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Human Nasal and Lung Tissues Infected Ex Vivo with SARS-CoV-2 Provide Insights into Differential Tissue-Specific and Virus-Specific Innate Immune Responses in the Upper and Lower Respiratory Tract.
J Virol. 2021 06 24; 95(14):e0013021.JV

Abstract

The nasal mucosa constitutes the primary entry site for respiratory viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While the imbalanced innate immune response of end-stage coronavirus disease 2019 (COVID-19) has been extensively studied, the earliest stages of SARS-CoV-2 infection at the mucosal entry site have remained unexplored. Here, we employed SARS-CoV-2 and influenza virus infection in native multi-cell-type human nasal turbinate and lung tissues ex vivo, coupled with genome-wide transcriptional analysis, to investigate viral susceptibility and early patterns of local mucosal innate immune response in the authentic milieu of the human respiratory tract. SARS-CoV-2 productively infected the nasal turbinate tissues, predominantly targeting respiratory epithelial cells, with a rapid increase in tissue-associated viral subgenomic mRNA and secretion of infectious viral progeny. Importantly, SARS-CoV-2 infection triggered robust antiviral and inflammatory innate immune responses in the nasal mucosa. The upregulation of interferon-stimulated genes, cytokines, and chemokines, related to interferon signaling and immune-cell activation pathways, was broader than that triggered by influenza virus infection. Conversely, lung tissues exhibited a restricted innate immune response to SARS-CoV-2, with a conspicuous lack of type I and III interferon upregulation, contrasting with their vigorous innate immune response to influenza virus. Our findings reveal differential tissue-specific innate immune responses in the upper and lower respiratory tracts that are specific to SARS-CoV-2. The studies shed light on the role of the nasal mucosa in active viral transmission and immune defense, implying a window of opportunity for early interventions, whereas the restricted innate immune response in early-SARS-CoV-2-infected lung tissues could underlie the unique uncontrolled late-phase lung damage of advanced COVID-19. IMPORTANCE In order to reduce the late-phase morbidity and mortality of COVID-19, there is a need to better understand and target the earliest stages of SARS-CoV-2 infection in the human respiratory tract. Here, we have studied the initial steps of SARS-CoV-2 infection and the consequent innate immune responses within the natural multicellular complexity of human nasal mucosal and lung tissues. Comparing the global innate response patterns of nasal and lung tissues infected in parallel with SARS-CoV-2 and influenza virus, we found distinct virus-host interactions in the upper and lower respiratory tract, which could determine the outcome and unique pathogenesis of SARS-CoV-2 infection. Studies in the nasal mucosal infection model can be employed to assess the impact of viral evolutionary changes and evaluate new therapeutic and preventive measures against SARS-CoV-2 and other human respiratory pathogens.

Authors+Show Affiliations

Clinical Virology Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel. Department of Biochemistry, IMRIC, The Hebrew University Faculty of Medicine, Jerusalem, Israel. Lautenberg Center for General and Tumor Immunology, The Hebrew University Faculty of Medicine, Jerusalem, Israel.Department of Otolaryngology-Head and Neck Surgery, Sheba Medical Center, Tel Hashomer, Israel. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.Department of Cardiothoracic Surgery, Hadassah University Hospital, Jerusalem, Israel.Clinical Virology Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel.Department of Cardiothoracic Surgery, Hadassah University Hospital, Jerusalem, Israel.Clinical Virology Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel.Bioinformatics Unit of the I-CORE Computation Center, The Hebrew University and Hadassah Hebrew University Medical Center, Jerusalem, Israel.Bioinformatics Unit of the I-CORE Computation Center, The Hebrew University and Hadassah Hebrew University Medical Center, Jerusalem, Israel.Department of Otolaryngology-Head and Neck Surgery, Sheba Medical Center, Tel Hashomer, Israel. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.Department of Otolaryngology-Head and Neck Surgery, Sheba Medical Center, Tel Hashomer, Israel. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.Department of Otolaryngology-Head and Neck Surgery, Sheba Medical Center, Tel Hashomer, Israel. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.Lautenberg Center for General and Tumor Immunology, The Hebrew University Faculty of Medicine, Jerusalem, Israel.Center for Genomic Technologies, Alexander Silberman Institute of Life Sciences, Hebrew University, Jerusalem, Israel.Clinical Virology Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel. Department of Biochemistry, IMRIC, The Hebrew University Faculty of Medicine, Jerusalem, Israel. Lautenberg Center for General and Tumor Immunology, The Hebrew University Faculty of Medicine, Jerusalem, Israel.Samueli Institute, Alexandria, Virginia, USA.Samueli Institute, Alexandria, Virginia, USA.Samueli Institute, Alexandria, Virginia, USA.Department of Biochemistry, IMRIC, The Hebrew University Faculty of Medicine, Jerusalem, Israel.The Center for Integrative Complementary Medicine, Shaare Zedek Medical Center, Jerusalem, Israel.Department of Biochemistry, IMRIC, The Hebrew University Faculty of Medicine, Jerusalem, Israel.Clinical Virology Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel. Lautenberg Center for General and Tumor Immunology, The Hebrew University Faculty of Medicine, Jerusalem, Israel.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33893170

