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Becker ME, Martin-Sancho L, Simons LM, McRaven MD, Chanda SK, Hultquist JF, Hope TJ. Live imaging of airway epithelium reveals that mucociliary clearance modulates SARS-CoV-2 spread. Nat Commun 2024; 15:9480. [PMID: 39488529 PMCID: PMC11531594 DOI: 10.1038/s41467-024-53791-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 10/20/2024] [Indexed: 11/04/2024] Open
Abstract
SARS-CoV-2 initiates infection in the conducting airways, where mucociliary clearance inhibits pathogen penetration. However, it is unclear how mucociliary clearance impacts SARS-CoV-2 spread after infection is established. To investigate viral spread at this site, we perform live imaging of SARS-CoV-2 infected differentiated primary human bronchial epithelium cultures for up to 12 days. Using a fluorescent reporter virus and markers for cilia and mucus, we longitudinally monitor mucus motion, ciliary motion, and infection. Infected cell numbers peak at 4 days post infection, forming characteristic foci that tracked mucus movement. Inhibition of MCC using physical and genetic perturbations limits foci. Later in infection, mucociliary clearance deteriorates. Increased mucus secretion accompanies ciliary motion defects, but mucociliary clearance and vectorial infection spread resume after mucus removal, suggesting that mucus secretion may mediate MCC deterioration. Our work shows that while MCC can facilitate SARS-CoV-2 spread after initial infection, subsequent MCC decreases inhibit spread, revealing a complex interplay between SARS-CoV-2 and MCC.
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Affiliation(s)
- Mark E Becker
- Department of Cell & Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | | | - Lacy M Simons
- Division of Infectious Diseases, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Michael D McRaven
- Department of Cell & Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Sumit K Chanda
- Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, CA, USA
| | - Judd F Hultquist
- Division of Infectious Diseases, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Thomas J Hope
- Department of Cell & Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
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2
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Cheng L, Rui Y, Wang Y, Chen S, Su J, Yu XF. A glimpse into viral warfare: decoding the intriguing role of highly pathogenic coronavirus proteins in apoptosis regulation. J Biomed Sci 2024; 31:70. [PMID: 39003473 PMCID: PMC11245872 DOI: 10.1186/s12929-024-01062-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Accepted: 06/18/2024] [Indexed: 07/15/2024] Open
Abstract
Coronaviruses employ various strategies for survival, among which the activation of endogenous or exogenous apoptosis stands out, with viral proteins playing a pivotal role. Notably, highly pathogenic coronaviruses such as SARS-CoV-2, SARS-CoV, and MERS-CoV exhibit a greater array of non-structural proteins compared to low-pathogenic strains, facilitating their ability to induce apoptosis via multiple pathways. Moreover, these viral proteins are adept at dampening host immune responses, thereby bolstering viral replication and persistence. This review delves into the intricate interplay between highly pathogenic coronaviruses and apoptosis, systematically elucidating the molecular mechanisms underpinning apoptosis induction by viral proteins. Furthermore, it explores the potential therapeutic avenues stemming from apoptosis inhibition as antiviral agents and the utilization of apoptosis-inducing viral proteins as therapeutic modalities. These insights not only shed light on viral pathogenesis but also offer novel perspectives for cancer therapy.
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Affiliation(s)
- Leyi Cheng
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Yajuan Rui
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Yanpu Wang
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Shiqi Chen
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Jiaming Su
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China.
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
| | - Xiao-Fang Yu
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China.
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
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3
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Hope T, Becker M, Martin-Sancho L, Simons L, McRaven M, Chanda S, Hultquist J. Live imaging of the airway epithelium reveals that mucociliary clearance modulates SARS-CoV-2 spread. RESEARCH SQUARE 2023:rs.3.rs-3246773. [PMID: 37720034 PMCID: PMC10503848 DOI: 10.21203/rs.3.rs-3246773/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2023]
Abstract
SARS-CoV-2 initiates infection in the conducting airways, which rely on mucocilliary clearance (MCC) to minimize pathogen penetration. However, it is unclear how MCC impacts SARS-CoV-2 spread after infection is established. To understand viral spread at this site, we performed live imaging of SARS-CoV-2 infected differentiated primary human bronchial epithelium cultures for up to 9 days. Fluorescent markers for cilia and mucus allowed longitudinal monitoring of MCC, ciliary motion, and infection. The number of infected cells peaked at 4 days post-infection in characteristic foci that followed mucus movement. Inhibition of MCC using physical and genetic perturbations limited foci. Later in infection, MCC was diminished despite relatively subtle ciliary function defects. Resumption of MCC and infection spread after mucus removal suggests that mucus secretion mediates this effect. We show that MCC facilitates SARS-CoV-2 spread early in infection while later decreases in MCC inhibit spread, suggesting a complex interplay between SARS-CoV-2 and MCC.
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Affiliation(s)
| | | | | | | | | | - Sumit Chanda
- Sanford Burnham Prebys Medical Discovery Institute
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4
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Wells EW, Parker MT. Regulating Select Agent Chimeras: Defining the Problem(s) Through the Lens of SARS-CoV-1/SARS-CoV-2 Chimeric Viruses. Health Secur 2023; 21:392-406. [PMID: 37703547 DOI: 10.1089/hs.2023.0008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/15/2023] Open
Abstract
In late 2021, the US Centers for Disease Control and Prevention (CDC) posted an interim final rule (86 FR 64075) to the federal register regulating the possession, use, and transfer of SARS-CoV-1/SARS-CoV-2 chimeric viruses. In doing so, the CDC provided the reasoning that viral chimeras combining the transmissibility of SARS-CoV-2 with the pathogenicity and lethality of SARS-CoV-1 pose a significant risk to public health and should thus be placed on the select agents and toxins list. However, 86 FR 64075 lacked clarity in its definitions and scope, some of which the CDC addressed in response to public comments in the final rule, 88 FR 13322, in early 2023. To evaluate these regulatory actions, we reviewed the existing select agent regulations to understand the landscape of chimeric virus regulation. Based on our findings, we first present clear definitions for the terms "chimeric virus," "viral chimera," and "virulence factor" and provide a list of SARS-CoV-1 virulence factors in an effort to aid researchers and federal rulemaking for these agents moving forward. We then provide suggestions for a combination of similarity and functional characteristic cutoffs that the government could use to enable researchers to distinguish between regulated and nonregulated chimeras. Finally, we discuss current select agent regulations and their overlaps with 86 FR 64075 and 88 FR 13322 and make suggestions for how to address chimera concerns within and/or without these regulations. Collectively, we believe that our findings fill important gaps in current federal regulations and provide forward-looking philosophical and practical analysis that can guide future decisionmaking.
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Affiliation(s)
- Elizabeth W Wells
- Elizabeth W. Wells is a Student, Department of Biology, Georgetown College of Arts & Sciences, Georgetown University, Washington, DC
| | - Michael T Parker
- Michael T. Parker, PhD, is Assistant Dean, Georgetown College of Arts & Sciences, Georgetown University, Washington, DC
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5
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Helou M, Nasr J, El Osta N, Jabbour E, Husni R. Liver manifestations in COVID-19 patients: A review article. World J Clin Cases 2023; 11:2189-2200. [PMID: 37122526 PMCID: PMC10131011 DOI: 10.12998/wjcc.v11.i10.2189] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 02/09/2023] [Accepted: 03/10/2023] [Indexed: 03/30/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) initially presented as a disease that affected the lungs. Then, studies revealed that it intricately affected disparate organs in the human body, with the liver being one of the most affected organs. This review aimed to assess the association between COVID-19 and liver function, shedding light on its clinical implication. However, its exact pathophysiology remains unclear, involving many factors, such as active viral replication in the liver cells, direct cytotoxic effects of the virus on the liver or adverse reactions to viral antigens. Liver symptoms are mild-to-moderate transaminase elevation. In some patients, with underlying liver disease, more serious outcomes are observed. Thus, liver function should be meticulously considered in patients with COVID-19.
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Affiliation(s)
- Mariana Helou
- Division of Emergency Medicine, Department of Internal Medicine, Lebanese American University Medical Center, Lebanese American University School of Medicine, Beirut 1102-2801, Lebanon
| | - Janane Nasr
- Division of Infectious Diseases, Department of Internal Medicine, Lebanese American University, School of Medicine, Beirut 1102-2801, Lebanon
| | - Nour El Osta
- Division of Emergency, Department of Internal Medicine, Lebanese American University, School of Medicine, Beirut 1102-2801, Lebanon
| | - Elsy Jabbour
- Division of Emergency, Department of Internal Medicine, Lebanese American University, School of Medicine, Beirut 1102-2801, Lebanon
| | - Rola Husni
- Division of Infectious Diseases, Department of Internal Medicine, Lebanese American University, School of Medicine, Beirut 1102-2801, Lebanon
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Ahsan K, Anwar MA, Munawar N. Gut microbiome therapeutic modulation to alleviate drug-induced hepatic damage in COVID-19 patients. World J Gastroenterol 2023; 29:1708-1720. [PMID: 37077515 PMCID: PMC10107217 DOI: 10.3748/wjg.v29.i11.1708] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 01/06/2023] [Accepted: 03/07/2023] [Indexed: 03/17/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) infection caused by the severe acute respiratory syndrome coronavirus 2 virus, its symptoms, treatment, and post-COVID-19 effects have been a major focus of research since 2020. In addition to respiratory symptoms, different clinical variants of the virus have been associated with dynamic symptoms and multiorgan diseases, including liver abnormalities. The release of cytokines by the activation of innate immune cells during viral infection and the high doses of drugs used for COVID-19 treatment are considered major drivers of liver injury in COVID-19 patients. The degree of hepatic inflammation in patients suffering from chronic liver disease and having COVID-19 could be severe and can be estimated through different liver chemistry abnormality markers. Gut microbiota influences liver chemistry through its metabolites. Gut dysbiosis during COVID-19 treatment can promote liver inflammation. Here, we highlighted the bidirectional association of liver physiology and gut microbiota (gut-liver axis) and its potential to manipulate drug-induced chemical abnormalities in the livers of COVID-19 patients.
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Affiliation(s)
- Khansa Ahsan
- Department of Chemistry, United Arab Emirates University, Al Ain 15551, United Arab Emirates
| | - Munir Ahmad Anwar
- Industrial Biotechnology Division, National Institute for Biotechnology and Genetic Engineering College, Pakistan Institute of Engineering and Applied Sciences (NIBGE-C, PIEAS), Faisalabad 38000, Pakistan
| | - Nayla Munawar
- Department of Chemistry, United Arab Emirates University, Al Ain 15551, United Arab Emirates
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7
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Hou P, Wang X, Wang H, Wang T, Yu Z, Xu C, Zhao Y, Wang W, Zhao Y, Chu F, Chang H, Zhu H, Lu J, Zhang F, Liang X, Li X, Wang S, Gao Y, He H. The ORF7a protein of SARS-CoV-2 initiates autophagy and limits autophagosome-lysosome fusion via degradation of SNAP29 to promote virus replication. Autophagy 2023; 19:551-569. [PMID: 35670302 PMCID: PMC9851267 DOI: 10.1080/15548627.2022.2084686] [Citation(s) in RCA: 61] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is closely related to various cellular aspects associated with autophagy. However, how SARS-CoV-2 mediates the subversion of the macroautophagy/autophagy pathway remains largely unclear. In this study, we demonstrate that overexpression of the SARS-CoV-2 ORF7a protein activates LC3-II and leads to the accumulation of autophagosomes in multiple cell lines, while knockdown of the viral ORF7a gene via shRNAs targeting ORF7a sgRNA during SARS-CoV-2 infection decreased autophagy levels. Mechanistically, the ORF7a protein initiates autophagy via the AKT-MTOR-ULK1-mediated pathway, but ORF7a limits the progression of autophagic flux by activating CASP3 (caspase 3) to cleave the SNAP29 protein at aspartic acid residue 30 (D30), ultimately impairing complete autophagy. Importantly, SARS-CoV-2 infection-induced accumulated autophagosomes promote progeny virus production, whereby ORF7a downregulates SNAP29, ultimately resulting in failure of autophagosome fusion with lysosomes to promote viral replication. Taken together, our study reveals a mechanism by which SARS-CoV-2 utilizes the autophagic machinery to facilitate its own propagation via ORF7a.Abbreviations: 3-MA: 3-methyladenine; ACE2: angiotensin converting enzyme 2; ACTB/β-actin: actin beta; ATG7: autophagy related 7; Baf A1: bafilomycin A1; BECN1: beclin 1; CASP3: caspase 3; COVID-19: coronavirus disease 2019; GFP: green fluorescent protein; hpi: hour post-infection; hpt: hour post-transfection; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MERS: Middle East respiratory syndrome; MTOR: mechanistic target of rapamycin kinase; ORF: open reading frame; PARP: poly(ADP-ribose) polymerase; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; shRNAs: short hairpin RNAs; siRNA: small interfering RNA; SNAP29: synaptosome associated protein 29; SQSTM1/p62: sequestosome 1; STX17: syntaxin 17; TCID50: tissue culture infectious dose; TEM: transmission electron microscopy; TUBB, tubulin, beta; ULK1: unc-51 like autophagy activating kinase 1.
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Affiliation(s)
- Peili Hou
- Ruminant Diseases Research Center, College of Life Sciences, Shandong Normal University, Jinan, China
| | - Xuefeng Wang
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Hongmei Wang
- Ruminant Diseases Research Center, College of Life Sciences, Shandong Normal University, Jinan, China,CONTACT Hongmei Wang ;; Ruminant Diseases Research Center, College of Life Sciences, Shandong Normal University, Jinan, Shandong250014, China; Yuwei Gao Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, Jilin130122, China; Hongbin He Ruminant Diseases Research Center, College of Life Sciences, Shandong Normal University, Jinan250014, China
| | - Tiecheng Wang
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Zhangping Yu
- Ruminant Diseases Research Center, College of Life Sciences, Shandong Normal University, Jinan, China
| | - Chunqing Xu
- Ruminant Diseases Research Center, College of Life Sciences, Shandong Normal University, Jinan, China
| | - Yudong Zhao
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Wenqi Wang
- Ruminant Diseases Research Center, College of Life Sciences, Shandong Normal University, Jinan, China,Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Yong Zhao
- College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong, China
| | - Fengyun Chu
- Ruminant Diseases Research Center, College of Life Sciences, Shandong Normal University, Jinan, China
| | - Huasong Chang
- Ruminant Diseases Research Center, College of Life Sciences, Shandong Normal University, Jinan, China
| | - Hongchao Zhu
- Ruminant Diseases Research Center, College of Life Sciences, Shandong Normal University, Jinan, China
| | - Jiahui Lu
- Ruminant Diseases Research Center, College of Life Sciences, Shandong Normal University, Jinan, China
| | - Fuzhen Zhang
- Ruminant Diseases Research Center, College of Life Sciences, Shandong Normal University, Jinan, China
| | - Xue Liang
- Ruminant Diseases Research Center, College of Life Sciences, Shandong Normal University, Jinan, China
| | - Xingyu Li
- Ruminant Diseases Research Center, College of Life Sciences, Shandong Normal University, Jinan, China
| | - Song Wang
- Ruminant Diseases Research Center, College of Life Sciences, Shandong Normal University, Jinan, China
| | - Yuwei Gao
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Hongbin He
- Ruminant Diseases Research Center, College of Life Sciences, Shandong Normal University, Jinan, China
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8
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Hurtado-Tamayo J, Requena-Platek R, Enjuanes L, Bello-Perez M, Sola I. Contribution to pathogenesis of accessory proteins of deadly human coronaviruses. Front Cell Infect Microbiol 2023; 13:1166839. [PMID: 37197199 PMCID: PMC10183600 DOI: 10.3389/fcimb.2023.1166839] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 04/11/2023] [Indexed: 05/19/2023] Open
Abstract
Coronaviruses (CoVs) are enveloped and positive-stranded RNA viruses with a large genome (∼ 30kb). CoVs include essential genes, such as the replicase and four genes coding for structural proteins (S, M, N and E), and genes encoding accessory proteins, which are variable in number, sequence and function among different CoVs. Accessory proteins are non-essential for virus replication, but are frequently involved in virus-host interactions associated with virulence. The scientific literature on CoV accessory proteins includes information analyzing the effect of deleting or mutating accessory genes in the context of viral infection, which requires the engineering of CoV genomes using reverse genetics systems. However, a considerable number of publications analyze gene function by overexpressing the protein in the absence of other viral proteins. This ectopic expression provides relevant information, although does not acknowledge the complex interplay of proteins during virus infection. A critical review of the literature may be helpful to interpret apparent discrepancies in the conclusions obtained by different experimental approaches. This review summarizes the current knowledge on human CoV accessory proteins, with an emphasis on their contribution to virus-host interactions and pathogenesis. This knowledge may help the search for antiviral drugs and vaccine development, still needed for some highly pathogenic human CoVs.
