. 2021 Sep 2;184(18):4713-4733.e22.

doi: 10.1016/j.cell.2021.07.023. Epub 2021 Jul 23.

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

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.

PMID: 34352228
PMCID: PMC8299217
DOI: 10.1016/j.cell.2021.07.023

Free PMC article

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

Carly G K Ziegler et al. Cell. 2021.

Free PMC article

. 2021 Sep 2;184(18):4713-4733.e22.

doi: 10.1016/j.cell.2021.07.023. Epub 2021 Jul 23.

Authors

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.

PMID: 34352228
PMCID: PMC8299217
DOI: 10.1016/j.cell.2021.07.023

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.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests A.K.S. reports compensation for consulting and/or SAB membership from Merck, Honeycomb Biotechnologies, Cellarity, Repertoire Immune Medicines, Hovione, Ochre Bio, Third Rock Ventures, Relation Therapeutics, and Dahlia Biosciences. J.O.-M. reports compensation for consulting services with Cellarity and Hovione. C.G.K.Z., V.N.M., A.H.O., A.W.N., Y.T., J.D.B., A.K.S., S.C.G., B.H.H., and J.O.-M. are co-inventors on a provisional patent application relating to methods of stratifying and treating viral infections.

Update of

Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19.
Ziegler CGK, Miao VN, Owings AH, Navia AW, Tang Y, Bromley JD, Lotfy P, Sloan M, Laird H, Williams HB, George M, Drake RS, Christian T, Parker A, Sindel CB, Burger MW, Pride Y, Hasan M, Abraham GE 3rd, Senitko M, Robinson TO, Shalek AK, Glover SC, Horwitz BH, Ordovas-Montanes J. Ziegler CGK, et al. bioRxiv [Preprint]. 2021 Feb 20:2021.02.20.431155. doi: 10.1101/2021.02.20.431155. bioRxiv. 2021. Update in: Cell. 2021 Sep 2;184(18):4713-4733.e22. doi: 10.1016/j.cell.2021.07.023. PMID: 33619488 Free PMC article. Updated. Preprint.

Comment in

Poor nasal immunity can lead to severe COVID-19.
Flemming A. Flemming A. Nat Rev Immunol. 2021 Sep;21(9):547. doi: 10.1038/s41577-021-00610-2. Nat Rev Immunol. 2021. PMID: 34376831 Free PMC article. No abstract available.

References

1. Science. 2020 Mar 13;367(6483):1260-1263 - PubMed
1. Cell. 2015 May 21;161(5):1202-1214 - PubMed
1. Cell. 2021 Jan 7;184(1):120-132.e14 - PubMed
1. Nature. 2021 Jul;595(7866):283-288 - PubMed
1. Nature. 2018 Aug;560(7720):649-654 - PubMed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

Comment in

References

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Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

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