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Tropism, replication competence, and innate immune responses of the coronavirus SARS-CoV-2 in human respiratory tract and conjunctiva: an analysis in ex-vivo and in-vitro cultures.
Lancet Respir Med. 2020 07; 8(7):687-695.LR

Abstract

BACKGROUND

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019, causing a respiratory disease (coronavirus disease 2019, COVID-19) of varying severity in Wuhan, China, and subsequently leading to a pandemic. The transmissibility and pathogenesis of SARS-CoV-2 remain poorly understood. We evaluate its tissue and cellular tropism in human respiratory tract, conjunctiva, and innate immune responses in comparison with other coronavirus and influenza virus to provide insights into COVID-19 pathogenesis.

METHODS

We isolated SARS-CoV-2 from a patient with confirmed COVID-19, and compared virus tropism and replication competence with SARS-CoV, Middle East respiratory syndrome-associated coronavirus (MERS-CoV), and 2009 pandemic influenza H1N1 (H1N1pdm) in ex-vivo cultures of human bronchus (n=5) and lung (n=4). We assessed extrapulmonary infection using ex-vivo cultures of human conjunctiva (n=3) and in-vitro cultures of human colorectal adenocarcinoma cell lines. Innate immune responses and angiotensin-converting enzyme 2 expression were investigated in human alveolar epithelial cells and macrophages. In-vitro studies included the highly pathogenic avian influenza H5N1 virus (H5N1) and mock-infected cells as controls.

FINDINGS

SARS-CoV-2 infected ciliated, mucus-secreting, and club cells of bronchial epithelium, type 1 pneumocytes in the lung, and the conjunctival mucosa. In the bronchus, SARS-CoV-2 replication competence was similar to MERS-CoV, and higher than SARS-CoV, but lower than H1N1pdm. In the lung, SARS-CoV-2 replication was similar to SARS-CoV and H1N1pdm, but was lower than MERS-CoV. In conjunctiva, SARS-CoV-2 replication was greater than SARS-CoV. SARS-CoV-2 was a less potent inducer of proinflammatory cytokines than H5N1, H1N1pdm, or MERS-CoV.

INTERPRETATION

The conjunctival epithelium and conducting airways appear to be potential portals of infection for SARS-CoV-2. Both SARS-CoV and SARS-CoV-2 replicated similarly in the alveolar epithelium; SARS-CoV-2 replicated more extensively in the bronchus than SARS-CoV. These findings provide important insights into the transmissibility and pathogenesis of SARS-CoV-2 infection and differences with other respiratory pathogens.

FUNDING

US National Institute of Allergy and Infectious Diseases, University Grants Committee of Hong Kong Special Administrative Region, China; Health and Medical Research Fund, Food and Health Bureau, Government of Hong Kong Special Administrative Region, China.

Authors+Show Affiliations

School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Special Administrative Region of Hong Kong, China.School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Special Administrative Region of Hong Kong, China.School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Special Administrative Region of Hong Kong, China.School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Special Administrative Region of Hong Kong, China.School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Special Administrative Region of Hong Kong, China.School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Special Administrative Region of Hong Kong, China.School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Special Administrative Region of Hong Kong, China.School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Special Administrative Region of Hong Kong, China.Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Special Administrative Region of Hong Kong, China.School of Biomedical Science, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Special Administrative Region of Hong Kong, China.School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Special Administrative Region of Hong Kong, China.School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Special Administrative Region of Hong Kong, China.School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Special Administrative Region of Hong Kong, China; Department of Pathology, Queen Mary Hospital, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Special Administrative Region of Hong Kong, China.School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Special Administrative Region of Hong Kong, China. Electronic address: mchan@hku.hk.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32386571