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Affiliation(s)
| | | | | | | | - Isabel Sola
- *Correspondence: Melissa Bello-Perez, ; Isabel Sola,
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9
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Domovitz T, Ayoub S, Werbner M, Alter J, Izhaki Tavor L, Yahalom-Ronen Y, Tikhonov E, Meirson T, Maman Y, Paran N, Israely T, Dessau M, Gal-Tanamy M. HCV Infection Increases the Expression of ACE2 Receptor, Leading to Enhanced Entry of Both HCV and SARS-CoV-2 into Hepatocytes and a Coinfection State. Microbiol Spectr 2022; 10:e0115022. [PMID: 36314945 PMCID: PMC9769977 DOI: 10.1128/spectrum.01150-22] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 09/28/2022] [Indexed: 11/09/2022] Open
Abstract
Recent studies suggest the enhancement of liver injury in COVID-19 patients infected with Hepatitis C virus (HCV). Hepatocytes express low levels of angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 entry receptor, raising the possibility of HCV-SARS-CoV-2 coinfection in the liver. This work aimed to explore whether HCV and SARS-CoV-2 coinfect hepatocytes and the interplay between these viruses. We demonstrate that SARS-CoV-2 coinfects HCV-infected Huh7.5 (Huh7.5HCV) cells. Both viruses replicated efficiently in the coinfected cells, with HCV replication enhanced in coinfected compared to HCV-mono-infected cells. Strikingly, Huh7.5HCV cells were eight fold more susceptible to SARS-CoV-2 pseudoviruses than naive Huh7.5 cells, suggesting enhanced SARS-CoV-2 entry into HCV-preinfected hepatocytes. In addition, we observed increased binding of spike receptor-binding domain (RBD) protein to Huh7.5HCV cells, as well as enhanced cell-to-cell fusion of Huh7.5HCV cells with spike-expressing Huh7.5 cells. We explored the mechanism of enhanced SARS-CoV-2 entry and identified an increased ACE2 mRNA and protein levels in Huh7.5HCV cells, primary hepatocytes, and in data from infected liver biopsies obtained from database. Importantly, higher expression of ACE2 increased HCV infection by enhancing its binding to the host cell, underscoring its role in the HCV life cycle as well. Transcriptome analysis revealed that shared host signaling pathways were induced in HCV-SARS-CoV-2 coinfection. This study revealed complex interactions between HCV and SARS-CoV-2 infections in hepatocytes, which may lead to the increased liver damage recently reported in HCV-positive COVID-19 patients. IMPORTANCE Here, we provide the first experimental evidence for the coexistence of SARS-CoV-2 infection with HCV, and the interplay between them. The study revealed a complex relationship of enhancement between the two viruses, where HCV infection increased the expression of the SARS-CoV-2 entry receptor ACE2, thus facilitating SARS-CoV-2 entry, and potentially, also HCV entry. Thereafter, SARS-CoV-2 infection enhanced HCV replication in hepatocytes. This study may explain the aggravation of liver damage that was recently reported in COVID-19 patients with HCV coinfection and suggests preinfection with HCV as a risk factor for severe COVID-19. Moreover, it highlights the possible importance of HCV treatment for coinfected patients. In a broader view, these findings emphasize the importance of identifying coinfecting pathogens that increase the risk of SARS-CoV-2 infection and that may accelerate COVID-19-related co-morbidities.
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Affiliation(s)
- Tom Domovitz
- Molecular Virology Lab, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Samer Ayoub
- Molecular Virology Lab, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Michal Werbner
- Molecular Virology Lab, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Joel Alter
- The Laboratory of Structural Biology of Infectious Diseases, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Lee Izhaki Tavor
- The Laboratory of Structural Biology of Infectious Diseases, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Yfat Yahalom-Ronen
- Department of Infectious Diseases, Israel Institute for Biological Research, Ness Ziona, Israel
| | - Evgeny Tikhonov
- The Lab of Genomic Instability and Cancer, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Tomer Meirson
- The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
- Davidoff Cancer Center, Rabin Medical Center-Beilinson Hospital, Petah Tikva, Israel
| | - Yaakov Maman
- The Lab of Genomic Instability and Cancer, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Nir Paran
- Department of Infectious Diseases, Israel Institute for Biological Research, Ness Ziona, Israel
| | - Tomer Israely
- Department of Infectious Diseases, Israel Institute for Biological Research, Ness Ziona, Israel
| | - Moshe Dessau
- The Laboratory of Structural Biology of Infectious Diseases, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Meital Gal-Tanamy
- Molecular Virology Lab, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
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10
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Liu Z, Fu Y, Huang Y, Zeng F, Rao J, Xiao X, Sun X, Jin H, Li J, Yang J, Du W, Liu L. Ubiquitination of SARS-CoV-2 ORF7a Prevents Cell Death Induced by Recruiting BclXL To Activate ER Stress. Microbiol Spectr 2022; 10:e0150922. [PMID: 36326498 PMCID: PMC9769937 DOI: 10.1128/spectrum.01509-22] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 10/18/2022] [Indexed: 11/06/2022] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), which has emerged in the last 2 years. The accessory protein ORF7a has been proposed as an immunomodulating factor that can cause dramatic inflammatory responses, but it is unknown how ORF7a interacts with host cells. We show that ORF7a induces cell apoptosis by recruiting the prosurvival factor BclXL to the endoplasmic reticulum (ER) via the exposed C-terminal residues Lys117 and Lys119. Simultaneously, ORF7a activates ER stress via the PERK-elF2α-CHOP pathway and inhibits the expression of endogenous BclXL, resulting in enhanced cell apoptosis. Ubiquitination of ORF7a interrupts the interaction with BclXL in the ER and weakens the activation of ER stress, which to some extent rescues the cells. Our work demonstrates that SARS-CoV-2 ORF7a hires antiapoptosis protein and aggregates on the ER, resulting in ER stress and apoptosis initiation. On the other hand, ORF7a utilizes the ubiquitin system to impede and escape host elimination, providing a promising potential target for developing strategies for minimizing the COVID-19 pandemic. IMPORTANCE Viruses struggle to reproduce after infecting cells, and the host eliminates infected cells through apoptosis to prevent virus spread. Cells adopt a special ubiquitination code to protect against viral infection, while ORF7a manipulates and exploits the ubiquitin system to eliminate host cells' effect on apoptosis and redirect cellular pathways in favor of virus survival. Our results revealed that SARS-CoV-2-encoded accessory protein ORF7a recruits prosurvival factor BclXL to the ER and activates the cellular ER stress response resulting in the initiation of programmed death to remove virus-infected cells. Ubiquitination of ORF7a blocked the recruitment of BclXL and suppressed the ER stress response, which helps to counteract cell apoptosis and rescue cell fate. These findings help us understand the mechanism of SARS-CoV-2 invasion and contribute to a theoretical foundation for the clinical prevention of COVID-19.
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Affiliation(s)
- Zhixin Liu
- Department of Infectious Diseases, Renmin Hospital, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
- Institute of Virology, Hubei University of Medicine, Shiyan, China
- Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, China
| | - Yanan Fu
- Department of Infectious Diseases, Renmin Hospital, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
- Institute of Virology, Hubei University of Medicine, Shiyan, China
| | - Yanping Huang
- Department of Infectious Diseases, Renmin Hospital, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
- Institute of Virology, Hubei University of Medicine, Shiyan, China
| | - Feng Zeng
- Department of Infectious Diseases, Renmin Hospital, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
- Institute of Virology, Hubei University of Medicine, Shiyan, China
| | - Jingjing Rao
- Department of Infectious Diseases, Renmin Hospital, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
- Institute of Virology, Hubei University of Medicine, Shiyan, China
| | - Xiao Xiao
- Department of Infectious Diseases, Renmin Hospital, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
- Institute of Virology, Hubei University of Medicine, Shiyan, China
| | - Xiaoguang Sun
- Department of Infectious Diseases, Renmin Hospital, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
- Institute of Virology, Hubei University of Medicine, Shiyan, China
| | - Hao Jin
- Department of Infectious Diseases, Renmin Hospital, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
| | - Jian Li
- Department of Infectious Diseases, Renmin Hospital, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
- Institute of Virology, Hubei University of Medicine, Shiyan, China
| | - Jing Yang
- Department of Infectious Diseases, Renmin Hospital, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
- Institute of Virology, Hubei University of Medicine, Shiyan, China
| | - Weixing Du
- Department of Infectious Diseases, Renmin Hospital, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
| | - Long Liu
- Department of Infectious Diseases, Renmin Hospital, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
- Institute of Virology, Hubei University of Medicine, Shiyan, China
- Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, China
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11
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Gopaul CD, Ventour D, Thomas D. Laboratory predictors for COVID-19 Intensive Care Unit admissions in Trinidad and Tobago. DIALOGUES IN HEALTH 2022; 1:100022. [PMID: 36785629 PMCID: PMC9170592 DOI: 10.1016/j.dialog.2022.100022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 05/20/2022] [Accepted: 05/31/2022] [Indexed: 01/08/2023]
Abstract
Understanding symptoms associated with COVID-19 cases requiring intensive care unit(ICU) attention is important in management of the life-threatening cases of the disease. This study aimed to determine laboratory indicators of ICU admission for COVID-19 patients. For this retrospective chart review study, data from 116 patients(ICU, n = 18, Non-ICU, n = 98) with confirmed SARS-CoV-2, managed at two hospitals in Trinidad and Tobago, from March 12th to April 12th 2020, were analyzed. The median age of non-ICU patients was 59.0(IQR = 23.5) years; ICU patients had a median age of 62.5(IR = 17.5). From univariate analysis, laboratory indicators significantly associated with ICU admission included WBC(P = 0.037), lymphocyte(P = 0.016), LDH(P = 0.002), AST(P = 0.005) and CRP(P = 0.0001). However, multivariate analysis including WBC, neutrophil, lymphocyte, PLT, AST, LDH, ALT and CRP indicated that only AST was associated with high odds of ICU admission(OR 0.002, 95% CI 0.000-0.004, P = 0.017). Statistically significant AUC were obtained for neutrophil(AUC = 0.704, P = 0.007), CRP (AUC = 0.81, p = 0.00) and LDH(AUC = 0.766, P = 0.00) and AST (AUC = 0.729, P = 0.003). The findings indicate that neutrophils, AST and LDH's ROC curves are good tests, CRP curve is a very good test, but lymphocyte curve is a poor test, in determining COVID-19 patients for ICU admission. Neutrophil, AST, LDH and CRP are suitable predictors of COVID-19 patients that should receive intensive unit care. The study provides significant insights into laboratory parameters that can be used to predict COVID-19 severity and important considerations for healthcare providers in making evidence-based decisions regarding COVID-19 patient management, especially in the context of limited ICU facilities. This study was not funded.
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Affiliation(s)
- Chavin D. Gopaul
- North Central Regional Health Authority, Champs Fleurs, Trinidad and Tobago
| | - Dale Ventour
- Faculty of Medical Sciences, University of the West Indies, St. Augustine, Trinidad and Tobago
| | - Davlin Thomas
- North Central Regional Health Authority, Champs Fleurs, Trinidad and Tobago
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12
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Wu HHL, Athwal VS, Kalra PA, Chinnadurai R. COVID-19 and hepatorenal syndrome. World J Gastroenterol 2022; 28:5666-5678. [PMID: 36338894 PMCID: PMC9627428 DOI: 10.3748/wjg.v28.i39.5666] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 09/21/2022] [Accepted: 10/02/2022] [Indexed: 02/06/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) is a highly infectious disease which emerged into a global pandemic. Although it primarily causes respiratory symptoms for affected patients, COVID-19 was shown to have multi-organ manifestations. Elevated liver enzymes appear to be commonly observed during the course of COVID-19, and there have been numerous reports of liver injury secondary to COVID-19 infection. It has been established that patients with pre-existing chronic liver disease (CLD) are more likely to have poorer outcomes following COVID-19 infection compared to those without CLD. Co-morbidities such as diabetes, hypertension, obesity, cardiovascular and chronic kidney disease frequently co-exist in individuals living with CLD, and a substantial population may also live with some degree of frailty. The mechanisms of how COVID-19 induces liver injury have been postulated. Hepatorenal syndrome (HRS) is the occurrence of kidney dysfunction in patients with severe CLD/fulminant liver failure in the absence of another identifiable cause, and is usually a marker of severe decompensated liver disease. Select reports of HRS following acute COVID-19 infection have been presented, although the risk factors and pathophysiological mechanisms leading to HRS in COVID-19 infection or following COVID-19 treatment remain largely unestablished due to the relative lack and novelty of published data. Evidence discussing the management of HRS in high-dependency care and intensive care contexts is only emerging. In this article, we provide an overview on the speculative pathophysiological mechanisms of COVID-19 induced HRS and propose strategies for clinical diagnosis and management to optimize outcomes in this scenario.