Citation

Alfi, Or, et al. "Human Nasal and Lung Tissues Infected Ex Vivo With SARS-CoV-2 Provide Insights Into Differential Tissue-Specific and Virus-Specific Innate Immune Responses in the Upper and Lower Respiratory Tract." Journal of Virology, vol. 95, no. 14, 2021, pp. e0013021.
Alfi O, Yakirevitch A, Wald O, et al. Human Nasal and Lung Tissues Infected Ex Vivo with SARS-CoV-2 Provide Insights into Differential Tissue-Specific and Virus-Specific Innate Immune Responses in the Upper and Lower Respiratory Tract. J Virol. 2021;95(14):e0013021.
Alfi, O., Yakirevitch, A., Wald, O., Wandel, O., Izhar, U., Oiknine-Djian, E., Nevo, Y., Elgavish, S., Dagan, E., Madgar, O., Feinmesser, G., Pikarsky, E., Bronstein, M., Vorontsov, O., Jonas, W., Ives, J., Walter, J., Zakay-Rones, Z., Oberbaum, M., ... Wolf, D. G. (2021). Human Nasal and Lung Tissues Infected Ex Vivo with SARS-CoV-2 Provide Insights into Differential Tissue-Specific and Virus-Specific Innate Immune Responses in the Upper and Lower Respiratory Tract. Journal of Virology, 95(14), e0013021. https://doi.org/10.1128/JVI.00130-21
Alfi O, et al. Human Nasal and Lung Tissues Infected Ex Vivo With SARS-CoV-2 Provide Insights Into Differential Tissue-Specific and Virus-Specific Innate Immune Responses in the Upper and Lower Respiratory Tract. J Virol. 2021 06 24;95(14):e0013021. PubMed PMID: 33893170.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Human Nasal and Lung Tissues Infected Ex Vivo with SARS-CoV-2 Provide Insights into Differential Tissue-Specific and Virus-Specific Innate Immune Responses in the Upper and Lower Respiratory Tract. AU - Alfi,Or, AU - Yakirevitch,Arkadi, AU - Wald,Ori, AU - Wandel,Ori, AU - Izhar,Uzi, AU - Oiknine-Djian,Esther, AU - Nevo,Yuval, AU - Elgavish,Sharona, AU - Dagan,Elad, AU - Madgar,Ory, AU - Feinmesser,Gilad, AU - Pikarsky,Eli, AU - Bronstein,Michal, AU - Vorontsov,Olesya, AU - Jonas,Wayne, AU - Ives,John, AU - Walter,Joan, AU - Zakay-Rones,Zichria, AU - Oberbaum,Menachem, AU - Panet,Amos, AU - Wolf,Dana G, Y1 - 2021/06/24/ PY - 2021/4/25/pubmed PY - 2021/7/6/medline PY - 2021/4/24/entrez KW - COVID-19 KW - SARS-CoV-2 KW - human respiratory viruses KW - nasal mucosa KW - organ culture KW - tissue innate immune response SP - e0013021 EP - e0013021 JF - Journal of virology JO - J Virol VL - 95 IS - 14 N2 - The nasal mucosa constitutes the primary entry site for respiratory viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While the imbalanced innate immune response of end-stage coronavirus disease 2019 (COVID-19) has been extensively studied, the earliest stages of SARS-CoV-2 infection at the mucosal entry site have remained unexplored. Here, we employed SARS-CoV-2 and influenza virus infection in native multi-cell-type human nasal turbinate and lung tissues ex vivo, coupled with genome-wide transcriptional analysis, to investigate viral susceptibility and early patterns of local mucosal innate immune response in the authentic milieu of the human respiratory tract. SARS-CoV-2 productively infected the nasal turbinate tissues, predominantly targeting respiratory epithelial cells, with a rapid increase in tissue-associated viral subgenomic mRNA and secretion of infectious viral progeny. Importantly, SARS-CoV-2 infection triggered robust antiviral and inflammatory innate immune responses in the nasal mucosa. The upregulation of interferon-stimulated genes, cytokines, and chemokines, related to interferon signaling and immune-cell activation pathways, was broader than that triggered by influenza virus infection. Conversely, lung tissues exhibited a restricted innate immune response to SARS-CoV-2, with a conspicuous lack of type I and III interferon upregulation, contrasting with their vigorous innate immune response to influenza virus. Our findings reveal differential tissue-specific innate immune responses in the upper and lower respiratory tracts that are specific to SARS-CoV-2. The studies shed light on the role of the nasal mucosa in active viral transmission and immune defense, implying a window of opportunity for early interventions, whereas the restricted innate immune response in early-SARS-CoV-2-infected lung tissues could underlie the unique uncontrolled late-phase lung damage of advanced COVID-19. IMPORTANCE In order to reduce the late-phase morbidity and mortality of COVID-19, there is a need to better understand and target the earliest stages of SARS-CoV-2 infection in the human respiratory tract. Here, we have studied the initial steps of SARS-CoV-2 infection and the consequent innate immune responses within the natural multicellular complexity of human nasal mucosal and lung tissues. Comparing the global innate response patterns of nasal and lung tissues infected in parallel with SARS-CoV-2 and influenza virus, we found distinct virus-host interactions in the upper and lower respiratory tract, which could determine the outcome and unique pathogenesis of SARS-CoV-2 infection. Studies in the nasal mucosal infection model can be employed to assess the impact of viral evolutionary changes and evaluate new therapeutic and preventive measures against SARS-CoV-2 and other human respiratory pathogens. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/33893170/Human_Nasal_and_Lung_Tissues_Infected_Ex_Vivo_with_SARS_CoV_2_Provide_Insights_into_Differential_Tissue_Specific_and_Virus_Specific_Innate_Immune_Responses_in_the_Upper_and_Lower_Respiratory_Tract_ DB - PRIME DP - Unbound Medicine ER -