Cells

Editorial

Jump to: Research, Review

3 pages, 181 KiB

Open AccessEditorial

Understanding Molecular Actors of SARS-CoV-2 Virulence to Tackle COVID-19 Outbreak

by Rita Berisio

Cells 2022, 11(22), 3597; https://doi.org/10.3390/cells11223597 - 14 Nov 2022

Viewed by 873

Abstract

COVID-19 (coronavirus disease 2019) is a threatening disease caused by the novel enveloped, positive-sense, single-stranded RNA beta-coronavirus, denoted as SARS-CoV-2 [...] Full article

(This article belongs to the Special Issue Understanding Molecular Actors of SARS-Cov-2 Virulence to Tackle COVID19 Outbreak)

Research

Jump to: Editorial, Review

10 pages, 1542 KiB

Open AccessCommunication

Circulating Platelet-Derived Extracellular Vesicles Are a Hallmark of Sars-Cov-2 Infection

by Giuseppe Cappellano, Davide Raineri, Roberta Rolla, Mara Giordano, Chiara Puricelli, Beatrice Vilardo, Marcello Manfredi, Vincenzo Cantaluppi, Pier Paolo Sainaghi, Luigi Castello, Nello De Vita, Lorenza Scotti, Rosanna Vaschetto, Umberto Dianzani and Annalisa Chiocchetti

Cells 2021, 10(1), 85; https://doi.org/10.3390/cells10010085 - 07 Jan 2021

Cited by 86 | Viewed by 4782

Abstract

Sars-Cov-2 infection causes fever and cough that may rapidly lead to acute respiratory distress syndrome (ARDS). Few biomarkers have been identified but, unfortunately, these are individually poorly specific, and novel biomarkers are needed to better predict patient outcome. The aim of this study [...] Read more.

Sars-Cov-2 infection causes fever and cough that may rapidly lead to acute respiratory distress syndrome (ARDS). Few biomarkers have been identified but, unfortunately, these are individually poorly specific, and novel biomarkers are needed to better predict patient outcome. The aim of this study was to evaluate the diagnostic performance of circulating platelets (PLT)-derived extracellular vesicles (EVs) as biomarkers for Sars-Cov-2 infection, by setting a rapid and reliable test on unmanipulated blood samples. PLT-EVs were quantified by flow cytometry on two independent cohorts of Sars-CoV-2+ (n = 69), Sars-Cov-2− (n = 62) hospitalized patients, and healthy controls. Diagnostic performance of PLT-EVs was evaluated by receiver operating characteristic (ROC) curve. PLT-EVs count were higher in Sars-Cov-2+ compared to Sars-Cov-2− patients or HC. ROC analysis of the combined cohorts showed an AUC = 0.79 and an optimal cut-off value of 1472 EVs/μL, with 75% sensitivity and 74% specificity. These data suggest that PLT-EVs might be an interesting biomarker deserving further investigations to test their predictive power. Full article

(This article belongs to the Special Issue Understanding Molecular Actors of SARS-Cov-2 Virulence to Tackle COVID19 Outbreak)

► Show Figures

Graphical abstract

17 pages, 1911 KiB

Open AccessEditor’s ChoiceArticle

Disharmonic Inflammatory Signatures in COVID-19: Augmented Neutrophils’ but Impaired Monocytes’ and Dendritic Cells’ Responsiveness

by Zuzana Parackova, Irena Zentsova, Marketa Bloomfield, Petra Vrabcova, Jitka Smetanova, Adam Klocperk, Grigorij Mesežnikov, Luis Fernando Casas Mendez, Tomas Vymazal and Anna Sediva

Cells 2020, 9(10), 2206; https://doi.org/10.3390/cells9102206 - 29 Sep 2020

Cited by 102 | Viewed by 4980

Abstract

COVID-19, caused by SARS-CoV-2 virus, emerged as a pandemic disease posing a severe threat to global health. To date, sporadic studies have demonstrated that innate immune mechanisms, specifically neutrophilia, NETosis, and neutrophil-associated cytokine responses, are involved in COVID-19 pathogenesis; however, our understanding of [...] Read more.