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Affiliation(s)
- Henry H L Wu
- Renal Research, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney 2065, New South Wales, Australia
| | - Varinder S Athwal
- Faculty of Biology, Medicine & Health (Division of Diabetes, Metabolism & Gastroenterology), The University of Manchester, Manchester M13 9PL, United Kingdom
| | - Philip A Kalra
- Department of Renal Medicine, Northern Care Alliance NHS Foundation Trust, Salford M6 8HD, United Kingdom
| | - Rajkumar Chinnadurai
- Department of Renal Medicine, Northern Care Alliance NHS Foundation Trust, Salford M6 8HD, United Kingdom
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13
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Goyal R, Gautam RK, Chopra H, Dubey AK, Singla RK, Rayan RA, Kamal MA. Comparative highlights on MERS-CoV, SARS-CoV-1, SARS-CoV-2, and NEO-CoV. EXCLI JOURNAL 2022; 21:1245-1272. [PMID: 36483910 PMCID: PMC9727256 DOI: 10.17179/excli2022-5355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Accepted: 09/23/2022] [Indexed: 01/25/2023]
Abstract
The severe acute respiratory syndrome (SARS-CoV, now SARS-CoV-1), middle east respiratory syndrome (MERS-CoV), Neo-CoV, and 2019 novel coronavirus (SARS-CoV-2/COVID-19) are the most notable coronaviruses, infecting the number of people worldwide by targeting the respiratory system. All these viruses are of zoonotic origin, predominantly from bats which are one of the natural reservoir hosts for coronaviruses. Thus, the major goal of our review article is to compare and contrast the characteristics and attributes of these coronaviruses. The SARS-CoV-1, MERS-CoV, and COVID-19 have many viral similarities due to their classification, they are not genetically related. COVID-19 shares approximately 79 % of its genome with SARS-CoV-1 and about 50 % with MERS-CoV. The shared receptor protein, ACE2 exhibit the most striking genetic similarities between SARS-CoV-1 and SARS-CoV-2. SARS-CoV primarily replicates in the epithelial cells of the respiratory system, but it may also affect macrophages, monocytes, activated T cells, and dendritic cells. MERS-CoV not only infects and replicates inside the epithelial and immune cells, but it may lyse them too, which is one of the common reasons for MERS's higher mortality rate. The details of infections caused by SARS-CoV-2 and lytic replication mechanisms in host cells are currently mysterious. In this review article, we will discuss the comparative highlights of SARS-CoV-1, MERS-CoV, SARS-CoV-2, and Neo-CoV, concerning their structural features, morphological characteristics, sources of virus origin and their evolutionary transitions, infection mechanism, computational study approaches, pathogenesis and their severity towards several diseases, possible therapeutic approaches, and preventive measures.
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Affiliation(s)
- Rajat Goyal
- MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, Haryana, India,MM School of Pharmacy, Maharishi Markandeshwar University, Sadopur-Ambala, India
| | - Rupesh K. Gautam
- Department of Pharmacology, Indore Institute of Pharmacy, Rau, Indore, India-453331,*To whom correspondence should be addressed: Rupesh K. Gautam, Department of Pharmacology, Indore Institute of Pharmacy, IIST Campus, Opposite IIM Indore, Rau-Pithampur Road, Indore – 453331 (M.P.), India; Tel.: +91 9413654324, E-mail:
| | - Hitesh Chopra
- Chitkara College of Pharmacy, Chitkara University, Punjab, India-140401
| | | | - Rajeev K. Singla
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China,School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab-144411, India
| | - Rehab A. Rayan
- Department of Epidemiology, High Institute of Public Health, Alexandria University, 5422031, Egypt
| | - Mohammad Amjad Kamal
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China,King Fahd Medical Research Center, King Abdulaziz University, Saudi Arabia,Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Bangladesh,Enzymoics, 7 Peterlee Place, Hebersham NSW 2770; Novel Global Community Educational Foundation, Australia
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14
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Jelley L, Douglas J, Ren X, Winter D, McNeill A, Huang S, French N, Welch D, Hadfield J, de Ligt J, Geoghegan JL. Genomic epidemiology of Delta SARS-CoV-2 during transition from elimination to suppression in Aotearoa New Zealand. Nat Commun 2022; 13:4035. [PMID: 35821124 PMCID: PMC9274967 DOI: 10.1038/s41467-022-31784-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 06/30/2022] [Indexed: 12/12/2022] Open
Abstract
New Zealand's COVID-19 elimination strategy heavily relied on the use of genomics to inform contact tracing, linking cases to the border and to clusters during community outbreaks. In August 2021, New Zealand entered its second nationwide lockdown after the detection of a single community case with no immediately apparent epidemiological link to the border. This incursion resulted in the largest outbreak seen in New Zealand caused by the Delta Variant of Concern. Here we generated 3806 high quality SARS-CoV-2 genomes from cases reported in New Zealand between 17 August and 1 December 2021, representing 43% of reported cases. We detected wide geographical spread coupled with undetected community transmission, characterised by the apparent extinction and reappearance of genomically linked clusters. We also identified the emergence, and near replacement, of genomes possessing a 10-nucleotide frameshift deletion that caused the likely truncation of accessory protein ORF7a. By early October, New Zealand moved from an elimination strategy to a suppression strategy and the role of genomics changed markedly from being used to track and trace, towards population-level surveillance.
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Affiliation(s)
- Lauren Jelley
- Institute of Environmental Science and Research, Wellington, New Zealand
- Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand
| | - Jordan Douglas
- Centre for Computational Evolution, School of Computer Science, University of Auckland, Auckland, New Zealand
| | - Xiaoyun Ren
- Institute of Environmental Science and Research, Wellington, New Zealand
| | - David Winter
- Institute of Environmental Science and Research, Wellington, New Zealand
| | - Andrea McNeill
- Institute of Environmental Science and Research, Wellington, New Zealand
| | - Sue Huang
- Institute of Environmental Science and Research, Wellington, New Zealand
| | - Nigel French
- Tāwharau Ora/School of Veterinary Science, Massey University, Palmerston North, New Zealand
| | - David Welch
- Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand
| | - James Hadfield
- Fred Hutchinson Cancer Research Centre, Seattle, Washington, USA
| | - Joep de Ligt
- Institute of Environmental Science and Research, Wellington, New Zealand
| | - Jemma L Geoghegan
- Institute of Environmental Science and Research, Wellington, New Zealand.
- Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.
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15
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Elnaggar M, Abomhya A, Elkhattib I, Dawoud N, Doshi R. COVID-19 and liver diseases, what we know so far. World J Clin Cases 2022; 10:3969-3980. [PMID: 35665122 PMCID: PMC9131221 DOI: 10.12998/wjcc.v10.i13.3969] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 10/15/2021] [Accepted: 03/26/2022] [Indexed: 02/06/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) pneumonia outbreak started in December 2019. On March 12, 2020, the World Health Organization (WHO) declared that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) constitutes a pandemic, and as of May 2021, SARS-CoV-2 has infected over 167.3 million patients, including 3.4 million deaths, reported to WHO. In this review, we will focus on the relationship between SARS-CoV-2 infection and the liver. We will discuss how chronic liver diseases affect the COVID-19 disease course and outcomes. We will also discuss the SARS-CoV-2 effects on the liver, mechanisms of acute liver injury, and potential management plans.
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Affiliation(s)
- Mohamed Elnaggar
- Department of Internal Medicine, University of Nevada Reno School of Medicine, Reno, NV 89052, United States
| | - Ahmed Abomhya
- Department of Internal Medicine, The Brooklyn Hospital Center, Brooklyn, NY 11200, United States
| | - Ismail Elkhattib
- Department of Internal Medicine, University of Connecticut, Farmington, CT 06030, United States
| | - Nabila Dawoud
- Department of Internal Medicine, University of Kentucky, Lexington, KY 40508, United States
| | - Rajkumar Doshi
- Department of Cardiology, St Joseph's University Medical Center, Paterson, NJ 07503, United States
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16
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Zhang R, Wang Q, Yang J. Potential of sphingosine-1-phosphate in preventing SARS-CoV-2 infection by stabilizing and protecting endothelial cells: Narrative review. Medicine (Baltimore) 2022; 101:e29164. [PMID: 35475801 PMCID: PMC9276324 DOI: 10.1097/md.0000000000029164] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Accepted: 03/07/2022] [Indexed: 02/05/2023] Open
Abstract
Coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread worldwide, resulting in over 250 million infections and >5 million deaths. Most antiviral drugs and vaccines have shown limited efficacy against SARS-CoV-2. Clinical data revealed that except for the large number of self-healing mild cases, moderate and severe cases mostly survived after supportive treatment but not specific drug administration or vaccination. The endothelial system is the first physiological barrier, and its structural stability is of critical importance in conferring disease resistance. Membrane lipid components, particularly sphingosine-1-phosphate (S1P), play a central role in stabilizing the cell membrane.Here, we used "Boolean Operators" such as AND, OR, and NOT, to search for relevant research articles in PubMed, then reviewed the potential of S1P in inhibiting SARS-CoV-2 infection by stabilizing the endothelial system, this is the major aim of this review work.Reportedly, vasculitis and systemic inflammatory vascular diseases are caused by endothelial damage resulting from SARS-CoV-2 infection. S1P, S1P receptor (SIPR), and signaling were involved in the process of SARS-CoV-2 infection, and S1P potentially regulated the function of EC barrier, in turn, inhibited the SARS-CoV-2 to infect the endothelial cells, and ultimately has the promising therapeutic value to coronavirus disease 2019.Taken together, we conclude that maintaining or administering a high level of S1P will preserve the integrity of the EC structure and function, in turn, lowering the risk of SARS-CoV-2 infection and reducing complications and mortality.
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Affiliation(s)
- Rongzhi Zhang
- Department of Anesthesiology, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Qiang Wang
- Gansu Medical College, Pingliang, Gansu, China
| | - Jianshe Yang
- Department of Anesthesiology, Lanzhou University Second Hospital, Lanzhou, Gansu, China
- Gansu Medical College, Pingliang, Gansu, China
- Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
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17
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Mukherjee PK, Efferth T, Das B, Kar A, Ghosh S, Singha S, Debnath P, Sharma N, Bhardwaj PK, Haldar PK. Role of medicinal plants in inhibiting SARS-CoV-2 and in the management of post-COVID-19 complications. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 98:153930. [PMID: 35114450 PMCID: PMC8730822 DOI: 10.1016/j.phymed.2022.153930] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 12/30/2021] [Accepted: 01/03/2022] [Indexed: 05/07/2023]
Abstract
BACKGROUND The worldwide corona virus disease outbreak, generally known as COVID-19 pandemic outbreak resulted in a major health crisis globally. The morbidity and transmission modality of COVID-19 appear more severe and uncontrollable. The respiratory failure and following cardiovascular complications are the main pathophysiology of this deadly disease. Several therapeutic strategies are put forward for the development of safe and effective treatment against SARS-CoV-2 virus from the pharmacological view point but till date there are no specific treatment regimen developed for this viral infection. PURPOSE The present review emphasizes the role of herbs and herbs-derived secondary metabolites in inhibiting SARS-CoV-2 virus and also for the management of post-COVID-19 related complications. This approach will foster and ensure the safeguards of using medicinal plant resources to support the healthcare system. Plant-derived phytochemicals have already been reported to prevent the viral infection and to overcome the post-COVID complications like parkinsonism, kidney and heart failure, liver and lungs injury and mental problems. In this review, we explored mechanistic approaches of herbal medicines and their phytocomponenets as antiviral and post-COVID complications by modulating the immunological and inflammatory states. STUDY DESIGN Studies related to diagnosis and treatment guidelines issued for COVID-19 by different traditional system of medicine were included. The information was gathered from pharmacological or non-pharmacological interventions approaches. The gathered information sorted based on therapeutic application of herbs and their components against SARSCoV-2 and COVID-19 related complications. METHODS A systemic search of published literature was conducted from 2003 to 2021 using different literature database like Google Scholar, PubMed, Science Direct, Scopus and Web of Science to emphasize relevant articles on medicinal plants against SARS-CoV-2 viral infection and Post-COVID related complications. RESULTS Collected published literature from 2003 onwards yielded with total 625 articles, from more than 18 countries. Among these 625 articles, more than 95 medicinal plants and 25 active phytomolecules belong to 48 plant families. Reports on the therapeutic activity of the medicinal plants belong to the Lamiaceae family (11 reports), which was found to be maximum reported from 4 different countries including India, China, Australia, and Morocco. Other reports on the medicinal plant of Asteraceae (7 reports), Fabaceae (8 reports), Piperaceae (3 reports), Zingiberaceae (3 reports), Ranunculaceae (3 reports), Meliaceae (4 reports) were found, which can be explored for the development of safe and efficacious products targeting COVID-19. CONCLUSION Keeping in mind that the natural alternatives are in the priority for the management and prevention of the COVID-19, the present review may help to develop an alternative approach for the management of COVID-19 viral infection and post-COVID complications from a mechanistic point of view.
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Affiliation(s)
- Pulok K Mukherjee
- Institute of Bioresources and Sustainable Development, Imphal-795001, India; School of Natural Product Studies, Department of Pharmaceutical Technology, Jadavpur University, Kolkata -700 032, India.
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany
| | - Bhaskar Das
- School of Natural Product Studies, Department of Pharmaceutical Technology, Jadavpur University, Kolkata -700 032, India
| | - Amit Kar
- Institute of Bioresources and Sustainable Development, Imphal-795001, India
| | - Suparna Ghosh
- School of Natural Product Studies, Department of Pharmaceutical Technology, Jadavpur University, Kolkata -700 032, India
| | - Seha Singha
- School of Natural Product Studies, Department of Pharmaceutical Technology, Jadavpur University, Kolkata -700 032, India
| | - Pradip Debnath
- School of Natural Product Studies, Department of Pharmaceutical Technology, Jadavpur University, Kolkata -700 032, India
| | - Nanaocha Sharma
- Institute of Bioresources and Sustainable Development, Imphal-795001, India
| | | | - Pallab Kanti Haldar
- School of Natural Product Studies, Department of Pharmaceutical Technology, Jadavpur University, Kolkata -700 032, India
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18
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Premeaux TA, Yeung ST, Bukhari Z, Bowler S, Alpan O, Gupta R, Ndhlovu LC. Emerging Insights on Caspases in COVID-19 Pathogenesis, Sequelae, and Directed Therapies. Front Immunol 2022; 13:842740. [PMID: 35265086 PMCID: PMC8899608 DOI: 10.3389/fimmu.2022.842740] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 02/01/2022] [Indexed: 01/08/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a significant global health emergency with new variants in some cases evading current therapies and approved vaccines. COVID-19 presents with a broad spectrum of acute and long-term manifestations. Severe COVID-19 is characterized by dysregulated cytokine release profile, dysfunctional immune responses, and hypercoagulation with a high risk of progression to multi-organ failure and death. Unraveling the fundamental immunological processes underlying the clinical manifestations of COVID-19 is vital for the identification and design of more effective therapeutic interventions for individuals at the highest risk of severe outcomes. Caspases are expressed in both immune and non-immune cells and mediate inflammation and cell death, including apoptosis and pyroptosis. Here we review accumulating evidence defining the importance of the expression and activity of caspase family members following SARS-CoV-2 infection and disease. Research suggests SARS-CoV-2 infection is linked to the function of multiple caspases, both mechanistically in vitro as well as in observational studies of individuals with severe COVID-19, which may further the impact on disease severity. We also highlight immunological mechanisms that occur in severe COVID-19 pathology upstream and downstream of activated caspase pathways, including innate recognition receptor signaling, inflammasomes, and other multiprotein complex assembly, inflammatory mediators IL-1β and IL-18, and apoptotic and pyroptotic cell death. Finally, we illuminate discriminate and indiscriminate caspase inhibitors that have been identified for clinical use that could emerge as potential therapeutic interventions that may benefit clinical efforts to prevent or ameliorate severe COVID-19.
