A comprehensive SARS-CoV-2 and COVID-19 review, Part 2: host extracellular to systemic effects of SARS-CoV-2 infection

doi:10.1038/s41431-023-01462-1

Review

. 2024 Jan;32(1):10-20.

doi: 10.1038/s41431-023-01462-1. Epub 2023 Nov 8.

A comprehensive SARS-CoV-2 and COVID-19 review, Part 2: host extracellular to systemic effects of SARS-CoV-2 infection

S Anand Narayanan^#^{1

2}, David A Jamison Jr^#³, Joseph W Guarnieri^{3

4}, Victoria Zaksas^{3

5

6}, Michael Topper^{3

7}, Andrew P Koutnik^{8

9}, Jiwoon Park^{10

11}, Kevin B Clark^{3

12

13

14

15

16}, Francisco J Enguita^{3

17}, Ana Lúcia Leitão¹⁸, Saswati Das^{3

19}, Pedro M Moraes-Vieira^{3

20

21}, Diego Galeano^{3

22}, Christopher E Mason^{3

10

23

24}, Nídia S Trovão^{3

25}, Robert E Schwartz^{3

26

27}, Jonathan C Schisler^{3

28}, Jordana G A Coelho-Dos-Reis^{3

29}, Eve Syrkin Wurtele^{3

30

31}, Afshin Beheshti^{32

33

34}

Affiliations

¹ COVID-19 International Research Team, Medford, MA, 02155, USA. anarayan09@gmail.com.
² Department of Health, Nutrition and Food Sciences, Florida State University, Tallahassee, FL, 32301, USA. anarayan09@gmail.com.
³ COVID-19 International Research Team, Medford, MA, 02155, USA.
⁴ Center for Mitochondrial and Epigenomic Medicine, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
⁵ Center for Translational Data Science, University of Chicago, Chicago, IL, 60637, USA.
⁶ Clever Research Lab, Springfield, IL, 62704, USA.
⁷ Departments of Oncology and Medicine and the Sidney Comprehensive Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
⁸ Human Healthspan, Resilience, and Performance, Florida Institute for Human and Machine Cognition, Pensacola, FL, 32502, USA.
⁹ Sansum Diabetes Research Institute, Santa Barbara, CA, 93015, USA.
¹⁰ Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, New York, NY, USA.
¹¹ Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, 10065, USA.
¹² Cures Within Reach, Chicago, IL, 60602, USA.
¹³ Campus and Domain Champions Program, Multi-Tier Assistance, Training, and Computational Help (MATCH) Track, National Science Foundation's Advanced Cyberinfrastructure Coordination Ecosystem: Services and Support (ACCESS), Philadelphia, PA, USA.
¹⁴ Expert Network, Penn Center for Innovation, University of Pennsylvania, Philadelphia, PA, 19104, USA.
¹⁵ Biometrics and Nanotechnology Councils, Institute for Electrical and Electronics Engineers, New York, NY, 10016, USA.
¹⁶ Peace Innovation Institute, The Hague 2511, Netherlands and Stanford University, Palo Alto, 94305, CA, USA.
¹⁷ Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028, Lisboa, Portugal.
¹⁸ MEtRICs, Department of Chemistry, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2829-516, Caparica, Portugal.
¹⁹ Atal Bihari Vajpayee Institute of Medical Sciences and Dr Ram Mannohar Lohia Hospital, New Delhi, 110001, India.
²⁰ Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil.
²¹ Experimental Medicine Research Cluster (EMRC) and Obesity and Comorbidities Research Center (OCRC), University of Campinas, Campinas, Brazil.
²² Facultad de Ingeniería, Universidad Nacional de Asunción, San Lorenzo, Paraguay.
²³ New York Genome Center, New York, NY, USA.
²⁴ The Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
²⁵ Fogarty International Center, National Institutes of Health, Bethesda, MD, 20892, USA.
²⁶ Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
²⁷ Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA.
²⁸ McAllister Heart Institute and Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
²⁹ Basic and Applied Virology Lab, Department of Microbiology, Institute for Biological Sciences (ICB), Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
³⁰ Genetics Program, Department of Genetics, Development and Cell Biology, Iowa State University, Ames, IA, 90011, USA.
³¹ Bioinformatics and Computational Biology Program, Center for Metabolomics, Department of Genetics, Development and Cell Biology, Iowa State University, Ames, IA, 90011, USA.
³² COVID-19 International Research Team, Medford, MA, 02155, USA. afshin.beheshti@nasa.gov.
³³ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. afshin.beheshti@nasa.gov.
³⁴ Blue Marble Space Institute of Science, Space Biosciences Division, NASA Ames Research Center, Moffett Field, Santa Clara, CA, 94035, USA. afshin.beheshti@nasa.gov.

