Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19

Carly G K Ziegler; Vincent N Miao; Anna H Owings; Andrew W Navia; Ying Tang; Joshua D Bromley; Peter Lotfy; Meredith Sloan; Hannah Laird; Haley B Williams; Micayla George; Riley S Drake; Taylor Christian; Adam Parker; Campbell B Sindel; Molly W Burger; Yilianys Pride; Mohammad Hasan; George E Abraham 3rd; Michal Senitko; Tanya O Robinson; Alex K Shalek; Sarah C Glover; Bruce H Horwitz; Jose Ordovas-Montanes

doi:10.1016/j.cell.2021.07.023

Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19

Cell. 2021 Sep 2;184(18):4713-4733.e22. doi: 10.1016/j.cell.2021.07.023. Epub 2021 Jul 23.

Authors

Carly G K Ziegler¹, Vincent N Miao², Anna H Owings³, Andrew W Navia⁴, Ying Tang⁵, Joshua D Bromley⁶, Peter Lotfy⁷, Meredith Sloan³, Hannah Laird⁸, Haley B Williams⁸, Micayla George⁹, Riley S Drake⁹, Taylor Christian³, Adam Parker⁸, Campbell B Sindel¹⁰, Molly W Burger¹¹, Yilianys Pride⁸, Mohammad Hasan⁸, George E Abraham 3rd¹⁰, Michal Senitko¹⁰, Tanya O Robinson⁸, Alex K Shalek¹², Sarah C Glover¹³, Bruce H Horwitz¹⁴, Jose Ordovas-Montanes¹⁵

Affiliations

¹ 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.
² 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.
³ Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
⁴ 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.
⁵ Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA.
⁶ 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.
⁷ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA.
⁸ Division of Digestive Diseases, University of Mississippi Medical Center, Jackson, MS 39216, USA.
⁹ 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.
¹⁰ Division of Pulmonary, Critical Care, and Sleep Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
¹¹ Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, MS 39216, USA.
¹² 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.
¹³ Division of Digestive Diseases, University of Mississippi Medical Center, Jackson, MS 39216, USA. Electronic address: scglover@umc.edu.
¹⁴ 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.
¹⁵ 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.

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, AZGP1^high 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.

Keywords: COVID-19; SARS-CoV-2; anti-viral; correlates of immunity; epithelial immunity; human; interferon; nasal mucosa; scRNA-seq.

Publication types

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

MeSH terms

Adult
Aged
Bystander Effect
COVID-19 / genetics
COVID-19 / immunology*
COVID-19 / virology*
Cohort Studies
Female
Humans
Immunity*
Male
Middle Aged
Nasopharynx / pathology
Nasopharynx / virology
RNA, Viral / analysis
RNA, Viral / genetics
Respiratory Mucosa / pathology
Respiratory Mucosa / virology
SARS-CoV-2 / physiology*
Severity of Illness Index*
Transcription, Genetic
Viral Load

Substances

RNA, Viral

Abstract

Publication types

MeSH terms

Substances

Grants and funding