed by 1232
Abstract
Cell response to novel coronavirus disease 19 (COVID-19) is currently a widely researched topic. The assessment of leukocytes population and the maturation of both B and T lymphocytes may be important in characterizing the immunological profile of COVID-19 patients. The aim of the [...] Read more.
Cell response to novel coronavirus disease 19 (COVID-19) is currently a widely researched topic. The assessment of leukocytes population and the maturation of both B and T lymphocytes may be important in characterizing the immunological profile of COVID-19 patients. The aim of the present study was to evaluate maturation of B and T cells in COVID-19 patients with interstitial lesions on chest X-ray (COVID-19 X-ray (+)), without changes on X-ray (COVID-19 X-ray (−)) and in healthy control. The study group consisted of 23 patients divided on two groups: COVID-19 X-ray (+) n = 14 and COVID-19 X-ray (−) n = 9 and control n = 20. The flow cytometry method was performed. We observed a significantly higher percentage of plasmablasts and lower CD4+ lymphocytes in COVID-19 X-ray (+) patients than in COVID-19 X-ray (−) and control. In the COVID-19 X-ray (+) patients, there was a lower proportion of effector CD4+ T cells, naïve CD8+ T cells and higher central memory CD4+ cells and effector CD8+ T cells than control. The above results showed that the assessment of selected cells of B and T lymphocytes by flow cytometry can distinguish patients with COVID-19 and differentiate patients with and without changes on chest X-ray. Full article
(This article belongs to the Special Issue The Cell Biology of Coronavirus Infection)
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Article
Single-Cell Transcriptome Analysis Highlights a Role for Neutrophils and Inflammatory Macrophages in the Pathogenesis of Severe COVID-19
Cells 2020, 9(11), 2374; https://doi.org/10.3390/cells9112374 - 29 Oct 2020
Cited by 42 | Viewed by 3686
Abstract
Cumulative data link cytokine storms with coronavirus disease 2019 (COVID-19) severity. The precise identification of immune cell subsets in bronchoalveolar lavage (BAL) and their correlation with COVID-19 disease severity are currently being unraveled. Herein, we employed iterative clustering and guide-gene selection 2 (ICGS2) [...] Read more.
Cumulative data link cytokine storms with coronavirus disease 2019 (COVID-19) severity. The precise identification of immune cell subsets in bronchoalveolar lavage (BAL) and their correlation with COVID-19 disease severity are currently being unraveled. Herein, we employed iterative clustering and guide-gene selection 2 (ICGS2) as well as uniform manifold approximation and projection (UMAP) dimensionality reduction computational algorithms to decipher the complex immune and cellular composition of BAL, using publicly available datasets from a total of 68,873 single cells derived from two healthy subjects, three patients with mild COVID-19, and five patients with severe COVID-19. Our analysis revealed the presence of neutrophils and macrophage cluster-1 as a hallmark of severe COVID-19. Among the identified gene signatures, IFITM2, IFITM1, H3F3B, SAT1, and S100A8 gene signatures were highly associated with neutrophils, while CCL8, CCL3, CCL2, KLF6, and SPP1 were associated with macrophage cluster-1 in severe-COVID-19 patients. Interestingly, although macrophages were also present in healthy subjects and patients with mild COVID-19, they had different gene signatures, indicative of interstitial and cluster-0 macrophage (i.e., FABP4, APOC1, APOE, C1QB, and NURP1). Additionally, MALAT1, NEAT1, and SNGH25 were downregulated in patients with mild and severe COVID-19. Interferon signaling, FCγ receptor-mediated phagocytosis, IL17, and Tec kinase canonical pathways were enriched in patients with severe COVID-19, while PD-1 and PDL-1 pathways were suppressed. A number of upstream regulators (IFNG, PRL, TLR7, PRL, TGM2, TLR9, IL1B, TNF, NFkB, IL1A, STAT3, CCL5, and others) were also enriched in BAL cells from severe COVID-19-affected patients compared to those from patients with mild COVID-19. Further analyses revealed genes associated with the inflammatory response and chemotaxis of myeloid cells, phagocytes, and granulocytes, among the top activated functional categories in BAL from severe COVID-19-affected patients. Transcriptome data from another cohort of COVID-19-derived peripheral blood mononuclear cells (PBMCs) revealed the presence of several genes common to those found in BAL from patients with severe and mild COVID-19 (IFI27, IFITM3, IFI6, IFIT3, MX1, IFIT1, OASL, IFI30, OAS1) or to those seen only in BAL from severe-COVID-19 patients (S100A8, IFI44, IFI44L, CXCL8, CCR1, PLSCR1, EPSTI1, FPR1, OAS2, OAS3, IL1RN, TYMP, BCL2A1). Taken together, our data reveal the presence of neutrophils and macrophage cluster-1 as the main immune cell subsets associated with severe COVID-19 and identify their inflammatory and chemotactic gene signatures, also partially reflected systemically in the circulation, for possible diagnostic and therapeutic interventions. Full article
(This article belongs to the Special Issue The Cell Biology of Coronavirus Infection)
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Article
Effects of Coronavirus Persistence on the Genome Structure and Subsequent Gene Expression, Pathogenicity and Adaptation Capability
Cells 2020, 9(10), 2322; https://doi.org/10.3390/cells9102322 - 19 Oct 2020
Cited by 2 | Viewed by 919
Abstract
Coronaviruses are able to establish persistence. However, how coronaviruses react to persistence and whether the selected viruses have altered their characteristics remain unclear. In this study, we found that the persistent infection of bovine coronavirus (BCoV), which is in the same genus as [...] Read more.