COVID-19, caused by SARS-CoV-2 virus, emerged as a pandemic disease posing a severe threat to global health. To date, sporadic studies have demonstrated that innate immune mechanisms, specifically neutrophilia, NETosis, and neutrophil-associated cytokine responses, are involved in COVID-19 pathogenesis; however, our understanding of the exact nature of this aspect of host–pathogen interaction is limited. Here, we present a detailed dissection of the features and functional profiles of neutrophils, dendritic cells, and monocytes in COVID-19. We portray the crucial role of neutrophils as drivers of hyperinflammation associated with COVID-19 disease via the shift towards their immature forms, enhanced degranulation, cytokine production, and augmented interferon responses. We demonstrate the impaired functionality of COVID-19 dendritic cells and monocytes, particularly their low expression of maturation markers, increased PD-L1 levels, and their inability to upregulate phenotype upon stimulation. In summary, our work highlights important data that prompt further research, as therapeutic targeting of neutrophils and their associated products may hold the potential to reduce the severity of COVID-19. Full article

(This article belongs to the Special Issue Understanding Molecular Actors of SARS-Cov-2 Virulence to Tackle COVID19 Outbreak)

► Show Figures

Graphical abstract

Review

Jump to: Editorial, Research

37 pages, 9300 KiB

Open AccessReview

Comprehensive Structural and Molecular Comparison of Spike Proteins of SARS-CoV-2, SARS-CoV and MERS-CoV, and Their Interactions with ACE2

by Ma’mon M. Hatmal, Walhan Alshaer, Mohammad A. I. Al-Hatamleh, Malik Hatmal, Othman Smadi, Mutasem O. Taha, Ayman J. Oweida, Jennifer C. Boer, Rohimah Mohamud and Magdalena Plebanski

Cells 2020, 9(12), 2638; https://doi.org/10.3390/cells9122638 - 08 Dec 2020

Cited by 127 | Viewed by 13326

Abstract

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has recently emerged in China and caused a disease called coronavirus disease 2019 (COVID-19). The virus quickly spread around the world, causing a sustained global outbreak. Although SARS-CoV-2, and other coronaviruses, SARS-CoV and Middle East respiratory [...] Read more.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has recently emerged in China and caused a disease called coronavirus disease 2019 (COVID-19). The virus quickly spread around the world, causing a sustained global outbreak. Although SARS-CoV-2, and other coronaviruses, SARS-CoV and Middle East respiratory syndrome CoV (MERS-CoV) are highly similar genetically and at the protein production level, there are significant differences between them. Research has shown that the structural spike (S) protein plays an important role in the evolution and transmission of SARS-CoV-2. So far, studies have shown that various genes encoding primarily for elements of S protein undergo frequent mutation. We have performed an in-depth review of the literature covering the structural and mutational aspects of S protein in the context of SARS-CoV-2, and compared them with those of SARS-CoV and MERS-CoV. Our analytical approach consisted in an initial genome and transcriptome analysis, followed by primary, secondary and tertiary protein structure analysis. Additionally, we investigated the potential effects of these differences on the S protein binding and interactions to angiotensin-converting enzyme 2 (ACE2), and we established, after extensive analysis of previous research articles, that SARS-CoV-2 and SARS-CoV use different ends/regions in S protein receptor-binding motif (RBM) and different types of interactions for their chief binding with ACE2. These differences may have significant implications on pathogenesis, entry and ability to infect intermediate hosts for these coronaviruses. This review comprehensively addresses in detail the variations in S protein, its receptor-binding characteristics and detailed structural interactions, the process of cleavage involved in priming, as well as other differences between coronaviruses. Full article

(This article belongs to the Special Issue Understanding Molecular Actors of SARS-Cov-2 Virulence to Tackle COVID19 Outbreak)

► Show Figures

Graphical abstract

15 pages, 1327 KiB

Open AccessReview

The Potential Role of Osteopontin and Furin in Worsening Disease Outcomes in COVID-19 Patients with Pre-Existing Diabetes

by Yvonne Adu-Agyeiwaah, Maria B. Grant and Alexander G. Obukhov

Cells 2020, 9(11), 2528; https://doi.org/10.3390/cells9112528 - 23 Nov 2020

Cited by 21 | Viewed by 4248

Abstract

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the ongoing coronavirus disease 2019 (COVID-19) pandemic, with more than 50 million cases reported globally. Findings have consistently identified an increased severity of SARS-CoV-2 infection in individuals with diabetes. Osteopontin, a cytokine-like [...] Read more.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the ongoing coronavirus disease 2019 (COVID-19) pandemic, with more than 50 million cases reported globally. Findings have consistently identified an increased severity of SARS-CoV-2 infection in individuals with diabetes. Osteopontin, a cytokine-like matrix-associated phosphoglycoprotein, is elevated in diabetes and drives the expression of furin, a proprotein convertase implicated in the proteolytic processing and activation of several precursors, including chemokines, growth factors, hormones, adhesion molecules, and receptors. Elevated serum furin is a signature of diabetes mellitus progression and is associated with a dysmetabolic phenotype and increased risk of diabetes-linked premature mortality. Additionally, furin plays an important role in enhancing the infectivity of SARS-CoV-2 by promoting its entry and replication in the host cell. Here, we hypothesize that diabetes-induced osteopontin and furin protein upregulation results in worse outcomes in diabetic patients with SARS-CoV-2 infection owing to the roles of these protein in promoting viral infection and increasing metabolic dysfunction. Thus, targeting the osteopontin-furin axis may be a plausible strategy for reducing mortality in SARS-CoV-2 patients with diabetes. Full article

