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Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19.
bioRxiv. 2021 Feb 20B

Abstract

Infection with SARS-CoV-2, the virus that causes COVID-19, can lead to severe lower respiratory illness including pneumonia and acute respiratory distress syndrome, which can result in profound morbidity and mortality. However, many infected individuals are either asymptomatic or have isolated upper respiratory symptoms, which suggests that the upper airways represent the initial site of viral infection, and that some individuals are able to largely constrain viral pathology to the nasal and oropharyngeal tissues. Which cell types in the human nasopharynx are the primary targets of SARS-CoV-2 infection, and how infection influences the cellular organization of the respiratory epithelium remains incompletely understood. Here, we present nasopharyngeal samples from a cohort of 35 individuals with COVID-19, representing a wide spectrum of disease states from ambulatory to critically ill, as well as 23 healthy and intubated patients without COVID-19. Using standard nasopharyngeal swabs, we collected viable cells and performed single-cell RNA-sequencing (scRNA-seq), simultaneously profiling both host and viral RNA. We find that following infection with SARS-CoV-2, the upper respiratory epithelium undergoes massive reorganization: secretory cells diversify and expand, and mature epithelial cells are preferentially lost. Further, we observe evidence for deuterosomal cell and immature ciliated cell expansion, potentially representing active repopulation of lost ciliated cells through coupled secretory cell differentiation. Epithelial cells from participants with mild/moderate COVID-19 show extensive induction of genes associated with anti-viral and type I interferon responses. In contrast, cells from participants with severe lower respiratory symptoms appear globally muted in their anti-viral capacity, despite substantially higher local inflammatory myeloid populations and equivalent nasal viral loads. This suggests an essential role for intrinsic, local epithelial immunity in curbing and constraining viral-induced pathology. Using a custom computational pipeline, we characterized cell-associated SARS-CoV-2 RNA and identified rare cells with RNA intermediates strongly suggestive of active replication. Both within and across individuals, we find remarkable diversity and heterogeneity among SARS-CoV-2 RNA+ host cells, including developing/immature and interferon-responsive ciliated cells, KRT13+ "hillock"-like cells, and unique subsets of secretory, goblet, and squamous cells. Finally, SARS-CoV-2 RNA+ cells, as compared to uninfected bystanders, are enriched for genes involved in susceptibility (e.g., CTSL , TMPRSS2) or response (e.g., MX1 , IFITM3 , EIF2AK2) to infection. Together, this work defines both protective and detrimental host responses to SARS-CoV-2, determines the direct viral targets of infection, and suggests that failed anti-viral epithelial immunity in the nasal mucosa may underlie the progression to severe COVID-19.

Authors+Show Affiliations

Program in Health Sciences & Technology, Harvard Medical School & MIT, Boston, MA 02115, USA. Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Harvard Graduate Program in Biophysics, Harvard University, Cambridge, MA 02138, USA. Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.Program in Health Sciences & Technology, Harvard Medical School & MIT, Boston, MA 02115, USA. Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA.Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Department of Microbiology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA.Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.Division of Digestive Diseases, University of Mississippi Medical Center, Jackson, MS 39216, USA.Division of Digestive Diseases, University of Mississippi Medical Center, Jackson, MS 39216, USA.Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.Division of Digestive Diseases, University of Mississippi Medical Center, Jackson, MS 39216, USA.Division of Pulmonary, Critical Care, and Sleep Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, MS 39216, USA.Division of Digestive Diseases, University of Mississippi Medical Center, Jackson, MS 39216, USA.Division of Digestive Diseases, University of Mississippi Medical Center, Jackson, MS 39216, USA.Division of Pulmonary, Critical Care, and Sleep Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.Division of Pulmonary, Critical Care, and Sleep Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.Division of Digestive Diseases, University of Mississippi Medical Center, Jackson, MS 39216, USA.Program in Health Sciences & Technology, Harvard Medical School & MIT, Boston, MA 02115, USA. Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Harvard Graduate Program in Biophysics, Harvard University, Cambridge, MA 02138, USA. Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Program in Immunology, Harvard Medical School, Boston, MA 02115, USA. Harvard Stem Cell Institute, Cambridge, MA 02138, USA.Division of Digestive Diseases, University of Mississippi Medical Center, Jackson, MS 39216, USA.Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA. Division of Emergency Medicine, Boston Children's Hospital, Boston, MA 02115, USA. Program in Immunology, Harvard Medical School, Boston, MA 02115, USA.Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA. Program in Immunology, Harvard Medical School, Boston, MA 02115, USA. Harvard Stem Cell Institute, Cambridge, MA 02138, USA.