Coronaviruses are able to establish persistence. However, how coronaviruses react to persistence and whether the selected viruses have altered their characteristics remain unclear. In this study, we found that the persistent infection of bovine coronavirus (BCoV), which is in the same genus as SARS-COV-2, led to alterations of genome structure, attenuation of gene expression, and the synthesis of subgenomic mRNA (sgmRNA) with a previously unidentified pattern. Subsequent analyses revealed that the altered genome structures were associated with the attenuation of gene expression. In addition, the genome structure at the 5′ terminus and the cellular environment during the persistence were responsible for the sgmRNA synthesis, solving the previously unanswered question regarding the selection of transcription regulatory sequence for synthesis of BCoV sgmRNA 12.7. Although the BCoV variants (BCoV-p95) selected under the persistence replicated efficiently in cells without persistent infection, its pathogenicity was still lower than that of wild-type (wt) BCoV. Furthermore, in comparison with wt BCoV, the variant BCoV-p95 was not able to efficiently adapt to the challenges of alternative environments, suggesting wt BCoV is genetically robust. We anticipate that the findings derived from this fundamental research can contribute to the disease control and treatments against coronavirus infection including SARS-CoV-2. Full article
(This article belongs to the Special Issue The Cell Biology of Coronavirus Infection)
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Article
Host Gene Expression of Macrophages in Response to Feline Coronavirus Infection
Cells 2020, 9(6), 1431; https://doi.org/10.3390/cells9061431 - 09 Jun 2020
Cited by 3 | Viewed by 1479
Abstract
Feline coronavirus is a highly contagious virus potentially resulting in feline infectious peritonitis (FIP), while the pathogenesis of FIP remains not well understood, particularly in the events leading to the disease. A predominant theory is that the pathogenic FIPV arises from a mutation, [...] Read more.
Feline coronavirus is a highly contagious virus potentially resulting in feline infectious peritonitis (FIP), while the pathogenesis of FIP remains not well understood, particularly in the events leading to the disease. A predominant theory is that the pathogenic FIPV arises from a mutation, so that it could replicate not only in enterocytes of the intestines but also in monocytes, subsequently systemically transporting the virus. The immune status and genetics of affected cats certainly play an important role in the pathogenesis. Considering the importance of genetics and host immune responses in viral infections, the goal of this study was to elucidate host gene expression in macrophages using RNA sequencing. Macrophages from healthy male cats infected with FIPV 79-1146 ex vivo displayed a differential host gene expression. Despite the virus uptake, aligned viral reads did not increase from 2 to 17 h. The overlap of host gene expression among macrophages from different cats was limited, even though viral transcripts were detected in the cells. Interestingly, some of the downregulated genes in all macrophages were involved in immune signaling, while some upregulated genes common for all cats were found to be inhibiting immune activation. Our results highlight individual host responses playing an important role, consistent with the fact that few cats develop feline infectious peritonitis despite a common presence of enteric FCoV. Full article
(This article belongs to the Special Issue The Cell Biology of Coronavirus Infection)
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Review

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Review
Assembly and Cellular Exit of Coronaviruses: Hijacking an Unconventional Secretory Pathway from the Pre-Golgi Intermediate Compartment via the Golgi Ribbon to the Extracellular Space
Cells 2021, 10(3), 503; https://doi.org/10.3390/cells10030503 - 26 Feb 2021
Cited by 7 | Viewed by 2908
Abstract
Coronaviruses (CoVs) assemble by budding into the lumen of the intermediate compartment (IC) at the endoplasmic reticulum (ER)-Golgi interface. However, why CoVs have chosen the IC as their intracellular site of assembly and how progeny viruses are delivered from this compartment to the [...] Read more.