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Affiliation(s)
- Thomas A. Premeaux
- Department of Medicine, Division of Infectious Diseases, Weill Cornell Medicine, New York, NY, United States
| | - Stephen T. Yeung
- Department of Medicine, Division of Infectious Diseases, Weill Cornell Medicine, New York, NY, United States
| | - Zaheer Bukhari
- Department of Pathology, The State University of New York (SUNY) Downstate Health Sciences University, Brooklyn, NY, United States
| | - Scott Bowler
- Department of Medicine, Division of Infectious Diseases, Weill Cornell Medicine, New York, NY, United States
| | - Oral Alpan
- Immunopathogenesis Section, Amerimmune, Fairfax, VA, United States
| | - Raavi Gupta
- Department of Pathology, The State University of New York (SUNY) Downstate Health Sciences University, Brooklyn, NY, United States
| | - Lishomwa C. Ndhlovu
- Department of Medicine, Division of Infectious Diseases, Weill Cornell Medicine, New York, NY, United States
- Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, United States
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19
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Ozkurt Z, Çınar Tanrıverdi E. COVID-19: Gastrointestinal manifestations, liver injury and recommendations. World J Clin Cases 2022; 10:1140-1163. [PMID: 35211548 PMCID: PMC8855202 DOI: 10.12998/wjcc.v10.i4.1140] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/28/2021] [Accepted: 12/23/2021] [Indexed: 02/06/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) has caused a pandemic that affected all countries with nearly 270 million patients and 5 million deaths, as of as of December, 2021. The severe acute respiratory syndrome coronavirus 2 virus targets the receptor, angiotensin-converting enzyme 2, which is frequently found in human intestinal epithelial cells, bile duct epithelial cells, and liver cells, and all gastrointestinal system organs are affected by COVID-19 infection. The aim of this study is to review the gastrointestinal manifestations and liver damage of COVID-19 infection and investigate the severe COVID-19 infection risk in patients that have chronic gastrointestinal disease, along with current treatment guidelines. A literature search was conducted on electronic databases of PubMed, Scopus, and Cochran Library, consisting of COVID-19, liver injury, gastrointestinal system findings, and treatment. Liver and intestinal involvements are the most common manifestations. Diarrhea, anorexia, nausea/vomiting, abdominal pain are the most frequent symptoms seen in intestinal involvement. Mild hepatitis occurs with elevated levels of transaminases. Gastrointestinal involvement is associated with long hospital stay, severity of the disease, and intensive care unit necessity. Treatments and follow-up of patients with inflammatory bowel diseases, cirrhosis, hepatocellular carcinoma, or liver transplant have been negatively affected during the pandemic. Patients with cirrhosis, hepatocellular carcinoma, auto-immune diseases, or liver transplantation may have a greater risk for severe COVID-19. Diagnostic or therapeutic procedures should be restricted with specific conditions. Telemedicine should be used in non-urgent periodic patient follow up. COVID-19 treatment should not be delayed in patients at the risk group. COVID-19 vaccination should be prioritized in this group.
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Affiliation(s)
- Zulal Ozkurt
- Department of Infectious Disease, Atatürk University, School of Medicine, Erzurum 25100, Turkey
| | - Esra Çınar Tanrıverdi
- Department of Medical Education, Atatürk University, School of Medicine, Erzurum 25100, Turkey
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20
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Abstract
BACKGROUND There is a high prevalence of liver injury (LI) in patients with coronavirus disease 2019 (COVID-19); however, few large-scale studies assessing risk factors and clinical outcomes in these patients have been done. AIMS To evaluate the risk factors and clinical outcomes associated with LI in a large inpatient cohort of COVID-19 patients. METHODS Adult patients with COVID-19 between March 1 and April 30, 2020, were included. LI was defined as peak levels of alanine aminotransferase/aspartate aminotransferase that were 3 times the ULN or peak levels in alkaline phosphatase/total bilirubin that were 2 times the ULN. Mild elevation in liver enzymes (MEL) was defined as abnormal peak liver enzyme levels lower than the threshold for LI. Patients with MEL and LI were compared to a control group comprising patients with normal liver enzymes throughout hospitalization. RESULTS Of 1935 hospitalized COVID-19 patients, 1031 (53.2%) had MEL and 396 (20.5%) had LI. Compared to control patients, MEL and LI groups contained proportionately more men. Patients in the MEL cohort were older compared to control, and African-Americans were more highly represented in the LI group. Patients with LI had an increased risk of mortality (relative risk [RR] 4.26), intensive care unit admission (RR, 5.52), intubation (RR, 11.01), 30-day readmission (RR, 1.81), length of hospitalization, and intensive care unit stay (10.49 and 10.06 days, respectively) compared to control. CONCLUSION Our study showed that patients with COVID-19 who presented with LI had a significantly increased risk of mortality and poor clinical outcomes.
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21
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Gato S, Lucena-Valera A, Muñoz-Hernández R, Sousa JM, Romero-Gómez M, Ampuero J. Impact of COVID-19 on liver disease: From the experimental to the clinic perspective. World J Virol 2021; 10:301-311. [PMID: 34909404 PMCID: PMC8641041 DOI: 10.5501/wjv.v10.i6.301] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 05/18/2021] [Accepted: 08/13/2021] [Indexed: 02/06/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) has caused a global pandemic unprecedented in over a century. Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a predominantly respiratory infection, various degrees of liver function abnormalities have been reported. Pre-existing liver disease in patients with SARS-CoV-2 infection has not been comprehensively evaluated in most studies, but it can critically compromise survival and trigger hepatic decompensation. The collapse of the healthcare services has negatively impacted the diagnosis, monitoring, and treatment of liver diseases in non-COVID-19 patients. In this review, we aim to discuss the impact of COVID-19 on liver disease from the experimental to the clinic perspective.
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Affiliation(s)
- Sheila Gato
- SeLiver Group, Instituto de Biomedicina de Sevilla, Sevilla 41013, Spain
| | - Ana Lucena-Valera
- Digestive Department, Hospital Universitario Virgen del Rocio, Sevilla 41013, Spain
| | - Rocío Muñoz-Hernández
- SeLiver Group, Instituto de Biomedicina de Sevilla, Sevilla 41013, Spain
- University of Seville, Sevilla 41013, Spain
| | - José Manuel Sousa
- Digestive Department, Hospital Universitario Virgen del Rocio, Sevilla 41013, Spain
| | - Manuel Romero-Gómez
- SeLiver Group, Instituto de Biomedicina de Sevilla, Sevilla 41013, Spain
- Digestive Department, Hospital Universitario Virgen del Rocio, Sevilla 41013, Spain
- University of Seville, Sevilla 41013, Spain
| | - Javier Ampuero
- SeLiver Group, Instituto de Biomedicina de Sevilla, Sevilla 41013, Spain
- Digestive Department, Hospital Universitario Virgen del Rocio, Sevilla 41013, Spain
- University of Seville, Sevilla 41013, Spain
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22
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Semikov VI, Aghayan DL, Shulutko AM, Khorobrykh TV, Aleksandrov YK, Mansurova GT, Kazaryan AM. Subacute thyroiditis after SARS-CoV-2 infection. Clin Case Rep 2021; 9:e05109. [PMID: 34849227 PMCID: PMC8607799 DOI: 10.1002/ccr3.5109] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 07/30/2021] [Accepted: 10/28/2021] [Indexed: 01/20/2023] Open
Abstract
Viral infections are considered as etiologic factors of subacute thyroiditis. The true incidence of subacute thyroiditis, caused by SARS-CoV-2 infection, is probably considerable since it is often masked by more dramatic affection of the respiratory system. This report presents two female patients who developed de Quervain's thyroiditis after COVID-19 disease.
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Affiliation(s)
- Vasiliy I. Semikov
- Department of Faculty Surgery N 2I.M.Sechenov First Moscow State Medical UniversityMoscowRussia
| | - Davit L. Aghayan
- Intervention CentreOslo University HospitalOsloNorway
- Department of Surgery N1Yerevan State Medical University after M. HeratsiYerevanArmenia
| | - Alexander M. Shulutko
- Department of Faculty Surgery N 2I.M.Sechenov First Moscow State Medical UniversityMoscowRussia
| | - Tatyana V. Khorobrykh
- Department of Faculty Surgery N 2I.M.Sechenov First Moscow State Medical UniversityMoscowRussia
| | | | - Gaukhar T. Mansurova
- Department of Faculty Surgery N 2I.M.Sechenov First Moscow State Medical UniversityMoscowRussia
| | - Airazat M. Kazaryan
- Department of Faculty Surgery N 2I.M.Sechenov First Moscow State Medical UniversityMoscowRussia
- Intervention CentreOslo University HospitalOsloNorway
- Department of Surgery N1Yerevan State Medical University after M. HeratsiYerevanArmenia
- Medical FacultyInstitute of Clinical MedicineUniversity of OsloOsloNorway
- Department of Gastrointestinal SurgeryØstfold Hospital TrustGrålumNorway
- Department of SurgeryFonna Hospital TrustOddaNorway
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23
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Idalsoaga F, Ayares G, Arab JP, Díaz LA. COVID-19 and Indirect Liver Injury: A Narrative Synthesis of the Evidence. J Clin Transl Hepatol 2021; 9:760-768. [PMID: 34722191 PMCID: PMC8516829 DOI: 10.14218/jcth.2020.00140] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 02/16/2021] [Accepted: 05/13/2021] [Indexed: 02/06/2023] Open
Abstract
The liver is frequently affected by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection. The most common manifestations are mildly elevated alanine aminotransferase and aspartate aminotransferase, with a prevalence of 16-53% among patients. Cases with severe coronavirus disease 2019 (COVID-19) seem to have higher rates of acute liver dysfunction, and the presence of abnormal liver tests at admission signifies a higher risk of severe disease during hospitalization. Patients with chronic liver diseases also have a higher risk of severe disease and mortality (mainly seen in patients with metabolic-associated fatty liver disease). Several pathways of damage have been proposed in the liver involvement of COVID-19 patients; although, the end-cause is most likely multifactorial. Abnormal liver tests have been attributed to the expression of angiotensin-converting enzyme 2 receptors in SARS-CoV-2 infection. This enzyme is expressed widely in cholangiocytes and less in hepatocytes. Other factors attributed to liver damage include drug-induced liver injury, uncontrolled release of proinflammatory molecules ("cytokine storm"), pneumonia-associated hypoxia, and direct damage by the infection. Hepatic steatosis, vascular thrombosis, fibrosis, and inflammatory features (including Kupffer cell hyperplasia) are the most common liver histopathological findings in deceased COVID-19 patients, suggesting important indirect mechanisms of liver damage. In this translational medicine-based narrative review, we summarize the current data on the possible indirect mechanisms involved in liver damage due to COVID-19, the histopathological findings, and the impact of these mechanisms in patients with chronic liver disease.
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Affiliation(s)
- Francisco Idalsoaga
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Gustavo Ayares
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Juan Pablo Arab
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
- Centro de Envejecimiento y Regeneración (CARE), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Luis Antonio Díaz
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
- Correspondence to: Luis Antonio Díaz, Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Marcoleta 367, Santiago 8330024, Chile. ORCID: https://orcid.org/0000-0002-8540-4930. Tel/Fax:+56-2-2354-3820, E-mail:
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24
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Wang X, Lei J, Li Z, Yan L. Potential Effects of Coronaviruses on the Liver: An Update. Front Med (Lausanne) 2021; 8:651658. [PMID: 34646834 PMCID: PMC8502894 DOI: 10.3389/fmed.2021.651658] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 07/22/2021] [Indexed: 02/06/2023] Open
Abstract
The coronaviruses that cause notable diseases, namely, severe acute respiratory syndrome (SARS), middle east respiratory syndrome (MERS) and coronavirus disease 2019 (COVID-19), exhibit remarkable similarities in genomic components and pathogenetic mechanisms. Although coronaviruses have widely been studied as respiratory tract pathogens, their effects on the hepatobiliary system have seldom been reported. Overall, the manifestations of liver injury caused by coronaviruses typically involve decreased albumin and elevated aminotransferase and bilirubin levels. Several pathophysiological hypotheses have been proposed, including direct damage, immune-mediated injury, ischemia and hypoxia, thrombosis and drug hepatotoxicity. The interaction between pre-existing liver disease and coronavirus infection has been illustrated, whereby coronaviruses influence the occurrence, severity, prognosis and treatment of liver diseases. Drugs and vaccines used for treating and preventing coronavirus infection also have hepatotoxicity. Currently, the establishment of optimized therapy for coronavirus infection and liver disease comorbidity is of significance, warranting further safety tests, animal trials and clinical trials.
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Affiliation(s)
- Xinyi Wang
- Thyroid and Parathyroid Surgery Center, West China Hospital of Sichuan University, Chengdu, China
- Liver Surgery Center, West China Hospital of Sichuan University, Chengdu, China
| | - Jianyong Lei
- Thyroid and Parathyroid Surgery Center, West China Hospital of Sichuan University, Chengdu, China
- Liver Surgery Center, West China Hospital of Sichuan University, Chengdu, China
| | - Zhihui Li
- Thyroid and Parathyroid Surgery Center, West China Hospital of Sichuan University, Chengdu, China
- Liver Surgery Center, West China Hospital of Sichuan University, Chengdu, China
| | - Lunan Yan
- Liver Surgery Center, West China Hospital of Sichuan University, Chengdu, China
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25
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Sodeifian F, Seyedalhosseini ZS, Kian N, Eftekhari M, Najari S, Mirsaeidi M, Farsi Y, Nasiri MJ. Drug-Induced Liver Injury in COVID-19 Patients: A Systematic Review. Front Med (Lausanne) 2021; 8:731436. [PMID: 34616757 PMCID: PMC8488138 DOI: 10.3389/fmed.2021.731436] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 08/25/2021] [Indexed: 02/06/2023] Open
Abstract
Introduction: The severity of COVID-19 may be correlated with the risk of liver injury development. An increasing number of studies indicate that degrees of hepatotoxicity has been associated with using some medications in the management of COVID-19 patients. However, limited studies had systematically investigated the evidence of drug-induced liver injury (DILI) in COVID-19 patients. Thus, this study aimed to examine DILI in COVID-19 patients. Methods: A systematic search was carried out in PubMed/Medline, EMBASE, and Web of Science up to December 30, 2020. Search items included "SARS-CoV-2", "Coronavirus," COVID-19, and liver injury. Results: We included 22 related articles. Among included studies, there was five case report, five case series, four randomizes control trial (RCT), seven cohort studies, and one cross-sectional study. The drugs included in this systematic review were remdesivir, favipiravir, tocilizumab, hydroxychloroquine, and lopinavir/ritonavir. Among included studies, some studies revealed a direct role of drugs, while others couldn't certainly confirm that the liver injury was due to SARS-CoV-2 itself or administration of medications. However, a significant number of studies reported that liver injury could be attributable to drug administration. Discussion: Liver injury in COVID-19 patients could be caused by the virus itself or the administration of some types of drug. Intensive liver function monitoring should be considered for patients, especially patients who are treated with drugs such as remdesivir, lopinavir/ritonavir, and tocilizumab.
