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COVID-19 Curbside Consults

COVID-19: Coronavirus replication, pathogenesis, and therapeutic strategies

Cornelia C. Bergmann, PhD and Robert H. Silverman, PhD
Cleveland Clinic Journal of Medicine June 2020, 87 (6) 321-327; DOI: https://doi.org/10.3949/ccjm.87a.20047
Cornelia C. Bergmann
Department of Neuroscience, Cleveland Clinic Lerner Research Institute; Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH
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  • For correspondence: [email protected] [email protected]
Robert H. Silverman
Department of Cancer Biology, Cleveland Clinic Lerner Research Institute; Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH
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    Figure 1

    Structure of coronaviruses.

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    Figure 2

    Overview of COVID-19, SARS-CoV-2 replication, and therapeutic targets.

    Upper left. Virus entry entails binding the angiotensin-converting enzyme 2 (ACE2) receptor and cleavage by the serine protease TMPRSS2 (in green) to allow fusion with the host membrane. Other cellular proteases, eg, furin (in orange), facilitate pH-dependent entry through the endocytic pathway. The predominant entry routes are cell type-specific and dependent on availability of select proteases.

    Middle. Following uncoating and release of viral RNA into the cytoplasm, translation of open reading frame 1a (ORF1a) and ORF1ab produces the polyproteins pp1a and pp1ab. These in turn are processed by viral proteases (encoded by ORF1a) to yield 16 nonstructural proteins. Formation of the RNA replicase–transcriptase complex (RTC) uses rough endoplasmic reticulum (ER)-derived membranes. The RTC drives synthesis of (−)RNAs. Full-length (−)RNA copies of the genome provide templates for full-length (+)RNA genomes. Transcription further produces a subset of subgenomic RNAs, including those encoding all structural and accessory proteins.

    Right. The translated structural proteins and genomic RNA are assembled into the viral nucleocapsid and envelope in the ER–Golgi intermediate compartment, and are subsequently released by exocytosis.

    Bottom. Potential strategies for treatment. Anti-TMPRSS2 or chloroquine treatment in experimental animals will reveal efficacy of targeting select proteases or entry pathways in limiting infection, while simultaneously monitoring effects on innate and adaptive immunity. The replication cycle can be blocked at several stages using single or combined treatment paradigms: virus entry can be inhibited by antispike antibodies elicited by vaccines to block attachment or by preventing fusion using relevant protease inhibitors.11 RTC formation and transcription-replication events can be targeted using viral protease inhibitors or nucleoside analogues (GS-5734 or EIDD-1931).15 Interferon (IFN) responsiveness can be increased by early exogenous IFN treatment,13 IFN inducer treatment, repression of viral IFN antagonists, and enhancement of host antiviral IFN pathways. The “cytokine storm” induced as a host response to rampant virus replication may be targeted by administration of select anti-inflammatory immune modulators, which are already given to patients with inflammatory disorders. Drugs targeting viral replication may also be combined with treatments that control detrimental immune responses. The ferret model will provide a useful tool to test multiple therapeutic and preventive treatments.8

    Based on information in references 1, 10, 12, and 14

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Cleveland Clinic Journal of Medicine: 87 (6)
Cleveland Clinic Journal of Medicine
Vol. 87, Issue 6
1 Jun 2020
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COVID-19: Coronavirus replication, pathogenesis, and therapeutic strategies
Cornelia C. Bergmann, Robert H. Silverman
Cleveland Clinic Journal of Medicine Jun 2020, 87 (6) 321-327; DOI: 10.3949/ccjm.87a.20047

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COVID-19: Coronavirus replication, pathogenesis, and therapeutic strategies
Cornelia C. Bergmann, Robert H. Silverman
Cleveland Clinic Journal of Medicine Jun 2020, 87 (6) 321-327; DOI: 10.3949/ccjm.87a.20047
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  • Article
    • A ZOONOTIC INFECTION
    • STRUCTURE AND GENOME OF CORONAVIRUSES
    • HOW THE VIRUS GETS IN
    • THE BODY MOUNTS AN INNATE IMMUNE RESPONSE
    • HOW THE VIRUS EVADES THE HOST RESPONSE
    • WHY DO SOME PEOPLE GET SO SICK, BUT OTHERS ARE FINE?
    • ONCE YOU GET IT, ARE YOU IMMUNE FOR LIFE?
    • VIRAL AND HOST TARGETS FOR THERAPIES AND VACCINES
    • Acknowledgments
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  • Update to COVID-19 serologic testing : FAQs and caveats
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  • COVID-19 in older adults
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