Citation

Hui, Kenrie P Y., et al. "Tropism, Replication Competence, and Innate Immune Responses of the Coronavirus SARS-CoV-2 in Human Respiratory Tract and Conjunctiva: an Analysis in Ex-vivo and In-vitro Cultures." The Lancet. Respiratory Medicine, vol. 8, no. 7, 2020, pp. 687-695.
Hui KPY, Cheung MC, Perera RAPM, et al. Tropism, replication competence, and innate immune responses of the coronavirus SARS-CoV-2 in human respiratory tract and conjunctiva: an analysis in ex-vivo and in-vitro cultures. Lancet Respir Med. 2020;8(7):687-695.
Hui, K. P. Y., Cheung, M. C., Perera, R. A. P. M., Ng, K. C., Bui, C. H. T., Ho, J. C. W., Ng, M. M. T., Kuok, D. I. T., Shih, K. C., Tsao, S. W., Poon, L. L. M., Peiris, M., Nicholls, J. M., & Chan, M. C. W. (2020). Tropism, replication competence, and innate immune responses of the coronavirus SARS-CoV-2 in human respiratory tract and conjunctiva: an analysis in ex-vivo and in-vitro cultures. The Lancet. Respiratory Medicine, 8(7), 687-695. https://doi.org/10.1016/S2213-2600(20)30193-4
Hui KPY, et al. Tropism, Replication Competence, and Innate Immune Responses of the Coronavirus SARS-CoV-2 in Human Respiratory Tract and Conjunctiva: an Analysis in Ex-vivo and In-vitro Cultures. Lancet Respir Med. 2020;8(7):687-695. PubMed PMID: 32386571.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tropism, replication competence, and innate immune responses of the coronavirus SARS-CoV-2 in human respiratory tract and conjunctiva: an analysis in ex-vivo and in-vitro cultures. AU - Hui,Kenrie P Y, AU - Cheung,Man-Chun, AU - Perera,Ranawaka A P M, AU - Ng,Ka-Chun, AU - Bui,Christine H T, AU - Ho,John C W, AU - Ng,Mandy M T, AU - Kuok,Denise I T, AU - Shih,Kendrick C, AU - Tsao,Sai-Wah, AU - Poon,Leo L M, AU - Peiris,Malik, AU - Nicholls,John M, AU - Chan,Michael C W, Y1 - 2020/05/07/ PY - 2020/03/10/received PY - 2020/04/20/revised PY - 2020/04/21/accepted PY - 2020/5/11/pubmed PY - 2020/5/11/medline PY - 2020/5/11/entrez SP - 687 EP - 695 JF - The Lancet. Respiratory medicine JO - Lancet Respir Med VL - 8 IS - 7 N2 - BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019, causing a respiratory disease (coronavirus disease 2019, COVID-19) of varying severity in Wuhan, China, and subsequently leading to a pandemic. The transmissibility and pathogenesis of SARS-CoV-2 remain poorly understood. We evaluate its tissue and cellular tropism in human respiratory tract, conjunctiva, and innate immune responses in comparison with other coronavirus and influenza virus to provide insights into COVID-19 pathogenesis. METHODS: We isolated SARS-CoV-2 from a patient with confirmed COVID-19, and compared virus tropism and replication competence with SARS-CoV, Middle East respiratory syndrome-associated coronavirus (MERS-CoV), and 2009 pandemic influenza H1N1 (H1N1pdm) in ex-vivo cultures of human bronchus (n=5) and lung (n=4). We assessed extrapulmonary infection using ex-vivo cultures of human conjunctiva (n=3) and in-vitro cultures of human colorectal adenocarcinoma cell lines. Innate immune responses and angiotensin-converting enzyme 2 expression were investigated in human alveolar epithelial cells and macrophages. In-vitro studies included the highly pathogenic avian influenza H5N1 virus (H5N1) and mock-infected cells as controls. FINDINGS: SARS-CoV-2 infected ciliated, mucus-secreting, and club cells of bronchial epithelium, type 1 pneumocytes in the lung, and the conjunctival mucosa. In the bronchus, SARS-CoV-2 replication competence was similar to MERS-CoV, and higher than SARS-CoV, but lower than H1N1pdm. In the lung, SARS-CoV-2 replication was similar to SARS-CoV and H1N1pdm, but was lower than MERS-CoV. In conjunctiva, SARS-CoV-2 replication was greater than SARS-CoV. SARS-CoV-2 was a less potent inducer of proinflammatory cytokines than H5N1, H1N1pdm, or MERS-CoV. INTERPRETATION: The conjunctival epithelium and conducting airways appear to be potential portals of infection for SARS-CoV-2. Both SARS-CoV and SARS-CoV-2 replicated similarly in the alveolar epithelium; SARS-CoV-2 replicated more extensively in the bronchus than SARS-CoV. These findings provide important insights into the transmissibility and pathogenesis of SARS-CoV-2 infection and differences with other respiratory pathogens. FUNDING: US National Institute of Allergy and Infectious Diseases, University Grants Committee of Hong Kong Special Administrative Region, China; Health and Medical Research Fund, Food and Health Bureau, Government of Hong Kong Special Administrative Region, China. SN - 2213-2619 UR - https://www.unboundmedicine.com/medline/citation/32386571/Tropism_replication_competence_and_innate_immune_responses_of_the_coronavirus_SARS_CoV_2_in_human_respiratory_tract_and_conjunctiva:_an_analysis_in_ex_vivo_and_in_vitro_cultures_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2213-2600(20)30193-4 DB - PRIME DP - Unbound Medicine ER -