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Affiliation(s)
- Fatemeh Sodeifian
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Sadat Seyedalhosseini
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Naghmeh Kian
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahya Eftekhari
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shaghayegh Najari
- School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Mirsaeidi
- Division of Pulmonary and Critical Care, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States
- Department of Pulmonary and Critical Care, Miami VA Medical Center, Miami, FL, United States
| | - Yeganeh Farsi
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Javad Nasiri
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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26
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Bhavaniramya S, Ramar V, Vishnupriya S, Palaniappan R, Sibiya A, Baskaralingam V. Comprehensive analysis of SARS-COV-2 drug targets and pharmacological aspects in treating the COVID-19. Curr Mol Pharmacol 2021; 15:393-417. [PMID: 34382513 DOI: 10.2174/1874467214666210811120635] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 01/27/2021] [Accepted: 02/22/2021] [Indexed: 11/22/2022]
Abstract
Corona viruses are enveloped, single-stranded RNA (Ribonucleic acid) viruses and they cause pandemic diseases having a devastating effect on both human healthcare and the global economy. To date, six corona viruses have been identified as pathogenic organisms which are significantly responsible for the infection and also cause severe respiratory diseases. Among them, the novel SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) caused a major outbreak of corona virus diseases 2019 (COVID-19). Coronaviridae family members can affects both humans and animals. In human, corona viruses cause severe acute respiratory syndrome with mild to severe outcomes. Several structural and genomics have been investigated, and the genome encodes about 28 proteins most of them with unknown function though it shares remarkable sequence identity with other proteins. There is no potent and licensed vaccine against SARS-CoV-2 and several trials are underway to investigate the possible therapeutic agents against viral infection. However, some of the antiviral drugs that have been investigated against SARS-CoV-2 are under clinical trials. In the current review we comparatively emphasize the emergence and pathogenicity of the SARS-CoV-2 and their infection and discuss the various putative drug targets of both viral and host receptors for developing effective vaccines and therapeutic combinations to overcome the viral outbreak.
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Affiliation(s)
- Sundaresan Bhavaniramya
- Biomaterials and Biotechnology in Animal Health Lab, Department of Animal Health and Management, Alagappa University, Karaikudi 630004, Tamil Nadu. India
| | - Vanajothi Ramar
- Department of Biomedical Science, Bharathidasan University, Tiruchirappalli, Tamil Nadu, 620024. India
| | - Selvaraju Vishnupriya
- College of Food and Dairy Technology, Tamil Nadu Veterinary and Animal Sciences University, Chennai 600052. India
| | - Ramasamy Palaniappan
- Research and Development Wing, Sree Balaji Medical College and Hospital, Bharath Institute of Higher Education (BIHER), Chennai-600044, Tamilnadu. India
| | - Ashokkumar Sibiya
- Biomaterials and Biotechnology in Animal Health Lab, Department of Animal Health and Management, Alagappa University, Karaikudi 630004, Tamil Nadu. India
| | - Vaseeharan Baskaralingam
- Biomaterials and Biotechnology in Animal Health Lab, Department of Animal Health and Management, Alagappa University, Karaikudi 630004, Tamil Nadu. India
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27
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Levy E, Stintzi A, Cohen A, Desjardins Y, Marette A, Spahis S. Critical appraisal of the mechanisms of gastrointestinal and hepatobiliary infection by COVID-19. Am J Physiol Gastrointest Liver Physiol 2021; 321:G99-G112. [PMID: 34009033 PMCID: PMC8289353 DOI: 10.1152/ajpgi.00106.2021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
COVID-19 represents a novel infectious disease induced by SARS-CoV-2. It has to date affected 24,240,000 individuals and killed 2,735,805 people worldwide. The highly infectious virus attacks mainly the lung, causing fever, cough, and fatigue in symptomatic patients, but also pneumonia in severe cases. However, growing evidence highlights SARS-CoV-2-mediated extrarespiratory manifestations, namely, gastrointestinal (GI) and hepatic complications. The detection of 1) the virus in the GI system (duodenum, colon, rectum, anal region, and feces); 2) the high expression of additional candidate coreceptors/auxiliary proteins to facilitate the virus entry; 3) the abundant viral angiotensin-converting enzyme 2 receptor; 4) the substantial expression of host transmembrane serine protease 2, necessary to induce virus-cell fusion; 5) the viral replication in the intestinal epithelial cells; and 6) the primarily GI disorders in the absence of respiratory symptoms lead to increased awareness of the risk of disease transmission via the fecal-oral route. The objectives of this review are to provide a brief update of COVID-19 pathogenesis and prevalence, present a critical overview of its GI and liver complications that affect clinical COVID-19 outcomes, clarify associated mechanisms (notably microbiota-related), define whether gut/liver disorders occur more frequently among critically ill patients with COVID-19, determine the impact of COVID-19 on preexisting gut/liver complications and vice versa, and discuss the available strategies for prevention and treatment to improve prognosis of the patients. The novel SARS-CoV-2 can cause gastrointestinal and hepatobiliary manifestations. Metagenomics studies of virobiota in response to SARS-CoV-2 infection are necessary to highlight the contribution of bacterial microflora to COVID-19 phenotype, which is crucial for developing biomarkers and therapeutics.
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Affiliation(s)
- Emile Levy
- 1Research Centre, Sainte-Justine University Health Center, Université de Montréal, Quebec, Canada,2Department of Nutrition, Université de Montréal, Quebec, Canada,3Department of Pediatrics, Gastroenterology and Hepatology Unit, Université de Montréal, Quebec, Canada,4Institute of Nutrition and Functional Foods, Laval University, Quebec, Canada
| | - Alain Stintzi
- 5Department of Biochemistry, Microbiology and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, Ontario, Canada
| | - Albert Cohen
- 6Division of Gastroenterology, Jewish General Hospital, Quebec, Canada
| | - Yves Desjardins
- 4Institute of Nutrition and Functional Foods, Laval University, Quebec, Canada
| | - André Marette
- 4Institute of Nutrition and Functional Foods, Laval University, Quebec, Canada
| | - Schohraya Spahis
- 1Research Centre, Sainte-Justine University Health Center, Université de Montréal, Quebec, Canada,2Department of Nutrition, Université de Montréal, Quebec, Canada,4Institute of Nutrition and Functional Foods, Laval University, Quebec, Canada
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28
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Pasini E, Corsetti G, Romano C, Scarabelli TM, Chen-Scarabelli C, Saravolatz L, Dioguardi FS. Serum Metabolic Profile in Patients With Long-Covid (PASC) Syndrome: Clinical Implications. Front Med (Lausanne) 2021; 8:714426. [PMID: 34368201 PMCID: PMC8339407 DOI: 10.3389/fmed.2021.714426] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 06/29/2021] [Indexed: 01/04/2023] Open
Abstract
Background: Many patients who have been suffering by Covid-19 suffer of long-Covid syndrome, with symptoms of fatigue and muscular weakness that characterize post-acute sequelae SARS-CoV-2 infection (PASC). However, there is limited knowledge about the molecular pathophysiology, and about the serum profile of these patients. Methods: We studied the blood serum profile of 75 selected patients, with previous confirmed Covid-19, 2 months after hospital discharge, who reported new-onset fatigue, muscle weakness and/or dyspnea not present prior to the virus infection and independently from concomitant diseases and/or clinical conditions. Results: All patients had very high serum concentrations of ferritin and D-Dimer. 87 and 72% of patients had clinically significant low levels of hemoglobin and albumin, respectively. Seventy three percentage had elevations in erythrocyte sedimentation rate and CRP. Twenty seven percentage had elevations in LDH. Conclusions: The co-existence of patient symptoms along with blood markers of coagulation, protein disarrangement and inflammation suggests ongoing alterations in the metabolism, promoting an inflammatory/hypercatabolic state which maintains a vicious circles implicated in the persistence of PASC. The persistence of altered D-Dimer levels raises the possibility of long-term risks of thromboembolic disease. All these markers levels should be accurately evaluated in the long-term follow-up, with individualized consideration for prophylactic nutritional, anti-inflammatory and/or anticoagulant therapy if indicated.
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Affiliation(s)
- Evasio Pasini
- Division of Cardiac Rehabilitation, Scientific Clinical Institutes Maugeri Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Lumezzane, Italy
| | - Giovanni Corsetti
- Division of Human Anatomy and Physiopathology, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Claudia Romano
- Division of Human Anatomy and Physiopathology, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Tiziano M Scarabelli
- Center for Heart and Vessel Preclinical Studies, St. John Hospital and Medical Center, Wayne State University, Detroit, MI, United States
| | - Carol Chen-Scarabelli
- Division of Cardiology, Richmond Veterans Affairs Medical Center, Richmond, VA, United States
| | - Louis Saravolatz
- Department of Medicine at St. John Hospital, Wayne State University, Detroit, MI, United States
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29
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Chazal N. Coronavirus, the King Who Wanted More Than a Crown: From Common to the Highly Pathogenic SARS-CoV-2, Is the Key in the Accessory Genes? Front Microbiol 2021; 12:682603. [PMID: 34335504 PMCID: PMC8317507 DOI: 10.3389/fmicb.2021.682603] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 06/22/2021] [Indexed: 12/14/2022] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that emerged in late 2019, is the etiologic agent of the current "coronavirus disease 2019" (COVID-19) pandemic, which has serious health implications and a significant global economic impact. Of the seven human coronaviruses, all of which have a zoonotic origin, the pandemic SARS-CoV-2, is the third emerging coronavirus, in the 21st century, highly pathogenic to the human population. Previous human coronavirus outbreaks (SARS-CoV-1 and MERS-CoV) have already provided several valuable information on some of the common molecular and cellular mechanisms of coronavirus infections as well as their origin. However, to meet the new challenge caused by the SARS-CoV-2, a detailed understanding of the biological specificities, as well as knowledge of the origin are crucial to provide information on viral pathogenicity, transmission and epidemiology, and to enable strategies for therapeutic interventions and drug discovery. Therefore, in this review, we summarize the current advances in SARS-CoV-2 knowledges, in light of pre-existing information of other recently emerging coronaviruses. We depict the specificity of the immune response of wild bats and discuss current knowledge of the genetic diversity of bat-hosted coronaviruses that promotes viral genome expansion (accessory gene acquisition). In addition, we describe the basic virology of coronaviruses with a special focus SARS-CoV-2. Finally, we highlight, in detail, the current knowledge of genes and accessory proteins which we postulate to be the major keys to promote virus adaptation to specific hosts (bat and human), to contribute to the suppression of immune responses, as well as to pathogenicity.
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Affiliation(s)
- Nathalie Chazal
- Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, CNRS, Montpellier, France
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30
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Sanguedolce F, Zanelli M, Froio E, Bisagni A, Zizzo M, Ascani S, Stallone G, Netti S, Ranieri E, Falagario U, Carrieri G, Cormio L. Pathological diagnosis of Coronavirus-related nephropathy: insight from postmortem studies. Crit Rev Clin Lab Sci 2021; 58:563-575. [PMID: 34236278 DOI: 10.1080/10408363.2021.1944047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
A novel coronavirus pneumonia first occurred in Wuhan, China in early December 2019; the causative agent was identified and named as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the World Health Organization (WHO), and the resulting disease termed coronavirus disease 2019 (COVID-19), according to the WHO coronavirus disease situation reports. This condition has spread rapidly all over the world and caused more than 125 million cases globally, with more than 2 million related deaths. Two previous outbreaks due to zoonotic coronaviruses have occurred in the last 20 years, namely the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV), causing high morbidity and mortality in human populations upon crossing the species barriers. SARS-CoV-2, SARS-CoV, and MERS-CoV show several similarities in pathogenicity and clinical presentations, the latter ranging from asymptomatic infection to severe acute respiratory distress syndrome (ARDS) and multiorgan impairment. Acute kidney injury (AKI) has been commonly reported in patients with CoV infections; therefore, pathological analysis of renal parenchyma in these patients has been carried out in order to improve knowledge about underlying mechanisms. Viral infection has been demonstrated in the renal tubular epithelial cells by electron microscopy (EM), immunohistochemistry (IHC), and in situ hybridization (ISH), although with conflicting results. Light microscopy (LM) changes have been described in the renal parenchyma primarily in the form of acute renal tubular damage, possibly due to direct viral cytopathic effect and immune-mediated mechanisms such as cytokine storm syndrome. In this review, we describe and discuss the spectrum of histological, ultrastructural, and molecular findings in SARS-CoV, MERS-CoV, and SARS-CoV-2-related renal pathology obtained from postmortem studies, as well as intrinsic limitations and pitfalls of current diagnostic techniques.
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Affiliation(s)
| | - Magda Zanelli
- Pathology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Emilia, Italy
| | - Elisabetta Froio
- Pathology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Emilia, Italy
| | - Alessandra Bisagni
- Pathology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Emilia, Italy
| | - Maurizio Zizzo
- Surgical Oncology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Emilia, Italy.,Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, Italy
| | - Stefano Ascani
- Pathology Unit, Azienda Ospedaliera S. Maria di Terni, University of Perugia, Terni, Italy
| | - Giovanni Stallone
- Nephrology Dialysis and Transplantation Unit, University of Foggia, Foggia, Italy
| | - Stefano Netti
- Clinical Pathology Unit, University of Foggia, Foggia, Italy
| | - Elena Ranieri
- Clinical Pathology Unit, University of Foggia, Foggia, Italy
| | - Ugo Falagario
- Urology and Renal Transplantation Unit, University of Foggia, Foggia, Italy
| | - Giuseppe Carrieri
- Urology and Renal Transplantation Unit, University of Foggia, Foggia, Italy
| | - Luigi Cormio
- Urology and Renal Transplantation Unit, University of Foggia, Foggia, Italy.,Department of Urology, Bonomo Teaching Hospital, Andria, Italy
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31
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Gorkhali R, Koirala P, Rijal S, Mainali A, Baral A, Bhattarai HK. Structure and Function of Major SARS-CoV-2 and SARS-CoV Proteins. Bioinform Biol Insights 2021; 15:11779322211025876. [PMID: 34220199 PMCID: PMC8221690 DOI: 10.1177/11779322211025876] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 05/25/2021] [Indexed: 01/20/2023] Open
Abstract
SARS-CoV-2 virus, the causative agent of COVID-19 pandemic, has a genomic organization consisting of 16 nonstructural proteins (nsps), 4 structural proteins, and 9 accessory proteins. Relative of SARS-CoV-2, SARS-CoV, has genomic organization, which is very similar. In this article, the function and structure of the proteins of SARS-CoV-2 and SARS-CoV are described in great detail. The nsps are expressed as a single or two polyproteins, which are then cleaved into individual proteins using two proteases of the virus, a chymotrypsin-like protease and a papain-like protease. The released proteins serve as centers of virus replication and transcription. Some of these nsps modulate the host’s translation and immune systems, while others help the virus evade the host immune system. Some of the nsps help form replication-transcription complex at double-membrane vesicles. Others, including one RNA-dependent RNA polymerase and one exonuclease, help in the polymerization of newly synthesized RNA of the virus and help minimize the mutation rate by proofreading. After synthesis of the viral RNA, it gets capped. The capping consists of adding GMP and a methylation mark, called cap 0 and additionally adding a methyl group to the terminal ribose called cap1. Capping is accomplished with the help of a helicase, which also helps remove a phosphate, two methyltransferases, and a scaffolding factor. Among the structural proteins, S protein forms the receptor of the virus, which latches on the angiotensin-converting enzyme 2 receptor of the host and N protein binds and protects the genomic RNA of the virus. The accessory proteins found in these viruses are small proteins with immune modulatory roles. Besides functions of these proteins, solved X-ray and cryogenic electron microscopy structures related to the function of the proteins along with comparisons to other coronavirus homologs have been described in the article. Finally, the rate of mutation of SARS-CoV-2 residues of the proteome during the 2020 pandemic has been described. Some proteins are mutated more often than other proteins, but the significance of these mutation rates is not fully understood.