^# Contributed equally.

PMID: 37938797
PMCID: PMC10772081
DOI: 10.1038/s41431-023-01462-1

Review

A comprehensive SARS-CoV-2 and COVID-19 review, Part 2: host extracellular to systemic effects of SARS-CoV-2 infection

S Anand Narayanan et al. Eur J Hum Genet. 2024 Jan.

. 2024 Jan;32(1):10-20.

doi: 10.1038/s41431-023-01462-1. Epub 2023 Nov 8.

Authors

Affiliations

¹ COVID-19 International Research Team, Medford, MA, 02155, USA. anarayan09@gmail.com.
² Department of Health, Nutrition and Food Sciences, Florida State University, Tallahassee, FL, 32301, USA. anarayan09@gmail.com.
³ COVID-19 International Research Team, Medford, MA, 02155, USA.
⁴ Center for Mitochondrial and Epigenomic Medicine, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
⁵ Center for Translational Data Science, University of Chicago, Chicago, IL, 60637, USA.
⁶ Clever Research Lab, Springfield, IL, 62704, USA.
⁷ Departments of Oncology and Medicine and the Sidney Comprehensive Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
⁸ Human Healthspan, Resilience, and Performance, Florida Institute for Human and Machine Cognition, Pensacola, FL, 32502, USA.
⁹ Sansum Diabetes Research Institute, Santa Barbara, CA, 93015, USA.
¹⁰ Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, New York, NY, USA.
¹¹ Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, 10065, USA.
¹² Cures Within Reach, Chicago, IL, 60602, USA.
¹³ Campus and Domain Champions Program, Multi-Tier Assistance, Training, and Computational Help (MATCH) Track, National Science Foundation's Advanced Cyberinfrastructure Coordination Ecosystem: Services and Support (ACCESS), Philadelphia, PA, USA.
¹⁴ Expert Network, Penn Center for Innovation, University of Pennsylvania, Philadelphia, PA, 19104, USA.
¹⁵ Biometrics and Nanotechnology Councils, Institute for Electrical and Electronics Engineers, New York, NY, 10016, USA.
¹⁶ Peace Innovation Institute, The Hague 2511, Netherlands and Stanford University, Palo Alto, 94305, CA, USA.
¹⁷ Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028, Lisboa, Portugal.
¹⁸ MEtRICs, Department of Chemistry, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2829-516, Caparica, Portugal.
¹⁹ Atal Bihari Vajpayee Institute of Medical Sciences and Dr Ram Mannohar Lohia Hospital, New Delhi, 110001, India.
²⁰ Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil.
²¹ Experimental Medicine Research Cluster (EMRC) and Obesity and Comorbidities Research Center (OCRC), University of Campinas, Campinas, Brazil.
²² Facultad de Ingeniería, Universidad Nacional de Asunción, San Lorenzo, Paraguay.
²³ New York Genome Center, New York, NY, USA.
²⁴ The Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
²⁵ Fogarty International Center, National Institutes of Health, Bethesda, MD, 20892, USA.
²⁶ Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
²⁷ Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA.
²⁸ McAllister Heart Institute and Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
²⁹ Basic and Applied Virology Lab, Department of Microbiology, Institute for Biological Sciences (ICB), Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
³⁰ Genetics Program, Department of Genetics, Development and Cell Biology, Iowa State University, Ames, IA, 90011, USA.
³¹ Bioinformatics and Computational Biology Program, Center for Metabolomics, Department of Genetics, Development and Cell Biology, Iowa State University, Ames, IA, 90011, USA.
³² COVID-19 International Research Team, Medford, MA, 02155, USA. afshin.beheshti@nasa.gov.
³³ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. afshin.beheshti@nasa.gov.
³⁴ Blue Marble Space Institute of Science, Space Biosciences Division, NASA Ames Research Center, Moffett Field, Santa Clara, CA, 94035, USA. afshin.beheshti@nasa.gov.