Coronaviruses (CoVs) assemble by budding into the lumen of the intermediate compartment (IC) at the endoplasmic reticulum (ER)-Golgi interface. However, why CoVs have chosen the IC as their intracellular site of assembly and how progeny viruses are delivered from this compartment to the extracellular space has remained unclear. Here we address these enigmatic late events of the CoV life cycle in light of recently described properties of the IC. Of particular interest are the emerging spatial and functional connections between IC elements and recycling endosomes (REs), defined by the GTPases Rab1 and Rab11, respectively. The establishment of IC-RE links at the cell periphery, around the centrosome and evidently also at the noncompact zones of the Golgi ribbon indicates that—besides traditional ER-Golgi communication—the IC also promotes a secretory process that bypasses the Golgi stacks, but involves its direct connection with the endocytic recycling system. The initial confinement of CoVs to the lumen of IC-derived large transport carriers and their preferential absence from Golgi stacks is consistent with the idea that they exit cells following such an unconventional route. In fact, CoVs may share this pathway with other intracellularly budding viruses, lipoproteins, procollagen, and/or protein aggregates experimentally introduced into the IC lumen. Full article
(This article belongs to the Special Issue The Cell Biology of Coronavirus Infection)
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Review
Mechanisms of Coronavirus Nsp1-Mediated Control of Host and Viral Gene Expression
Cells 2021, 10(2), 300; https://doi.org/10.3390/cells10020300 - 02 Feb 2021
Cited by 10 | Viewed by 1693
Abstract
Many viruses disrupt host gene expression by degrading host mRNAs and/or manipulating translation activities to create a cellular environment favorable for viral replication. Often, virus-induced suppression of host gene expression, including those involved in antiviral responses, contributes to viral pathogenicity. Accordingly, clarifying the [...] Read more.
Many viruses disrupt host gene expression by degrading host mRNAs and/or manipulating translation activities to create a cellular environment favorable for viral replication. Often, virus-induced suppression of host gene expression, including those involved in antiviral responses, contributes to viral pathogenicity. Accordingly, clarifying the mechanisms of virus-induced disruption of host gene expression is important for understanding virus–host cell interactions and virus pathogenesis. Three highly pathogenic human coronaviruses (CoVs), including severe acute respiratory syndrome (SARS)-CoV, Middle East respiratory syndrome (MERS)-CoV, and SARS-CoV-2, have emerged in the past two decades. All of them encode nonstructural protein 1 (nsp1) in their genomes. Nsp1 of SARS-CoV and MERS-CoV exhibit common biological functions for inducing endonucleolytic cleavage of host mRNAs and inhibition of host translation, while viral mRNAs evade the nsp1-induced mRNA cleavage. SARS-CoV nsp1 is a major pathogenic determinant for this virus, supporting the notion that a viral protein that suppresses host gene expression can be a virulence factor, and further suggesting the possibility that SARS-CoV-2 nsp1, which has high amino acid identity with SARS-CoV nsp1, may serve as a major virulence factor. This review summarizes the gene expression suppression functions of nsp1 of CoVs, with a primary focus on SARS-CoV nsp1 and MERS-CoV nsp1. Full article
(This article belongs to the Special Issue The Cell Biology of Coronavirus Infection)
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Review
Significance of NETs Formation in COVID-19
Cells 2021, 10(1), 151; https://doi.org/10.3390/cells10010151 - 14 Jan 2021
Cited by 18 | Viewed by 1815
Abstract
Severe contagious respiratory disease—COVID-19—caused by the SARS-CoV-2 coronavirus, can lead to fatal respiratory failure associated with an excessive inflammatory response. Infiltration and spread of SARS-CoV-2 are based on the interaction between the virus’ structural protein S and the cell’s receptor–angiotensin-converting enzyme 2 (ACE2), [...] Read more.
Severe contagious respiratory disease—COVID-19—caused by the SARS-CoV-2 coronavirus, can lead to fatal respiratory failure associated with an excessive inflammatory response. Infiltration and spread of SARS-CoV-2 are based on the interaction between the virus’ structural protein S and the cell’s receptor–angiotensin-converting enzyme 2 (ACE2), with the simultaneous involvement of human trans-membrane protease, serine 2 (TMPRSS2). Many scientific reports stress the importance of elevated recruitment and activity of neutrophils, which can form extracellular neutrophil traps (NETs) playing a significant role in the mechanism of combating pathogens, in the pathogenesis of COVID-19. Excessive generation of NETs during prolonged periods of inflammation predisposes for the occurrence of undesirable reactions including thromboembolic complications and damage to surrounding tissues and organs. Within the present manuscript, we draw attention to the impact of NET generation on the severe course of COVID-19 in patients with concurrent cardiovascular and metabolic diseases. Additionally, we indicate the necessity to explore not only the cellular but also the molecular bases of COVID-19 pathogenesis, which may aid the development of dedicated therapies meant to improve chances for the successful treatment of patients. We also present new directions of research into medications that display NETs formation regulatory properties as potential significant therapeutic strategies in the progress of COVID-19. Full article
(This article belongs to the Special Issue The Cell Biology of Coronavirus Infection)
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Review
Dendritic Cells and SARS-CoV-2 Infection: Still an Unclarified Connection
Cells 2020, 9(9), 2046; https://doi.org/10.3390/cells9092046 - 08 Sep 2020
Cited by 18 | Viewed by 2648
Abstract
The ongoing pandemic due to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has so far infected about 2.42 × 107 (as at 27 August 2020) subjects with more than 820,000 deaths. It is the third zoonotic coronavirus-dependent outbreak in the last twenty [...] Read more.
The ongoing pandemic due to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has so far infected about 2.42 × 107 (as at 27 August 2020) subjects with more than 820,000 deaths. It is the third zoonotic coronavirus-dependent outbreak in the last twenty years and represents a major infective threat for public health worldwide. A main aspect of the infection, in analogy to other viral infections, is the so-called “cytokine storm”, an inappropriate molecular response to virus spread which plays major roles in tissue and organ damage. Immunological therapies, including vaccines and humanized monoclonal antibodies, have been proposed as major strategies for prevention and treatment of the disease. Accordingly, a detailed mechanistic knowledge of the molecular events with which the virus infects cells and induces an immunological response appears necessary. In this review, we will report details of the initial process of SARS-CoV-2 cellular entry with major emphasis on the maturation of the spike protein. Then, a particular focus will be devoted to describe the possible mechanisms by which dendritic cells, a major cellular component of innate and adaptive immune responses, may play a role in the spread of the virus in the human body and in the clinical evolution of the disease. Full article
(This article belongs to the Special Issue The Cell Biology of Coronavirus Infection)
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Review
Targeting the sAC-Dependent cAMP Pool to Prevent SARS-Cov-2 Infection
Cells 2020, 9(9), 1962; https://doi.org/10.3390/cells9091962 - 25 Aug 2020
Cited by 4 | Viewed by 1758
Abstract
An outbreak of the novel coronavirus (CoV) SARS-CoV-2, the causative agent of COVID-19 respiratory disease, infected millions of people since the end of 2019, led to high-level morbidity and mortality and caused worldwide social and economic disruption. There are currently no antiviral drugs [...] Read more.
An outbreak of the novel coronavirus (CoV) SARS-CoV-2, the causative agent of COVID-19 respiratory disease, infected millions of people since the end of 2019, led to high-level morbidity and mortality and caused worldwide social and economic disruption. There are currently no antiviral drugs available with proven efficacy or vaccines for its prevention. An understanding of the underlying cellular mechanisms involved in virus replication is essential for repurposing the existing drugs and/or the discovery of new ones. Endocytosis is the important mechanism of entry of CoVs into host cells. Endosomal maturation followed by the fusion with lysosomes are crucial events in endocytosis. Late endosomes and lysosomes are characterized by their acidic pH, which is generated by a proton transporter V-ATPase and required for virus entry via endocytic pathway. The cytoplasmic cAMP pool produced by soluble adenylyl cyclase (sAC) promotes V-ATPase recruitment to endosomes/lysosomes and thus their acidification. In this review, we discuss targeting the sAC-specific cAMP pool as a potential strategy to impair the endocytic entry of the SARS-CoV-2 into the host cell. Furthermore, we consider the potential impact of sAC inhibition on CoV-induced disease via modulation of autophagy and apoptosis. Full article
(This article belongs to the Special Issue The Cell Biology of Coronavirus Infection)
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Review
Canonical and Noncanonical Autophagy as Potential Targets for COVID-19
Cells 2020, 9(7), 1619; https://doi.org/10.3390/cells9071619 - 05 Jul 2020
Cited by 24 | Viewed by 3334
Abstract
The SARS-CoV-2 pandemic necessitates a review of the molecular mechanisms underlying cellular infection by coronaviruses, in order to identify potential therapeutic targets against the associated new disease (COVID-19). Previous studies on its counterparts prove a complex and concomitant interaction between coronaviruses and autophagy. [...] Read more.