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Affiliation(s)
- Ritesh Gorkhali
- Department of Biotechnology, Kathmandu University, Dhulikhel, Nepal
| | | | - Sadikshya Rijal
- Department of Biotechnology, Kathmandu University, Dhulikhel, Nepal
| | - Ashmita Mainali
- Department of Biotechnology, Kathmandu University, Dhulikhel, Nepal
| | - Adesh Baral
- Department of Biotechnology, Kathmandu University, Dhulikhel, Nepal
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Cai Y, Ye LP, Song YQ, Mao XL, Wang L, Jiang YZ, Que WT, Li SW. Liver injury in COVID-19: Detection, pathogenesis, and treatment. World J Gastroenterol 2021; 27:3022-3036. [PMID: 34168405 PMCID: PMC8192279 DOI: 10.3748/wjg.v27.i22.3022] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 03/24/2021] [Accepted: 04/22/2021] [Indexed: 02/06/2023] Open
Abstract
In the early December 2019, a novel coronavirus named severe acute respiratory syndrome coronavirus 2 was first reported in Wuhan, China, followed by an outbreak that spread around the world. Numerous studies have shown that liver injury is common in patients with coronavirus disease 2019 (COVID-19), and may aggravate the severity of the disease. However, the exact cause and specific mechanism of COVID-associated liver injury needs to be elucidated further. In this review, we present an analysis of the clinical features, potential mechanisms, and treatment strategies for liver injury associated with COVID-19. We hope that this review would benefit clinicians in devising better strategies for management of such patients.
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Affiliation(s)
- Yue Cai
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
| | - Li-Ping Ye
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
- School of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Ya-Qi Song
- School of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Xin-Li Mao
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
| | - Li Wang
- College of Basic Medicine, Inner Mongolia Medical University, Hohhot 010000, Inner Mongolia Autonomous Region, China
| | - Yan-Zhi Jiang
- Department of Gastroenterology and Hepatology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200000, China
| | - Wei-Tao Que
- Department of Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200000, China
| | - Shao-Wei Li
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
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Fang P, Fang L, Zhang H, Xia S, Xiao S. Functions of Coronavirus Accessory Proteins: Overview of the State of the Art. Viruses 2021; 13:1139. [PMID: 34199223 PMCID: PMC8231932 DOI: 10.3390/v13061139] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 06/11/2021] [Accepted: 06/11/2021] [Indexed: 02/07/2023] Open
Abstract
Coronavirus accessory proteins are a unique set of proteins whose genes are interspersed among or within the genes encoding structural proteins. Different coronavirus genera, or even different species within the same coronavirus genus, encode varying amounts of accessory proteins, leading to genus- or species-specificity. Though accessory proteins are dispensable for the replication of coronavirus in vitro, they play important roles in regulating innate immunity, viral proliferation, and pathogenicity. The function of accessory proteins on virus infection and pathogenesis is an area of particular interest. In this review, we summarize the current knowledge on accessory proteins of several representative coronaviruses that infect humans or animals, including the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with an emphasis on their roles in interaction between virus and host, mainly involving stress response, innate immunity, autophagy, and apoptosis. The cross-talking among these pathways is also discussed.
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Affiliation(s)
- Puxian Fang
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (P.F.); (L.F.); (H.Z.); (S.X.)
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, the Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China
| | - Liurong Fang
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (P.F.); (L.F.); (H.Z.); (S.X.)
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, the Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China
| | - Huichang Zhang
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (P.F.); (L.F.); (H.Z.); (S.X.)
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, the Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China
| | - Sijin Xia
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (P.F.); (L.F.); (H.Z.); (S.X.)
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, the Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China
| | - Shaobo Xiao
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (P.F.); (L.F.); (H.Z.); (S.X.)
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, the Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China
- Laboratory of Animal Virology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China
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Gholami M, Safari S, Ulloa L, Motaghinejad M. Neuropathies and neurological dysfunction induced by coronaviruses. J Neurovirol 2021; 27:380-396. [PMID: 33983506 PMCID: PMC8117458 DOI: 10.1007/s13365-021-00977-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 01/23/2021] [Accepted: 04/05/2021] [Indexed: 02/03/2023]
Abstract
During the recent years, viral epidemic due to coronaviruses, such as SARS (Severe Acute Respiratory Syndrome), Middle East Respiratory Coronavirus Syndrome (MERS), and COVID-19 (coronavirus disese-19), has become a global problem. In addition to causing cardiovascular and respiratory lethal dysfunction, these viruses can cause neurodegeneration leading to neurological disorders. Review of the current scientific literature reveals the multiple neuropathies and neuronal dysfunction associated with these viruses. Here, we review the major findings of these studies and discuss the main neurological sequels and outcomes of coronavirus infections with SARS, MERS, and COVID-19. This article analyzes and discusses the main mechanisms of coronavirus-induced neurodegeneration according to the current experimental and clinical studies. Coronaviruses can damage the nerves directly through endovascular dysfunctions thereby affecting nerve structures and synaptic connections. Coronaviruses can also induce neural cell degeneration indirectly via mitochondrial dysfunction inducing oxidative stress, inflammation, and apoptosis. Thus, coronaviruses can cause neurological disorders by inducing neurovascular dysfunction affecting nerve structures and synaptic connections, and by inducing inflammation, oxidative stress, and apoptosis. While some of these mechanisms are similar to other RNA viruses, the neurotoxic mechanisms of COVID-19, MERS, and SARS-CoV viruses are unknown and need detailed clinical and experimental studies.
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Affiliation(s)
- Mina Gholami
- Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Sepideh Safari
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Luis Ulloa
- Center for Perioperative Organ Protection, Department of Anesthesiology, Duke University, NC, 27710, Durham, USA.
| | - Majid Motaghinejad
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran.
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Ongaro A, Oselladore E, Memo M, Ribaudo G, Gianoncelli A. Insight into the LFA-1/SARS-CoV-2 Orf7a Complex by Protein-Protein Docking, Molecular Dynamics, and MM-GBSA Calculations. J Chem Inf Model 2021; 61:2780-2787. [PMID: 34043356 PMCID: PMC8189040 DOI: 10.1021/acs.jcim.1c00198] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
In the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) genome, open reading frames (ORFs) encode for viral accessory proteins. Among these, Orf7a structurally resembles the members of the immunoglobulin (Ig) superfamily and intracellular adhesion molecules (ICAMs), in particular. ICAMs are involved in integrin binding through lymphocyte function-associated antigen 1 (LFA-1). Based on such considerations and on previous findings on SARS-CoV, it has been postulated that the formation of the LFA-1/Orf7a complex could contribute to SARS-CoV-2 infectivity and pathogenicity. With the current work, we aim at providing insight into this macromolecular assembly, taking advantage of the recently reported SARS-CoV-2 Orf7a structure. Protein-protein docking, molecular dynamics (MD) simulations, and a Molecular Mechanical-Generalized Born Surface Area (MM-GBSA)-based stage were enrolled to provide refined models.
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Affiliation(s)
- Alberto Ongaro
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy
| | - Erika Oselladore
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy
| | - Maurizio Memo
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy
| | - Giovanni Ribaudo
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy
| | - Alessandra Gianoncelli
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy
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Fakhri S, Nouri Z, Moradi SZ, Akkol EK, Piri S, Sobarzo-Sánchez E, Farzaei MH, Echeverría J. Targeting Multiple Signal Transduction Pathways of SARS-CoV-2: Approaches to COVID-19 Therapeutic Candidates. Molecules 2021; 26:2917. [PMID: 34068970 PMCID: PMC8156180 DOI: 10.3390/molecules26102917] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 04/30/2021] [Accepted: 05/11/2021] [Indexed: 02/06/2023] Open
Abstract
Due to the complicated pathogenic pathways of coronavirus disease 2019 (COVID-19), related medicinal therapies have remained a clinical challenge. COVID-19 highlights the urgent need to develop mechanistic pathogenic pathways and effective agents for preventing/treating future epidemics. As a result, the destructive pathways of COVID-19 are in the line with clinical symptoms induced by severe acute coronary syndrome (SARS), including lung failure and pneumonia. Accordingly, revealing the exact signaling pathways, including inflammation, oxidative stress, apoptosis, and autophagy, as well as relative representative mediators such as tumor necrosis factor-α (TNF-α), nuclear factor erythroid 2-related factor 2 (Nrf2), Bax/caspases, and Beclin/LC3, respectively, will pave the road for combating COVID-19. Prevailing host factors and multiple steps of SARS-CoV-2 attachment/entry, replication, and assembly/release would be hopeful strategies against COVID-19. This is a comprehensive review of the destructive signaling pathways and host-pathogen interaction of SARS-CoV-2, as well as related therapeutic targets and treatment strategies, including potential natural products-based candidates.
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Affiliation(s)
- Sajad Fakhri
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran; (S.F.); (S.Z.M.); (S.P.)
| | - Zeinab Nouri
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah 6714415153, Iran;
| | - Seyed Zachariah Moradi
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran; (S.F.); (S.Z.M.); (S.P.)
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran
| | - Esra Küpeli Akkol
- Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, Etiler, Ankara 06330, Turkey;
| | - Sana Piri
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran; (S.F.); (S.Z.M.); (S.P.)
| | - Eduardo Sobarzo-Sánchez
- Instituto de Investigación y Postgrado, Facultad de Ciencias de la Salud, Universidad Central de Chile, Santiago 8330507, Chile
- Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Mohammad Hosein Farzaei
- Medical Technology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran
| | - Javier Echeverría
- Departamento de Ciencias del Ambiente, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago 9170022, Chile
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Chakraborty S, Mallajosyula V, Tato CM, Tan GS, Wang TT. SARS-CoV-2 vaccines in advanced clinical trials: Where do we stand? Adv Drug Deliv Rev 2021; 172:314-338. [PMID: 33482248 PMCID: PMC7816567 DOI: 10.1016/j.addr.2021.01.014] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 01/11/2021] [Accepted: 01/14/2021] [Indexed: 02/07/2023]
Abstract
The ongoing SARS-CoV-2 pandemic has led to the focused application of resources and scientific expertise toward the goal of developing investigational vaccines to prevent COVID-19. The highly collaborative global efforts by private industry, governments and non-governmental organizations have resulted in a number of SARS-CoV-2 vaccine candidates moving to Phase III trials in a period of only months since the start of the pandemic. In this review, we provide an overview of the preclinical and clinical data on SARS-CoV-2 vaccines that are currently in Phase III clinical trials and in few cases authorized for emergency use. We further discuss relevant vaccine platforms and provide a discussion of SARS-CoV-2 antigens that may be targeted to increase the breadth and durability of vaccine responses.
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Affiliation(s)
- Saborni Chakraborty
- Department of Medicine, Division of Infectious Diseases, Stanford University, Stanford, CA, USA
| | - Vamsee Mallajosyula
- Institute for Immunity, Transplantation, and Infection, Stanford University, Stanford, CA, USA
| | - Cristina M Tato
- Infectious Disease Initiative, Chan Zuckerberg Biohub, San Francisco, CA, USA
| | - Gene S Tan
- J. Craig Venter Institute, 4120 Capricorn Lane, La Jolla, CA 92037, USA; Department of Infectious Diseases, University of California San Diego, La Jolla, CA 92037, USA
| | - Taia T Wang
- Department of Medicine, Division of Infectious Diseases, Stanford University, Stanford, CA, USA; Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA.
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Skariyachan S, Gopal D, Muddebihalkar AG, Uttarkar A, Niranjan V. Structural insights on the interaction potential of natural leads against major protein targets of SARS-CoV-2: Molecular modelling, docking and dynamic simulation studies. Comput Biol Med 2021; 132:104325. [PMID: 33751995 PMCID: PMC7954774 DOI: 10.1016/j.compbiomed.2021.104325] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 03/07/2021] [Accepted: 03/08/2021] [Indexed: 12/16/2022]
Abstract
Though significant efforts are in progress for developing drugs and vaccines against COVID-19, limited therapeutic agents are available currently. Thus, it is essential to undertake COVID-19 research and to identify therapeutic interventions in which computational modeling and virtual screening of lead molecules provide significant insights. The present study aimed to predict the interaction potential of natural lead molecules against prospective protein targets of SARS-CoV-2 by molecular modeling, docking, and dynamic simulation. Based on the literature survey and database search, fourteen molecular targets were selected and the three targets which lack the native structures were computationally modeled. The drug-likeliness and pharmacokinetic features of ninety-two natural molecules were predicted. Four lead molecules with ideal drug-likeliness and pharmacokinetic properties were selected and docked against fourteen targets, and their binding energies were compared with the binding energy of the interaction between Chloroquine and Hydroxychloroquine to their usual targets. The stabilities of selected docked complexes were confirmed by MD simulation and energy calculations. Four natural molecules demonstrated profound binding to most of the prioritized targets, especially, Hyoscyamine and Tamaridone to spike glycoprotein and Rotiorinol-C and Scutifoliamide-A to replicase polyprotein-1ab main protease of SARS-CoV-2 showed better binding energy, conformational and dynamic stabilities compared to the binding energy of Chloroquine and its usual target glutathione-S-transferase. The aforementioned lead molecules can be used to develop novel therapeutic agents towards the protein targets of SARS-CoV-2, and the study provides significant insight for structure-based drug development against COVID-19.