^# Contributed equally.

PMID: 37938797
PMCID: PMC10772081
DOI: 10.1038/s41431-023-01462-1

Abstract

COVID-19, the disease caused by SARS-CoV-2, has caused significant morbidity and mortality worldwide. The betacoronavirus continues to evolve with global health implications as we race to learn more to curb its transmission, evolution, and sequelae. The focus of this review, the second of a three-part series, is on the biological effects of the SARS-CoV-2 virus on post-acute disease in the context of tissue and organ adaptations and damage. We highlight the current knowledge and describe how virological, animal, and clinical studies have shed light on the mechanisms driving the varied clinical diagnoses and observations of COVID-19 patients. Moreover, we describe how investigations into SARS-CoV-2 effects have informed the understanding of viral pathogenesis and provide innovative pathways for future research on the mechanisms of viral diseases.

PubMed Disclaimer

Conflict of interest statement

RES is on the scientific advisory board of Miromatrix Inc and Lime Therapeutics and is a consultant and speaker for Alnylam Inc. The remaining authors declare no competing financial interests.

Figures

**Fig. 1. Different RNA and their role in COVID-19.**
Structure and description of different categories of RNA involved in COVID-19.

**Fig. 2. SARS-CoV-2 Intracellular Replication and Extracellular Release of Circulating Factors.**
An overview of the processes involved with SARS-CoV-2 infection and replication that lead to cellular adaptations (see ref. [3] for more details) and extracellular release of various biological factors into the circulation causing systemic physiological effects.

**Fig. 3. COVID-19 organ adaptations and symptoms.**
An overview of the systemic organ adaptations resulting from SARS-CoV-2 infection as well as symptoms that develop.

**Fig. 4. COVID-19 biological adaptations and effects.**
The multi-faceted and multiplex physiological adaptations resulting from SARS-CoV-2 infection, including the different cells, tissues, and organs that respond to viral infection. The airway milieu refers to the viral factors contained from inhalation and response to these factors in the lungs, while the systemic milieu refers to the viral factors transported through the circulation system and across body, and in turn, the physiological responses to these factors.

See this image and copyright information in PMC

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References

1. Rydland HT, Friedman J, Stringhini S, Link BG, Eikemo TA. The radically unequal distribution of Covid-19 vaccinations: a predictable yet avoidable symptom of the fundamental causes of inequality. Humanit Soc Sci Commun. 2022;9:1–16.
1. Jalali N, Brustad HK, Frigessi A, MacDonald EA, Meijerink H, Feruglio SL, et al. Increased household transmission and immune escape of the SARS-CoV-2 Omicron compared to Delta variants. Nat Commun. 2022;13:5706. doi: 10.1038/s41467-022-33233-9. - DOI - PMC - PubMed
1. Jamison DA, Jr, Anand Narayanan S, Trovão NS, Guarnieri JW, Topper MJ, Moraes-Vieira PM, et al. A comprehensive SARS-CoV-2 and COVID-19 review, Part 1: Intracellular overdrive for SARS-CoV-2 infection. Eur J Hum Genet. 2022;30:889–98. doi: 10.1038/s41431-022-01108-8. - DOI - PMC - PubMed
1. Prasad K, Khatoon F, Rashid S, Ali N, AlAsmari AF, Ahmed MZ, et al. Targeting hub genes and pathways of innate immune response in COVID-19: a network biology perspective. Int J Biol Macromol. 2020;163:1–8. doi: 10.1016/j.ijbiomac.2020.06.228. - DOI - PMC - PubMed
1. Minakshi R, Padhan K, Rani M, Khan N, Ahmad F, Jameel S. The SARS Coronavirus 3a protein causes endoplasmic reticulum stress and induces ligand-independent downregulation of the type 1 interferon receptor. PLoS ONE. 2009;4:e8342. doi: 10.1371/journal.pone.0008342. - DOI - PMC - PubMed

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[1] Rydland HT, Friedman J, Stringhini S, Link BG, Eikemo TA. The radically unequal distribution of Covid-19 vaccinations: a predictable yet avoidable symptom of the fundamental causes of inequality. Humanit Soc Sci Commun. 2022;9:1–16.

