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      Coronavirus Infection and Cholesterol Metabolism

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          Abstract

          Host cholesterol metabolism remodeling is significantly associated with the spread of human pathogenic coronaviruses, suggesting virus-host relationships could be affected by cholesterol-modifying drugs. Cholesterol has an important role in coronavirus entry, membrane fusion, and pathological syncytia formation, therefore cholesterol metabolic mechanisms may be promising drug targets for coronavirus infections. Moreover, cholesterol and its metabolizing enzymes or corresponding natural products exert antiviral effects which are closely associated with individual viral steps during coronavirus replication. Furthermore, the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 infections are associated with clinically significant low cholesterol levels, suggesting cholesterol could function as a potential marker for monitoring viral infection status. Therefore, weaponizing cholesterol dysregulation against viral infection could be an effective antiviral strategy. In this review, we comprehensively review the literature to clarify how coronaviruses exploit host cholesterol metabolism to accommodate viral replication requirements and interfere with host immune responses. We also focus on targeting cholesterol homeostasis to interfere with critical steps during coronavirus infection.

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          Most cited references253

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          A Novel Coronavirus from Patients with Pneumonia in China, 2019

          Summary In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.)
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            SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

            Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.
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              An interactive web-based dashboard to track COVID-19 in real time

              In December, 2019, a local outbreak of pneumonia of initially unknown cause was detected in Wuhan (Hubei, China), and was quickly determined to be caused by a novel coronavirus, 1 namely severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The outbreak has since spread to every province of mainland China as well as 27 other countries and regions, with more than 70 000 confirmed cases as of Feb 17, 2020. 2 In response to this ongoing public health emergency, we developed an online interactive dashboard, hosted by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University, Baltimore, MD, USA, to visualise and track reported cases of coronavirus disease 2019 (COVID-19) in real time. The dashboard, first shared publicly on Jan 22, illustrates the location and number of confirmed COVID-19 cases, deaths, and recoveries for all affected countries. It was developed to provide researchers, public health authorities, and the general public with a user-friendly tool to track the outbreak as it unfolds. All data collected and displayed are made freely available, initially through Google Sheets and now through a GitHub repository, along with the feature layers of the dashboard, which are now included in the Esri Living Atlas. The dashboard reports cases at the province level in China; at the city level in the USA, Australia, and Canada; and at the country level otherwise. During Jan 22–31, all data collection and processing were done manually, and updates were typically done twice a day, morning and night (US Eastern Time). As the outbreak evolved, the manual reporting process became unsustainable; therefore, on Feb 1, we adopted a semi-automated living data stream strategy. Our primary data source is DXY, an online platform run by members of the Chinese medical community, which aggregates local media and government reports to provide cumulative totals of COVID-19 cases in near real time at the province level in China and at the country level otherwise. Every 15 min, the cumulative case counts are updated from DXY for all provinces in China and for other affected countries and regions. For countries and regions outside mainland China (including Hong Kong, Macau, and Taiwan), we found DXY cumulative case counts to frequently lag behind other sources; we therefore manually update these case numbers throughout the day when new cases are identified. To identify new cases, we monitor various Twitter feeds, online news services, and direct communication sent through the dashboard. Before manually updating the dashboard, we confirm the case numbers with regional and local health departments, including the respective centres for disease control and prevention (CDC) of China, Taiwan, and Europe, the Hong Kong Department of Health, the Macau Government, and WHO, as well as city-level and state-level health authorities. For city-level case reports in the USA, Australia, and Canada, which we began reporting on Feb 1, we rely on the US CDC, the government of Canada, the Australian Government Department of Health, and various state or territory health authorities. All manual updates (for countries and regions outside mainland China) are coordinated by a team at Johns Hopkins University. The case data reported on the dashboard aligns with the daily Chinese CDC 3 and WHO situation reports 2 for within and outside of mainland China, respectively (figure ). Furthermore, the dashboard is particularly effective at capturing the timing of the first reported case of COVID-19 in new countries or regions (appendix). With the exception of Australia, Hong Kong, and Italy, the CSSE at Johns Hopkins University has reported newly infected countries ahead of WHO, with Hong Kong and Italy reported within hours of the corresponding WHO situation report. Figure Comparison of COVID-19 case reporting from different sources Daily cumulative case numbers (starting Jan 22, 2020) reported by the Johns Hopkins University Center for Systems Science and Engineering (CSSE), WHO situation reports, and the Chinese Center for Disease Control and Prevention (Chinese CDC) for within (A) and outside (B) mainland China. Given the popularity and impact of the dashboard to date, we plan to continue hosting and managing the tool throughout the entirety of the COVID-19 outbreak and to build out its capabilities to establish a standing tool to monitor and report on future outbreaks. We believe our efforts are crucial to help inform modelling efforts and control measures during the earliest stages of the outbreak.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                21 April 2022
                2022
                21 April 2022
                : 13
                : 791267
                Affiliations
                [1] 1 College of Animal Science and Technology, Guangxi University , Nanning, China
                [2] 2 Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences , Shanghai, China
                [3] 3 Experimental Animal Center, Zunyi Medical University , Zunyi City, China
                [4] 4 Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University , Yangzhou, China
                Author notes

                Edited by: Vishwanath Venketaraman, Western University of Health Sciences, United States

                Reviewed by: Jiansheng Huang, Vanderbilt University Medical Center, United States; Peter Van Der Voort, University Medical Center Groningen, Netherlands; Damjana Rozman, University of Ljubljana, Slovenia

                *Correspondence: Xusheng Qiu, xsqiu1981@ 123456shvri.ac.cn ; Chan Ding, shoveldeen@ 123456shvri.ac.cn

                †These authors share first authorship

                This article was submitted to Viral Immunology, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2022.791267
                9069556
                35529872
                c80e9dde-2a72-4852-afa9-c6dbebd2b649
                Copyright © 2022 Dai, Wang, Liao, Tan, Sun, Song, Liu, Qiu and Ding

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 08 October 2021
                : 21 March 2022
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 253, Pages: 16, Words: 6657
                Funding
                Funded by: National Natural Science Foundation of China , doi 10.13039/501100001809;
                Funded by: Natural Science Foundation of Shanghai , doi 10.13039/100007219;
                Funded by: Natural Science Foundation of Shanghai , doi 10.13039/100007219;
                Categories
                Immunology
                Review

                Immunology
                coronavirus,cholesterol,metabolism dysregulation,immune response,therapy
                Immunology
                coronavirus, cholesterol, metabolism dysregulation, immune response, therapy

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