(This article belongs to the Special Issue Understanding Molecular Actors of SARS-Cov-2 Virulence to Tackle COVID19 Outbreak)

► Show Figures

Figure 1

16 pages, 3897 KiB

Open AccessReview

The SARS-CoV-2 Spike Glycoprotein as a Drug and Vaccine Target: Structural Insights into Its Complexes with ACE2 and Antibodies

by Anastassios C. Papageorgiou and Imran Mohsin

Cells 2020, 9(11), 2343; https://doi.org/10.3390/cells9112343 - 22 Oct 2020

Cited by 57 | Viewed by 8009

Abstract

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of the Coronavirus disease (COVID-19) pandemic, has so far resulted in more than 1.1 M deaths and 40 M cases worldwide with no confirmed remedy yet available. Since the first outbreak in Wuhan, [...] Read more.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of the Coronavirus disease (COVID-19) pandemic, has so far resulted in more than 1.1 M deaths and 40 M cases worldwide with no confirmed remedy yet available. Since the first outbreak in Wuhan, China in December 2019, researchers across the globe have been in a race to develop therapies and vaccines against the disease. SARS-CoV-2, similar to other previously identified Coronaviridae family members, encodes several structural proteins, such as spike, envelope, membrane, and nucleocapsid, that are responsible for host penetration, binding, recycling, and pathogenesis. Structural biology has been a key player in understanding the viral infection mechanism and in developing intervention strategies against the new coronavirus. The spike glycoprotein has drawn considerable attention as a means to block viral entry owing to its interactions with the human angiotensin-converting enzyme 2 (ACE2), which acts as a receptor. Here, we review the current knowledge of SARS-CoV-2 and its interactions with ACE2 and antibodies. Structural information of SARS-CoV-2 spike glycoprotein and its complexes with ACE2 and antibodies can provide key input for the development of therapies and vaccines against the new coronavirus. Full article

(This article belongs to the Special Issue Understanding Molecular Actors of SARS-Cov-2 Virulence to Tackle COVID19 Outbreak)

► Show Figures

Graphical abstract

24 pages, 2170 KiB

Open AccessReview

A Message from the Human Placenta: Structural and Immunomodulatory Defense against SARS-CoV-2

by Nina-Naomi Kreis, Andreas Ritter, Frank Louwen and Juping Yuan

Cells 2020, 9(8), 1777; https://doi.org/10.3390/cells9081777 - 25 Jul 2020

Cited by 56 | Viewed by 10196

Abstract

The outbreak of the coronavirus disease 2019 (COVID-19) pandemic has caused a global public health crisis. Viral infections may predispose pregnant women to a higher rate of pregnancy complications, including preterm births, miscarriage and stillbirth. Despite reports of neonatal COVID-19, definitive proof of [...] Read more.

The outbreak of the coronavirus disease 2019 (COVID-19) pandemic has caused a global public health crisis. Viral infections may predispose pregnant women to a higher rate of pregnancy complications, including preterm births, miscarriage and stillbirth. Despite reports of neonatal COVID-19, definitive proof of vertical transmission is still lacking. In this review, we summarize studies regarding the potential evidence for transplacental transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), characterize the expression of its receptors and proteases, describe the placental pathology and analyze virus-host interactions at the maternal-fetal interface. We focus on the syncytium, the barrier between mother and fetus, and describe in detail its physical and structural defense against viral infections. We further discuss the potential molecular mechanisms, whereby the placenta serves as a defense front against pathogens by regulating the interferon type III signaling, microRNA-triggered autophagy and the nuclear factor-κB pathway. Based on these data, we conclude that vertical transmission may occur but rare, ascribed to the potent physical barrier, the fine-regulated placental immune defense and modulation strategies. Particularly, immunomodulatory mechanisms employed by the placenta may mitigate violent immune response, maybe soften cytokine storm tightly associated with severely ill COVID-19 patients, possibly minimizing cell and tissue damages, and potentially reducing SARS-CoV-2 transmission. Full article

(This article belongs to the Special Issue Understanding Molecular Actors of SARS-Cov-2 Virulence to Tackle COVID19 Outbreak)

► Show Figures

Figure 1

17 pages, 1296 KiB

Open AccessReview

Reaction Cycles of Halogen Species in the Immune Defense: Implications for Human Health and Diseases and the Pathology and Treatment of COVID-19

by Qing-Bin Lu

Cells 2020, 9(6), 1461; https://doi.org/10.3390/cells9061461 - 13 Jun 2020

Cited by 11 | Viewed by 4686

Abstract

There is no vaccine or specific antiviral treatment for COVID-19, which is causing a global pandemic. One current focus is drug repurposing research, but those drugs have limited therapeutic efficacies and known adverse effects. The pathology of COVID-19 is essentially unknown. Without this [...] Read more.