[2] Rydland HT, Friedman J, Stringhini S, Link BG, Eikemo TA. The radically unequal distribution of Covid-19 vaccinations: a predictable yet avoidable symptom of the fundamental causes of inequality. Humanit Soc Sci Commun. 2022;9:1–16.

[3] Jalali N, Brustad HK, Frigessi A, MacDonald EA, Meijerink H, Feruglio SL, et al. Increased household transmission and immune escape of the SARS-CoV-2 Omicron compared to Delta variants. Nat Commun. 2022;13:5706. doi: 10.1038/s41467-022-33233-9. - DOI - PMC - PubMed

[4] Jalali N, Brustad HK, Frigessi A, MacDonald EA, Meijerink H, Feruglio SL, et al. Increased household transmission and immune escape of the SARS-CoV-2 Omicron compared to Delta variants. Nat Commun. 2022;13:5706. doi: 10.1038/s41467-022-33233-9. - DOI - PMC - PubMed

[5] Jamison DA, Jr, Anand Narayanan S, Trovão NS, Guarnieri JW, Topper MJ, Moraes-Vieira PM, et al. A comprehensive SARS-CoV-2 and COVID-19 review, Part 1: Intracellular overdrive for SARS-CoV-2 infection. Eur J Hum Genet. 2022;30:889–98. doi: 10.1038/s41431-022-01108-8. - DOI - PMC - PubMed

[6] Jamison DA, Jr, Anand Narayanan S, Trovão NS, Guarnieri JW, Topper MJ, Moraes-Vieira PM, et al. A comprehensive SARS-CoV-2 and COVID-19 review, Part 1: Intracellular overdrive for SARS-CoV-2 infection. Eur J Hum Genet. 2022;30:889–98. doi: 10.1038/s41431-022-01108-8. - DOI - PMC - PubMed

[7] Prasad K, Khatoon F, Rashid S, Ali N, AlAsmari AF, Ahmed MZ, et al. Targeting hub genes and pathways of innate immune response in COVID-19: a network biology perspective. Int J Biol Macromol. 2020;163:1–8. doi: 10.1016/j.ijbiomac.2020.06.228. - DOI - PMC - PubMed

[8] Prasad K, Khatoon F, Rashid S, Ali N, AlAsmari AF, Ahmed MZ, et al. Targeting hub genes and pathways of innate immune response in COVID-19: a network biology perspective. Int J Biol Macromol. 2020;163:1–8. doi: 10.1016/j.ijbiomac.2020.06.228. - DOI - PMC - PubMed

[9] Minakshi R, Padhan K, Rani M, Khan N, Ahmad F, Jameel S. The SARS Coronavirus 3a protein causes endoplasmic reticulum stress and induces ligand-independent downregulation of the type 1 interferon receptor. PLoS ONE. 2009;4:e8342. doi: 10.1371/journal.pone.0008342. - DOI - PMC - PubMed

[10] Minakshi R, Padhan K, Rani M, Khan N, Ahmad F, Jameel S. The SARS Coronavirus 3a protein causes endoplasmic reticulum stress and induces ligand-independent downregulation of the type 1 interferon receptor. PLoS ONE. 2009;4:e8342. doi: 10.1371/journal.pone.0008342. - DOI - PMC - PubMed

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A comprehensive SARS-CoV-2 and COVID-19 review, Part 2: host extracellular to systemic effects of SARS-CoV-2 infection

Affiliations

A comprehensive SARS-CoV-2 and COVID-19 review, Part 2: host extracellular to systemic effects of SARS-CoV-2 infection

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Abstract

Conflict of interest statement

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