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Affiliation(s)
- Sinosh Skariyachan
- Department of Microbiology, St. Pius X College Rajapuram, Kasaragod, Kerala, India,Corresponding author
| | - Dharshini Gopal
- Department of Bioinformatics, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | | | - Akshay Uttarkar
- Department of Biotechnology, RV College of Engineering, Bengaluru, Karnataka, India
| | - Vidya Niranjan
- Department of Biotechnology, RV College of Engineering, Bengaluru, Karnataka, India
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Hu CAA, Murphy I, Klimaj S, Reece J, Chand HS. SARS-CoV-2, Inflammatory Apoptosis, and Cytokine Storm Syndrome. ACTA ACUST UNITED AC 2021. [DOI: 10.2174/2666958702101010022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), a novel and currently intensively studied beta coronavirus, is the causing agent of COVID-19 (Coronavirus Disease 2019), a highly contagious and devastating disease that has killed more than 2 million human beings since December 2019. Building on what has already been understood from studying SARS-CoV, a closely related single-strand RNA virus that set off SARS in 2002 and 2003, researchers began to learn how SARS-CoV-2 operates its vicious effects on the host cells. In essence, COVID-19 patients display hyperinflammatory and dysregulated cell death phenotypes that give a spectrum of symptoms ranging from mild to moderate upper-respiratory tract illnesses. However, SARS-CoV-2 can elicit serious pathologies, such as acute respiratory distress syndrome, sepsis-like multi-organ failure and even death, depending on the individual and their pre-existing condition(s). As viruses cannot reproduce independently, they hijack the machinery within the host cells and enslave them for the purpose of propagation. SARS-CoV-2 RNA genome harbors the genes that produce the protein products for manipulating host cell, viral replication, and repeating the vicious viral cycle. For counteracting the viral invasion, human cells have developed layers of defense mechanisms, such as restriction factors, Regulated Cell Death (RCD) pathways, interferon production, inflammatory response, and innate and adaptive immunity that are used to recognize and thwart viral infection. Unfortunately, some coronavirus encoded proteins are capable of attacking the host anti-viral system to achieve parasitic advantages. We reviewed the proteins of SARS-CoV and SARS-CoV-2 that possess manipulating effects on the host cell and cause tissue damage, immune cascade, cytokine production and release. We also discuss the means to restore the homeostatic balance between inflammatory response and RCD pathways and the potential targeted interventions that can be used to treat and/or prevent COVID-19.
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Higuera-de-la-Tijera F, Servín-Caamaño A, Reyes-Herrera D, Flores-López A, Robiou-Vivero EJA, Martínez-Rivera F, Galindo-Hernández V, Rosales-Salyano VH, Casillas-Suárez C, Chapa-Azuela O, Chávez-Morales A, Jiménez-Bobadilla B, Hernández-Medel ML, Orozco-Zúñiga B, Zacarías-Ezzat JR, Camacho S, Pérez-Hernández JL. The Age-AST-D Dimer (AAD) Regression Model Predicts Severe COVID-19 Disease. DISEASE MARKERS 2021; 2021:6658270. [PMID: 33791045 PMCID: PMC7996042 DOI: 10.1155/2021/6658270] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 01/08/2021] [Accepted: 03/12/2021] [Indexed: 02/07/2023]
Abstract
AIM Coronavirus disease (COVID-19) ranges from mild clinical phenotypes to life-threatening conditions like severe acute respiratory syndrome (SARS). It has been suggested that early liver injury in these patients could be a risk factor for poor outcome. We aimed to identify early biochemical predictive factors related to severe disease development with intensive care requirements in patients with COVID-19. METHODS Data from COVID-19 patients were collected at admission time to our hospital. Differential biochemical factors were identified between seriously ill patients requiring intensive care unit (ICU) admission (ICU patients) versus stable patients without the need for ICU admission (non-ICU patients). Multiple linear regression was applied, then a predictive model of severity called Age-AST-D dimer (AAD) was constructed (n = 166) and validated (n = 170). RESULTS Derivation cohort: from 166 patients included, there were 27 (16.3%) ICU patients that showed higher levels of liver injury markers (P < 0.01) compared with non-ICU patients: alanine aminotrasnferase (ALT) 225.4 ± 341.2 vs. 41.3 ± 41.1, aspartate aminotransferase (AST) 325.3 ± 382.4 vs. 52.8 ± 47.1, lactic dehydrogenase (LDH) 764.6 ± 401.9 vs. 461.0 ± 185.6, D-dimer (DD) 7765 ± 9109 vs. 1871 ± 4146, and age 58.6 ± 12.7 vs. 49.1 ± 12.8. With these finding, a model called Age-AST-DD (AAD), with a cut-point of <2.75 (sensitivity = 0.797 and specificity = 0.391, c - statistic = 0.74; 95%IC: 0.62-0.86, P < 0.001), to predict the risk of need admission to ICU (OR = 5.8; 95% CI: 2.2-15.4, P = 0.001), was constructed. Validation cohort: in 170 different patients, the AAD model < 2.75 (c - statistic = 0.80 (95% CI: 0.70-0.91, P < 0.001) adequately predicted the risk (OR = 8.8, 95% CI: 3.4-22.6, P < 0.001) to be admitted in the ICU (27 patients, 15.95%). CONCLUSIONS The elevation of AST (a possible marker of early liver injury) along with DD and age efficiently predict early (at admission time) probability of ICU admission during the clinical course of COVID-19. The AAD model can improve the comprehensive management of COVID-19 patients, and it could be useful as a triage tool to early classify patients with a high risk of developing a severe clinical course of the disease.
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Affiliation(s)
- Fátima Higuera-de-la-Tijera
- Multidisciplinary Team for the Attention and Care of Patients with COVID-19, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
- Gastroenterology and Hepatology Department, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
| | - Alfredo Servín-Caamaño
- Multidisciplinary Team for the Attention and Care of Patients with COVID-19, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
- Internal Medicine Department, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
| | - Daniel Reyes-Herrera
- Multidisciplinary Team for the Attention and Care of Patients with COVID-19, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
- Internal Medicine Department, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
| | - Argelia Flores-López
- Multidisciplinary Team for the Attention and Care of Patients with COVID-19, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
- Internal Medicine Department, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
| | - Enrique J. A. Robiou-Vivero
- Multidisciplinary Team for the Attention and Care of Patients with COVID-19, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
- Internal Medicine Department, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
| | - Felipe Martínez-Rivera
- Multidisciplinary Team for the Attention and Care of Patients with COVID-19, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
- Internal Medicine Department, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
| | - Victor Galindo-Hernández
- Multidisciplinary Team for the Attention and Care of Patients with COVID-19, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
- Internal Medicine Department, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
| | - Victor H. Rosales-Salyano
- Multidisciplinary Team for the Attention and Care of Patients with COVID-19, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
- Internal Medicine Department, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
| | - Catalina Casillas-Suárez
- Multidisciplinary Team for the Attention and Care of Patients with COVID-19, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
- Pneumology Department, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
| | - Oscar Chapa-Azuela
- Multidisciplinary Team for the Attention and Care of Patients with COVID-19, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
- General Surgery Department, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
| | - Alfonso Chávez-Morales
- Multidisciplinary Team for the Attention and Care of Patients with COVID-19, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
- Intensive Care Unit, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
| | - Billy Jiménez-Bobadilla
- Multidisciplinary Team for the Attention and Care of Patients with COVID-19, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
- Colorectal Surgery Department, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
| | - María L. Hernández-Medel
- Multidisciplinary Team for the Attention and Care of Patients with COVID-19, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
- Infectious Disease Department, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
| | - Benjamín Orozco-Zúñiga
- Multidisciplinary Team for the Attention and Care of Patients with COVID-19, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
- Ginecology Department, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
| | - Jed R. Zacarías-Ezzat
- Multidisciplinary Team for the Attention and Care of Patients with COVID-19, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
- General Surgery Department, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
| | - Santiago Camacho
- Multidisciplinary Team for the Attention and Care of Patients with COVID-19, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
- Gastroenterology and Hepatology Department, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
| | - José L. Pérez-Hernández
- Multidisciplinary Team for the Attention and Care of Patients with COVID-19, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
- Gastroenterology and Hepatology Department, Hospital General de México ¨Dr. Eduardo Liceaga¨, Mexico City, Mexico
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Abstract
We have reviewed the available literature on thyroid diseases and coronavirus disease 2019 (COVID-19), and data from the previous coronavirus pandemic, the severe acute respiratory syndrome (SARS) epidemic. We learned that both SARS and COVID-19 patients had thyroid abnormalities. In the limited number of SARS cases, where it was examined, decreased serum T3, T4 and TSH levels were detected. In a study of survivors of SARS approximately 7% of the patients had hypothyroidism. In the previous evaluation evidence was found that pituitary function was also affected in SARS. Others suggested a hypothalamic-pituitary-adrenal axis dysfunction. One result published recently indicates that a primary injury to the thyroid gland itself may play a key role in the pathogenesis of thyroid disorders in COVID-19 patients, too. Subacute thyroiditis, autoimmune thyroiditis and an atypical form of thyroiditis are complications of COVID-19. Thyroid hormone dysfunction affects the outcome by increasing mortality in critical illnesses like acute respiratory distress syndrome, which is a leading complication in COVID-19. Angiotensin-converting enzyme 2 is a membrane-bound enzyme, which is also expressed in the thyroid gland and the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) uses it for docking, entering as well as replication. Based on the available results obtained in the SARS-CoV-2 pandemic, beside others, we suggest that it is necessary to monitor thyroid hormones in COVID-19.
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Affiliation(s)
- Gábor Speer
- Department of Endocrinology, Municipal Clinic Biatorbágy, H-2051, Biatorbágy, Hungary
| | - Péter Somogyi
- Department of Orthopaedics, Municipal Clinic Biatorbágy, H-2051, Biatorbágy, Hungary
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42
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Khatri A, Charlap E, Kim A. Subacute Thyroiditis from COVID-19 Infection: A Case Report and Review of Literature. Eur Thyroid J 2021; 9:324-328. [PMID: 33708634 PMCID: PMC7705942 DOI: 10.1159/000511872] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 09/24/2020] [Indexed: 01/08/2023] Open
Abstract
INTRODUCTION The novel severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2) virus has led to the ongoing Coronavirus disease 2019 (COVID-19) disease pandemic. There are increasing reports of extrapulmonary clinical features of COVID-19, either as initial presentations or sequelae of disease. We report a patient diagnosed with subacute thyroiditis precipitated by COVID-19 infection, as well as review the literature of similar cases. CASE PRESENTATION A 41-year-old female with no significant personal or family history of endocrinologic disorders presented with clinical features of thyroiditis that began after COVID-19 infection. Clinical, laboratory, and radiologic findings were indicative of subacute thyroiditis. Workup for potential triggers other than SARS-CoV-2 was negative. DISCUSSION/CONCLUSION We compared the clinical and diagnostic findings of our patient with other well-documented cases of subacute thyroiditis presumed to be triggered by SARS-CoV-2 viral infection. We also reviewed the literature related to the potential mechanisms leading to thyroiditis. Clinicians must be aware of the possibility of thyroid dysfunction after COVID-19 infection. Early recognition and timely anti-inflammatory therapy help in successful management.
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Affiliation(s)
- Akshay Khatri
- Division of Infectious Diseases, Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, Manhasset, New York, USA
- *Akshay Khatri, Division of Infectious Diseases, Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, 400 Community Drive, ID Suite, Manhasset, NY 11030 (USA),
| | - Esti Charlap
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, Great Neck, New York, USA
| | - Angela Kim
- Division of Infectious Diseases, Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, Manhasset, New York, USA
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43
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Da BL, Kushner T, El Halabi M, Paka P, Khalid M, Uberoi A, Lee BT, Perumalswami PV, Rutledge SM, Schiano TD, Friedman SL, Saberi B. Liver Injury in Patients Hospitalized with Coronavirus Disease 2019 Correlates with Hyperinflammatory Response and Elevated Interleukin-6. Hepatol Commun 2021; 5:177-188. [PMID: 33230491 PMCID: PMC7675519 DOI: 10.1002/hep4.1631] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 09/22/2020] [Accepted: 10/11/2020] [Indexed: 02/06/2023] Open
Abstract
Liver injury is commonly seen in coronavirus disease 2019 (COVID-19); however, the mechanism behind liver injury, particularly in patients with severe and critical COVID-19, remains unclear, and the clinical course is poorly described. We conducted a single-center retrospective cohort study of consecutive patients hospitalized with severe and critical COVID-19 with or without liver injury and who underwent immunologic testing (interleukin [IL]-6, IL-8, tumor necrosis factor alpha [TNF-α], and IL-1β). Liver injury was defined as peak aminotransferases ≥3 times the upper limit of normal (40 U/L) or ≥120 U/L. Patients with liver injury were compared to those who had normal aminotransferases throughout the hospital course. We studied 176 patients: 109 with liver injury and 67 controls. Patients with liver injury were more likely to be men (71.6% vs. 37.3%, P < 0.001). Peak inflammatory markers and IL-6 were higher in the liver injury group: C-reactive protein (CRP), 247 vs. 168 mg/L, P < 0.001; lactate dehydrogenase (LDH), 706 vs. 421 U/L; ferritin, 2,973 vs. 751 ng/mL, P < 0.001; IL-6, 121.0 vs. 71.8 pg/mL, P < 0.001. There was no difference in the levels of IL-8, TNF-α, and IL-1β. The liver injury group had a longer length of stay in the hospital and more severe COVID-19 despite having less diabetes and chronic kidney disease. Conclusion: An exaggerated hyperinflammatory response (cytokine storm) characterized by significantly elevated CRP, LDH, ferritin, and IL-6 levels and increasing severity of COVID-19 appears to be associated with the occurrence of liver injury in patients with severe/critical COVID-19.
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Affiliation(s)
- Ben L Da
- Division of Liver DiseasesIcahn School of Medicine at Mount SinaiNew YorkNYUSA.,Sandra Atlas Bass Center for Liver Diseases & Transplantation, Division of Hepatology, Department of Internal MedicineDonald and Barabara Zucker School of Medicine for Hofstra/Northwell HealthManhasset, New YorkNYUSA
| | - Tatyana Kushner
- Division of Liver DiseasesIcahn School of Medicine at Mount SinaiNew YorkNYUSA
| | - Maan El Halabi
- Department of Internal MedicineMount Sinai Saint Luke's and Mount Sinai WestNew YorkNYUSA
| | - Pavan Paka
- Department of Internal MedicineMount Sinai Saint Luke's and Mount Sinai WestNew YorkNYUSA
| | - Mian Khalid
- Department of Internal MedicineIcahn School of Medicine at Mount SinaiNew YorkNYUSA
| | - Angad Uberoi
- Department of Internal MedicineMount Sinai Saint Luke's and Mount Sinai WestNew YorkNYUSA
| | - Brian T Lee
- Division of Liver DiseasesIcahn School of Medicine at Mount SinaiNew YorkNYUSA
| | | | - Stephanie M Rutledge
- Division of GastroenterologyIcahn School of Medicine at Mount SinaiNew YorkNYUSA
| | - Thomas D Schiano
- Division of Liver DiseasesIcahn School of Medicine at Mount SinaiNew YorkNYUSA
| | - Scott L Friedman
- Division of Liver DiseasesIcahn School of Medicine at Mount SinaiNew YorkNYUSA
| | - Behnam Saberi
- Division of Liver DiseasesIcahn School of Medicine at Mount SinaiNew YorkNYUSA.,Division of Gastroenterology and HepatologyBeth Israel Deaconess Medical Center, Harvard Medical SchoolBostonMAUSA
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44
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Nizamudeen ZA, Xu ER, Karthik V, Halawa M, Arkill KP, Jackson AM, Bates DO, Emsley J. Structural assessment of SARS-CoV2 accessory protein ORF7a predicts LFA-1 and Mac-1 binding potential. Biosci Rep 2021; 41:BSR20203837. [PMID: 33305306 PMCID: PMC7796194 DOI: 10.1042/bsr20203837] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 12/09/2020] [Accepted: 12/10/2020] [Indexed: 01/17/2023] Open
Abstract
ORF7a is an accessory protein common to SARS-CoV1 and the recently discovered SARS-CoV2, which is causing the COVID-19 pandemic. The ORF7a protein has a structural homology with ICAM-1 which binds to the T lymphocyte integrin receptor LFA-1. As COVID-19 has a strong immune component as part of the disease, we sought to determine whether SARS-CoV2 would have a similar structural interaction with LFA-1. Using molecular docking simulations, we found that SARS-CoV2 ORF7a has the key structural determinants required to bind LFA-1 but also the related leukocyte integrin Mac-1, which is also known to be expressed by macrophages. Our study shows that SARS-CoV2 ORF7a protein has a conserved Ig immunoglobulin-like fold containing an integrin binding site that provides a mechanistic hypothesis for SARS-CoV2's interaction with the human immune system. This suggests that experimental investigation of ORF7a-mediated effects on immune cells such as T lymphocytes and macrophages (leukocytes) could help understand the disease further and develop effective treatments.
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Affiliation(s)
- Zubair Ahmed Nizamudeen
- Division of Cancer and Stem Cells, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, U.K
| | - Emma-Ruoqi Xu
- School of Pharmacy, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, U.K
| | - Vivin Karthik
- Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME 04469, U.S.A
| | - Mohamed Halawa
- School of Pharmacy, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, U.K
| | - Kenton P. Arkill
- Division of Cancer and Stem Cells, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, U.K
| | - Andrew M. Jackson
- Division of Cancer and Stem Cells, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, U.K
| | - David O. Bates
- Division of Cancer and Stem Cells, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, U.K
| | - Jonas Emsley
- School of Pharmacy, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, U.K
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45
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Panzera Y, Ramos N, Frabasile S, Calleros L, Marandino A, Tomás G, Techera C, Grecco S, Fuques E, Goñi N, Ramas V, Coppola L, Chiparelli H, Sorhouet C, Mogdasy C, Arbiza J, Delfraro A, Pérez R. A deletion in SARS-CoV-2 ORF7 identified in COVID-19 outbreak in Uruguay. Transbound Emerg Dis 2021; 68:3075-3082. [PMID: 33501730 PMCID: PMC8014828 DOI: 10.1111/tbed.14002] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/15/2021] [Accepted: 01/21/2021] [Indexed: 01/20/2023]
Abstract
The analysis of genetic diversity in SARS‐CoV‐2 is the focus of several studies, providing insights into how the virus emerged and evolves. Most common changes in SARS‐CoV‐2 are single or point nucleotide substitutions; meanwhile, insertions and deletions (indels) have been identified as a less frequent source of viral genetic variability. Here, we report the emergence of a 12‐nucleotide deletion in ORF7a, resulting in a 4‐amino acid in‐frame deletion. The Δ12 variant was identified in viruses from patients of a single outbreak and represents the first report of this deletion in South American isolates. Phylogenetic analysis revealed that Δ12 strains belong to the lineage B.1.1 and clustered separated from the remaining Uruguayan strains. The ∆12 variant was detected in 14 patients of this outbreak by NGS sequencing and/or two rapid and economic methodologies: Sanger amplicon sequencing and capillary electrophoresis. The presence of strong molecular markers as the deletion described here are useful for tracking outbreaks and reveal a significant aspect of the SARS‐CoV‐2 evolution on the robustness of the virus to keep its functionality regardless loss of genetic material.
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Affiliation(s)
- Yanina Panzera
- Sección Genética Evolutiva, Departamento de Biología Animal, Instituto de Biología, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
| | - Natalia Ramos
- Sección Virología. Instituto de Biología e Instituto de Química Biológica. Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
| | - Sandra Frabasile
- Sección Virología. Instituto de Biología e Instituto de Química Biológica. Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
| | - Lucía Calleros
- Sección Genética Evolutiva, Departamento de Biología Animal, Instituto de Biología, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
| | - Ana Marandino
- Sección Genética Evolutiva, Departamento de Biología Animal, Instituto de Biología, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
| | - Gonzalo Tomás
- Sección Genética Evolutiva, Departamento de Biología Animal, Instituto de Biología, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
| | - Claudia Techera
- Sección Genética Evolutiva, Departamento de Biología Animal, Instituto de Biología, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
| | - Sofía Grecco
- Sección Genética Evolutiva, Departamento de Biología Animal, Instituto de Biología, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
| | - Eddie Fuques
- Sección Genética Evolutiva, Departamento de Biología Animal, Instituto de Biología, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
| | - Natalia Goñi
- Departamento de Laboratorios de Salud Pública. Ministerio de Salud Pública, Centro Nacional de Referencia de Influenza y otros Virus Respiratorios, Montevideo, Uruguay
| | - Viviana Ramas
- Departamento de Laboratorios de Salud Pública. Ministerio de Salud Pública, Centro Nacional de Referencia de Influenza y otros Virus Respiratorios, Montevideo, Uruguay
| | - Leticia Coppola
- Departamento de Laboratorios de Salud Pública. Ministerio de Salud Pública, Centro Nacional de Referencia de Influenza y otros Virus Respiratorios, Montevideo, Uruguay
| | - Héctor Chiparelli
- Departamento de Laboratorios de Salud Pública. Ministerio de Salud Pública, Centro Nacional de Referencia de Influenza y otros Virus Respiratorios, Montevideo, Uruguay
| | - Cecilia Sorhouet
- Laboratorio de Biología Molecular, Mutualista Médica Uruguaya, Montevideo, Uruguay
| | - Cristina Mogdasy
- Departamento de Laboratorios de Salud Pública. Ministerio de Salud Pública, Centro Nacional de Referencia de Influenza y otros Virus Respiratorios, Montevideo, Uruguay
| | - Juan Arbiza
- Sección Virología. Instituto de Biología e Instituto de Química Biológica. Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
| | - Adriana Delfraro
- Sección Virología. Instituto de Biología e Instituto de Química Biológica. Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
| | - Ruben Pérez
- Sección Genética Evolutiva, Departamento de Biología Animal, Instituto de Biología, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
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46
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Desai J, Patel U, Arjun S, Farraj K, Yeroushalmi K, Paz SG, Im J, Castillo A, Rammohan R, Mustacchia P. Impact of Liver Injury in COVID-19 Patients: Single-center Retrospective Cohort Analysis. J Clin Transl Hepatol 2020; 8:476-478. [PMID: 33447534 PMCID: PMC7782108 DOI: 10.14218/jcth.2020.00075] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 10/07/2020] [Accepted: 10/08/2020] [Indexed: 01/08/2023] Open
Affiliation(s)
- Jiten Desai
- Department of Internal Medicine, Nassau University Medical Center, East Meadow, NY, USA
- *Correspondence to: Jiten Desai, Department of Internal Medicine, Nassau University Medical Center, 2201 Hempstead Turnpike, East Meadow, NY 11554, USA. Tel: +1-516-296-2253, E-mail:
| | - Upenkumar Patel
- Department of Internal Medicine, Nassau University Medical Center, East Meadow, NY, USA
| | - Shiva Arjun
- Department of Internal Medicine, Nassau University Medical Center, East Meadow, NY, USA
| | - Kristen Farraj
- Department of Internal Medicine, Nassau University Medical Center, East Meadow, NY, USA
| | - Kevin Yeroushalmi
- Department of Internal Medicine, Nassau University Medical Center, East Meadow, NY, USA
| | - Sandra Gomez Paz
- Department of Internal Medicine, Nassau University Medical Center, East Meadow, NY, USA
| | - Jaehyuck Im
- Department of Internal Medicine, Nassau University Medical Center, East Meadow, NY, USA
| | - Andres Castillo
- Department of Internal Medicine, Nassau University Medical Center, East Meadow, NY, USA
| | - Rajmohan Rammohan
- Department of Internal Medicine, Nassau University Medical Center, East Meadow, NY, USA
| | - Paul Mustacchia
- Department of Internal Medicine, Nassau University Medical Center, East Meadow, NY, USA
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47
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Abstract
Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [COVID-19] quickly turned into a pandemic. Gastrointestinal involvement, especially liver diseases, is one of the main complications of COVID-19 patients. Objectives: The current study aimed to evaluate the high incidence of liver involvement in COVID-19 hospitalized patients and its association with mortality. Methods: A total of 560 hospitalized patients with a confirmed diagnosis of COVID-19 were included. Death was considered as the outcome. In addition to liver enzymes, demographic, clinical, and other laboratory data were also collected. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels ≥ 40 were considered as abnormal. To investigate the association between abnormal levels of liver enzymes and death, multiple regression logistic was used. Results: According to the findings, 29.1% (95% CI = 25.3% - 32.9%) of patients had high levels (≥ 40 IU) of ALT, and 45.1% (95% CI = 40.9% - 49.3%) had high levels of AST (≥ 40 IU). The frequency (based on %) of high levels of AST (≥ 40 U/liter) was significantly higher in patients who died [67.3% (95% CI = 54.5% - 80.1%] of COVID-19 than those who survived [44.9% (95% CI = 39.7% - 50.0%)] (P-value < 0.001). No significant difference was detected in ALT between expired [29.1% (95% CI = 16.7% - 41.5%)] and survived patients [30.7% (95% CI = 25.9% - 35.5%] (P-value = 0.791). AST was found to have an independent association with death in multiple logistic regression (Wald = 4.429, OR (95% CI) = 1.014 (1.008 - 1.020), P-value = 0.035). Conclusions: Liver involvement is a common finding in COVID-19 hospitalized patients. Higher levels of AST were significantly associated with an increased mortality rate in COVID-19 patients.
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48
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Krishnamoorthy S, Swain B, Verma RS, Gunthe SS. SARS-CoV, MERS-CoV, and 2019-nCoV viruses: an overview of origin, evolution, and genetic variations. Virusdisease 2020; 31:411-423. [PMID: 33102628 PMCID: PMC7567416 DOI: 10.1007/s13337-020-00632-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Accepted: 09/24/2020] [Indexed: 02/06/2023] Open
Abstract
Coronaviruses are single stranded RNA viruses usually present in bats (reservoir hosts), and are generally lethal, highly transmissible, and pathogenic viruses causing sever morbidity and mortality rates in human. Several animals including civets, camels, etc. have been identified as intermediate hosts enabling effective recombination of these viruses to emerge as new virulent and pathogenic strains. Among the seven known human coronaviruses SARS-CoV, MERS-CoV, and SARS-CoV-2 (2019-nCoV) have evolved as severe pathogenic forms infecting the human respiratory tract. About 8096 cases and 774 deaths were reported worldwide with the SARS-CoV infection during year 2002; 2229 cases and 791 deaths were reported for the MERS-CoV that emerged during 2012. Recently ~ 33,849,737 cases and 1,012,742 deaths (data as on 30 Sep 2020) were reported from the recent evolver SARS-CoV-2 infection. Studies on epidemiology and pathogenicity have shown that the viral spread was potentially caused by the contact route especially through the droplets, aerosols, and contaminated fomites. Genomic studies have confirmed the role of the viral spike protein in virulence and pathogenicity. They target the respiratory tract of the human causing severe progressive pneumonia affecting other organs like central nervous system in case of SARS-CoV, severe renal failure in MERS-CoV, and multi-organ failure in SARS-CoV-2. Herein, with respect to current awareness and role of coronaviruses in global public health, we review the various factors involving the origin, evolution, and transmission including the genetic variations observed, epidemiology, and pathogenicity of the three potential coronaviruses variants SARS-CoV, MERS-CoV, and 2019-nCoV.
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Affiliation(s)
- Sarayu Krishnamoorthy
- EWRE Division, Department of Civil Engineering, Indian Institute of Technology Madras, Chennai, 600 036 India
| | - Basudev Swain
- EWRE Division, Department of Civil Engineering, Indian Institute of Technology Madras, Chennai, 600 036 India
| | - R. S. Verma
- Bhupat and Jyoti Mehta School of Biosciences, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, 600 036 India
| | - Sachin S. Gunthe
- EWRE Division, Department of Civil Engineering, Indian Institute of Technology Madras, Chennai, 600 036 India
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49
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Ogando NS, Dalebout TJ, Zevenhoven-Dobbe JC, Limpens RWAL, van der Meer Y, Caly L, Druce J, de Vries JJC, Kikkert M, Bárcena M, Sidorov I, Snijder EJ. SARS-coronavirus-2 replication in Vero E6 cells: replication kinetics, rapid adaptation and cytopathology. J Gen Virol 2020; 101:925-940. [PMID: 32568027 PMCID: PMC7654748 DOI: 10.1099/jgv.0.001453] [Citation(s) in RCA: 393] [Impact Index Per Article: 78.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
The sudden emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the end of 2019 from the Chinese province of Hubei and its subsequent pandemic spread highlight the importance of understanding the full molecular details of coronavirus infection and pathogenesis. Here, we compared a variety of replication features of SARS-CoV-2 and SARS-CoV and analysed the cytopathology caused by the two closely related viruses in the commonly used Vero E6 cell line. Compared to SARS-CoV, SARS-CoV-2 generated higher levels of intracellular viral RNA, but strikingly about 50-fold less infectious viral progeny was recovered from the culture medium. Immunofluorescence microscopy of SARS-CoV-2-infected cells established extensive cross-reactivity of antisera previously raised against a variety of non-structural proteins, membrane and nucleocapsid protein of SARS-CoV. Electron microscopy revealed that the ultrastructural changes induced by the two SARS viruses are very similar and occur within comparable time frames after infection. Furthermore, we determined that the sensitivity of the two viruses to three established inhibitors of coronavirus replication (remdesivir, alisporivir and chloroquine) is very similar, but that SARS-CoV-2 infection was substantially more sensitive to pre-treatment of cells with pegylated interferon alpha. An important difference between the two viruses is the fact that – upon passaging in Vero E6 cells – SARS-CoV-2 apparently is under strong selection pressure to acquire adaptive mutations in its spike protein gene. These mutations change or delete a putative furin-like cleavage site in the region connecting the S1 and S2 domains and result in a very prominent phenotypic change in plaque assays.
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Affiliation(s)
- Natacha S Ogando
- Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Tim J Dalebout
- Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Jessika C Zevenhoven-Dobbe
- Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Ronald W A L Limpens
- Section Electron Microscopy, Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands
| | - Yvonne van der Meer
- Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Leon Caly
- Virus Identification Laboratory, Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Victoria, 3000, Australia
| | - Julian Druce
- Virus Identification Laboratory, Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Victoria, 3000, Australia
| | - Jutte J C de Vries
- Clinical Microbiology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Marjolein Kikkert
- Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Montserrat Bárcena
- Section Electron Microscopy, Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands
| | - Igor Sidorov
- Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Eric J Snijder
- Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
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Wang Y, Lu F, Zhao J. Reply to: Correspondence relating to "SARS-CoV-2 infection of the liver directly contributes to hepatic impairment in patients with COVID-19". J Hepatol 2020; 73:996-998. [PMID: 32589896 PMCID: PMC7309894 DOI: 10.1016/j.jhep.2020.06.028] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 06/15/2020] [Accepted: 06/16/2020] [Indexed: 12/22/2022]
Affiliation(s)
- Yijin Wang
- Department of Pathology and Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Fengmin Lu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Jingmin Zhao
- Department of Pathology and Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China.
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