There is no vaccine or specific antiviral treatment for COVID-19, which is causing a global pandemic. One current focus is drug repurposing research, but those drugs have limited therapeutic efficacies and known adverse effects. The pathology of COVID-19 is essentially unknown. Without this understanding, it is challenging to discover a successful treatment to be approved for clinical use. This paper addresses several key biological processes of reactive oxygen, halogen and nitrogen species (ROS, RHS and RNS) that play crucial physiological roles in organisms from plants to humans. These include why superoxide dismutases, the enzymes to catalyze the formation of H₂O₂, are required for protecting ROS-induced injury in cell metabolism, why the amount of ROS/RNS produced by ionizing radiation at clinically relevant doses is ~1000 fold lower than the endogenous ROS/RNS level routinely produced in the cell and why a low level of endogenous RHS plays a crucial role in phagocytosis for immune defense. Herein we propose a plausible amplification mechanism in immune defense: ozone-depleting-like halogen cyclic reactions enhancing RHS effects are responsible for all the mentioned physiological functions, which are activated by H₂O₂ and deactivated by NO signaling molecule. Our results show that the reaction cycles can be repeated thousands of times and amplify the RHS pathogen-killing (defense) effects by 100,000 fold in phagocytosis, resembling the cyclic ozone-depleting reactions in the stratosphere. It is unraveled that H₂O₂ is a required protective signaling molecule (angel) in the defense system for human health and its dysfunction can cause many diseases or conditions such as autoimmune disorders, aging and cancer. We also identify a class of potent drugs for effective treatment of invading pathogens such as HIV and SARS-CoV-2 (COVID-19), cancer and other diseases, and provide a molecular mechanism of action of the drugs or candidates. Full article

(This article belongs to the Special Issue Understanding Molecular Actors of SARS-Cov-2 Virulence to Tackle COVID19 Outbreak)

► Show Figures

Graphical abstract

22 pages, 4622 KiB

Open AccessEditor’s ChoiceReview

A Structural View of SARS-CoV-2 RNA Replication Machinery: RNA Synthesis, Proofreading and Final Capping

by Maria Romano, Alessia Ruggiero, Flavia Squeglia, Giovanni Maga and Rita Berisio

Cells 2020, 9(5), 1267; https://doi.org/10.3390/cells9051267 - 20 May 2020

Cited by 368 | Viewed by 29155

Abstract

The current coronavirus disease-2019 (COVID-19) pandemic is due to the novel coronavirus SARS-CoV-2. The scientific community has mounted a strong response by accelerating research and innovation, and has quickly set the foundation for understanding the molecular determinants of the disease for the development [...] Read more.

The current coronavirus disease-2019 (COVID-19) pandemic is due to the novel coronavirus SARS-CoV-2. The scientific community has mounted a strong response by accelerating research and innovation, and has quickly set the foundation for understanding the molecular determinants of the disease for the development of targeted therapeutic interventions. The replication of the viral genome within the infected cells is a key stage of the SARS-CoV-2 life cycle. It is a complex process involving the action of several viral and host proteins in order to perform RNA polymerization, proofreading and final capping. This review provides an update of the structural and functional data on the key actors of the replicatory machinery of SARS-CoV-2, to fill the gaps in the currently available structural data, which is mainly obtained through homology modeling. Moreover, learning from similar viruses, we collect data from the literature to reconstruct the pattern of interactions among the protein actors of the SARS-CoV-2 RNA polymerase machinery. Here, an important role is played by co-factors such as Nsp8 and Nsp10, not only as allosteric activators but also as molecular connectors that hold the entire machinery together to enhance the efficiency of RNA replication. Full article

(This article belongs to the Special Issue Understanding Molecular Actors of SARS-Cov-2 Virulence to Tackle COVID19 Outbreak)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Understanding Molecular Actors of SARS-Cov-2 Virulence to Tackle COVID19 Outbreak

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Published Papers (9 papers)

Editorial

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI