Tags

Type your tag names separated by a space and hit enter

Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19.
Cell. 2021 09 02; 184(18):4713-4733.e22.Cell

Abstract

SARS-CoV-2 infection can cause severe respiratory COVID-19. However, many individuals present with isolated upper respiratory symptoms, suggesting potential to constrain viral pathology to the nasopharynx. Which cells SARS-CoV-2 primarily targets and how infection influences the respiratory epithelium remains incompletely understood. We performed scRNA-seq on nasopharyngeal swabs from 58 healthy and COVID-19 participants. During COVID-19, we observe expansion of secretory, loss of ciliated, and epithelial cell repopulation via deuterosomal cell expansion. In mild and moderate COVID-19, epithelial cells express anti-viral/interferon-responsive genes, while cells in severe COVID-19 have muted anti-viral responses despite equivalent viral loads. SARS-CoV-2 RNA+ host-target cells are highly heterogenous, including developing ciliated, interferon-responsive ciliated, AZGP1high goblet, and KRT13+ "hillock"-like cells, and we identify genes associated with susceptibility, resistance, or infection response. Our study defines protective and detrimental responses to SARS-CoV-2, the direct viral targets of infection, and suggests that failed nasal epithelial anti-viral immunity may underlie and precede severe COVID-19.

Links

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. Electronic address: shalek@mit.edu.

Division of Digestive Diseases, University of Mississippi Medical Center, Jackson, MS 39216, USA. Electronic address: scglover@umc.edu.

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. Electronic address: bruce.horwitz@childrens.harvard.edu.

Ordovas-Montanes J

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. Electronic address: jose.ordovas-montanes@childrens.harvard.edu.

MeSH

AdultAgedBystander EffectCOVID-19Cohort StudiesFemaleHumansImmunityMaleMiddle AgedNasopharynxRNA, ViralRespiratory MucosaSARS-CoV-2Severity of Illness IndexTranscription, GeneticViral Load

Pub Type(s)

Journal Article

Research Support, N.I.H., Extramural

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

Language

eng

PubMed ID

34352228

Citation

Ziegler, Carly G K., et al. "Impaired Local Intrinsic Immunity to SARS-CoV-2 Infection in Severe COVID-19." Cell, vol. 184, no. 18, 2021, pp. 4713-4733.e22.

Ziegler CGK, Miao VN, Owings AH, et al. Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19. Cell. 2021;184(18):4713-4733.e22.

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. Cell, 184(18), 4713-e22. https://doi.org/10.1016/j.cell.2021.07.023

Ziegler CGK, et al. Impaired Local Intrinsic Immunity to SARS-CoV-2 Infection in Severe COVID-19. Cell. 2021 09 2;184(18):4713-4733.e22. PubMed PMID: 34352228.

* 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 - 2021/07/23/ PY - 2021/02/16/received PY - 2021/05/24/revised PY - 2021/07/14/accepted PY - 2021/8/6/pubmed PY - 2021/9/15/medline PY - 2021/8/5/entrez KW - COVID-19 KW - SARS-CoV-2 KW - anti-viral KW - correlates of immunity KW - epithelial immunity KW - human KW - interferon KW - nasal mucosa KW - scRNA-seq SP - 4713 EP - 4733.e22 JF - Cell JO - Cell VL - 184 IS - 18 N2 - SARS-CoV-2 infection can cause severe respiratory COVID-19. However, many individuals present with isolated upper respiratory symptoms, suggesting potential to constrain viral pathology to the nasopharynx. Which cells SARS-CoV-2 primarily targets and how infection influences the respiratory epithelium remains incompletely understood. We performed scRNA-seq on nasopharyngeal swabs from 58 healthy and COVID-19 participants. During COVID-19, we observe expansion of secretory, loss of ciliated, and epithelial cell repopulation via deuterosomal cell expansion. In mild and moderate COVID-19, epithelial cells express anti-viral/interferon-responsive genes, while cells in severe COVID-19 have muted anti-viral responses despite equivalent viral loads. SARS-CoV-2 RNA+ host-target cells are highly heterogenous, including developing ciliated, interferon-responsive ciliated, AZGP1high goblet, and KRT13+ "hillock"-like cells, and we identify genes associated with susceptibility, resistance, or infection response. Our study defines protective and detrimental responses to SARS-CoV-2, the direct viral targets of infection, and suggests that failed nasal epithelial anti-viral immunity may underlie and precede severe COVID-19. SN - 1097-4172 UR - https://www.unboundmedicine.com/medline/citation/34352228/Impaired_local_intrinsic_immunity_to_SARS_CoV_2_infection_in_severe_COVID_19_ DB - PRIME DP - Unbound Medicine ER -