Pub Type(s)

Preprint

Language

eng

PubMed ID

33619488

Citation

Ziegler, Carly G K., et al. "Impaired Local Intrinsic Immunity to SARS-CoV-2 Infection in Severe COVID-19." BioRxiv : the Preprint Server for Biology, 2021.
Ziegler CGK, Miao VN, Owings AH, et al. Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19. bioRxiv. 2021.
Ziegler, C. G. K., Miao, V. N., Owings, A. H., Navia, A. W., Tang, Y., Bromley, J. D., Lotfy, P., Sloan, M., Laird, H., Williams, H. B., George, M., Drake, R. S., Christian, T., Parker, A., Sindel, C. B., Burger, M. W., Pride, Y., Hasan, M., Abraham, G. E., ... Ordovas-Montanes, J. (2021). Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19. BioRxiv : the Preprint Server for Biology. https://doi.org/10.1101/2021.02.20.431155
Ziegler CGK, et al. Impaired Local Intrinsic Immunity to SARS-CoV-2 Infection in Severe COVID-19. bioRxiv. 2021 Feb 20; PubMed PMID: 33619488.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19. AU - Ziegler,Carly G K, AU - Miao,Vincent N, AU - Owings,Anna H, AU - Navia,Andrew W, AU - Tang,Ying, AU - Bromley,Joshua D, AU - Lotfy,Peter, AU - Sloan,Meredith, AU - Laird,Hannah, AU - Williams,Haley B, AU - George,Micayla, AU - Drake,Riley S, AU - Christian,Taylor, AU - Parker,Adam, AU - Sindel,Campbell B, AU - Burger,Molly W, AU - Pride,Yilianys, AU - Hasan,Mohammad, AU - Abraham,George E,3rd AU - Senitko,Michal, AU - Robinson,Tanya O, AU - Shalek,Alex K, AU - Glover,Sarah C, AU - Horwitz,Bruce H, AU - Ordovas-Montanes,Jose, Y1 - 2021/02/20/ PY - 2021/2/23/entrez PY - 2021/2/24/pubmed PY - 2021/2/24/medline JF - bioRxiv : the preprint server for biology JO - bioRxiv N2 - Infection with SARS-CoV-2, the virus that causes COVID-19, can lead to severe lower respiratory illness including pneumonia and acute respiratory distress syndrome, which can result in profound morbidity and mortality. However, many infected individuals are either asymptomatic or have isolated upper respiratory symptoms, which suggests that the upper airways represent the initial site of viral infection, and that some individuals are able to largely constrain viral pathology to the nasal and oropharyngeal tissues. Which cell types in the human nasopharynx are the primary targets of SARS-CoV-2 infection, and how infection influences the cellular organization of the respiratory epithelium remains incompletely understood. Here, we present nasopharyngeal samples from a cohort of 35 individuals with COVID-19, representing a wide spectrum of disease states from ambulatory to critically ill, as well as 23 healthy and intubated patients without COVID-19. Using standard nasopharyngeal swabs, we collected viable cells and performed single-cell RNA-sequencing (scRNA-seq), simultaneously profiling both host and viral RNA. We find that following infection with SARS-CoV-2, the upper respiratory epithelium undergoes massive reorganization: secretory cells diversify and expand, and mature epithelial cells are preferentially lost. Further, we observe evidence for deuterosomal cell and immature ciliated cell expansion, potentially representing active repopulation of lost ciliated cells through coupled secretory cell differentiation. Epithelial cells from participants with mild/moderate COVID-19 show extensive induction of genes associated with anti-viral and type I interferon responses. In contrast, cells from participants with severe lower respiratory symptoms appear globally muted in their anti-viral capacity, despite substantially higher local inflammatory myeloid populations and equivalent nasal viral loads. This suggests an essential role for intrinsic, local epithelial immunity in curbing and constraining viral-induced pathology. Using a custom computational pipeline, we characterized cell-associated SARS-CoV-2 RNA and identified rare cells with RNA intermediates strongly suggestive of active replication. Both within and across individuals, we find remarkable diversity and heterogeneity among SARS-CoV-2 RNA+ host cells, including developing/immature and interferon-responsive ciliated cells, KRT13+ "hillock"-like cells, and unique subsets of secretory, goblet, and squamous cells. Finally, SARS-CoV-2 RNA+ cells, as compared to uninfected bystanders, are enriched for genes involved in susceptibility (e.g., CTSL , TMPRSS2) or response (e.g., MX1 , IFITM3 , EIF2AK2) to infection. Together, this work defines both protective and detrimental host responses to SARS-CoV-2, determines the direct viral targets of infection, and suggests that failed anti-viral epithelial immunity in the nasal mucosa may underlie the progression to severe COVID-19. UR - https://www.unboundmedicine.com/medline/citation/33619488/Impaired_local_intrinsic_immunity_to_SARS_CoV_2_infection_in_severe_COVID_19_ L2 - https://doi.org/10.1101/2021.02.20.431155 DB - PRIME DP - Unbound Medicine ER -
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