The SARS-CoV-2 pandemic necessitates a review of the molecular mechanisms underlying cellular infection by coronaviruses, in order to identify potential therapeutic targets against the associated new disease (COVID-19). Previous studies on its counterparts prove a complex and concomitant interaction between coronaviruses and autophagy. The precise manipulation of this pathway allows these viruses to exploit the autophagy molecular machinery while avoiding its protective apoptotic drift and cellular innate immune responses. In turn, the maneuverability margins of such hijacking appear to be so narrow that the modulation of the autophagy, regardless of whether using inducers or inhibitors (many of which are FDA-approved for the treatment of other diseases), is usually detrimental to viral replication, including SARS-CoV-2. Recent discoveries indicate that these interactions stretch into the still poorly explored noncanonical autophagy pathway, which might play a substantial role in coronavirus replication. Still, some potential therapeutic targets within this pathway, such as RAB9 and its interacting proteins, look promising considering current knowledge. Thus, the combinatory treatment of COVID-19 with drugs affecting both canonical and noncanonical autophagy pathways may be a turning point in the fight against this and other viral infections, which may also imply beneficial prospects of long-term protection. Full article
(This article belongs to the Special Issue The Cell Biology of Coronavirus Infection)
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Review
Vasculopathy and Coagulopathy Associated with SARS-CoV-2 Infection
Cells 2020, 9(7), 1583; https://doi.org/10.3390/cells9071583 - 30 Jun 2020
Cited by 37 | Viewed by 5827
Abstract
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has resulted in >500,000 deaths worldwide, including >125,000 deaths in the U.S. since its emergence in late December 2019 and June 2020. Neither curative anti-viral [...] Read more.
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has resulted in >500,000 deaths worldwide, including >125,000 deaths in the U.S. since its emergence in late December 2019 and June 2020. Neither curative anti-viral drugs nor a protective vaccine is currently available for the treatment and prevention of COVID-19. Recently, new clinical syndromes associated with coagulopathy and vasculopathy have emerged as a cause of sudden death and other serious clinical manifestations in younger patients infected with SARS-CoV-2 infection. Angiotensin converting enzyme 2 (ACE2), the receptor for SARS-CoV-2 and other coronaviruses, is a transmembrane protein expressed by lung alveolar epithelial cells, enterocytes, and vascular endothelial cells, whose physiologic role is to induce the maturation of angiotensin I to generate angiotensin 1-7, a peptide hormone that controls vasoconstriction and blood pressure. In this review, we provide the general context of the molecular and cellular mechanisms of SARS-CoV-2 infection with a focus on endothelial cells, describe the vasculopathy and coagulopathy syndromes in patients with SARS-CoV-2, and outline current understanding of the underlying mechanistic aspects. Full article
(This article belongs to the Special Issue The Cell Biology of Coronavirus Infection)
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Other

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Opinion
The PIKfyve Inhibitor Apilimod: A Double-Edged Sword against COVID-19
Cells 2021, 10(1), 30; https://doi.org/10.3390/cells10010030 - 27 Dec 2020
Cited by 10 | Viewed by 2019
Abstract
The PIKfyve inhibitor apilimod is currently undergoing clinical trials for treatment of COVID-19. However, although apilimod might prevent viral invasion by inhibiting host cell proteases, the same proteases are critical for antigen presentation leading to T cell activation and there is good evidence [...] Read more.
The PIKfyve inhibitor apilimod is currently undergoing clinical trials for treatment of COVID-19. However, although apilimod might prevent viral invasion by inhibiting host cell proteases, the same proteases are critical for antigen presentation leading to T cell activation and there is good evidence from both in vitro studies and the clinic that apilimod blocks antiviral immune responses. We therefore warn that the immunosuppression observed in many COVID-19 patients might be aggravated by apilimod. Full article
(This article belongs to the Special Issue The Cell Biology of Coronavirus Infection)
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