COVID-19 severity correlates with airway epithelium–immune cell interactions identified by single-cell analysis
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Abstract
To investigate the immune response and mechanisms associated with severe coronavirus disease 2019 (COVID-19), we performed single-cell RNA sequencing on nasopharyngeal and bronchial samples from 19 clinically well-characterized patients with moderate or critical disease and from five healthy controls. We identified airway epithelial cell types and states vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In patients with COVID-19, epithelial cells showed an average three-fold increase in expression of the SARS-CoV-2 entry receptor ACE2, which correlated with interferon signals by immune cells. Compared to moderate cases, critical cases exhibited stronger interactions between epithelial and immune cells, as indicated by ligand-receptor expression profiles, and activated immune cells, including inflammatory macrophages expressing CCL2, CCL3, CCL20, CXCL1, CXCL3, CXCL10, IL8, IL1B and TNF. The transcriptional differences in critical cases compared to moderate cases likely contribute to clinical observations of heightened inflammatory tissue damage, lung injury and respiratory failure. Our data suggest that pharmacologic inhibition of the CCR1 and/or CCR5 pathways might suppress immune hyperactivation in critical COVID-19.
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The described features may help reveal the immunopathology of similar conditions, including immune-related adverse events and cytokine release syndrome from other immunotherapies or COVID-19, and may inform how long and what type of clinical and immune monitoring is needed.
“We believe that the features described herein may help to identify the immunopathology of similar illnesses, such as irAEs and CRS due to other immunotherapies (e.g. checkpoint inhibitors, CAR-T-cells) or COVID-19 [4, 18, 19], and to inform discussions on the type and length of clinical and immune monitoring warranted in such patients.”
From Immune reconstitution and clinical recovery following anti-CD28 antibody (TGN1412)-induced cytokine storm (2021) · cites this paper as [18]
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Experimental — accuracy not yet measuredClinical-pathologic correlation in these individuals resulted in valuable observations that may be instructive in understanding mechanisms of immune-induced pathologies, including those of checkpoint inhibitors, CAR-T cells, and infections such as COVID-19.
“Clinical–pathologic correlation in these individuals resulted in valuable observations that may be instructive in understanding mechanisms of immune-induced pathologies, including those of checkpoint inhibitors, CAR-T cells, and infections such as COVID-19, known to target mucosal tissues and cause severe CRS [1, 5, 8, 18, 19].”
From Immune reconstitution and clinical recovery following anti-CD28 antibody (TGN1412)-induced cytokine storm (2021) · cites this paper as [18]
In vitro and in vivo experiments show that macrophages near SASP-producing virus-infected epithelial cells can undergo paracrine secondary senescence or acquire a senescence-like condition.
“in vitro and in vivo experiments have shown that resident and non-resident macrophages in the vicinity of SASP-producing virus-infected epithelial cells can undergo paracrine secondary senescence or acquire a senescence-like condition28,63,66,77,78.”
From COVID-19 and cellular senescence (2023) · cites this paper as [66]
Viral RNA was also detected in a subset of macrophages (SPP1+ macrophages).
“Viral RNA was also detected in a subset of macrophages (SPP1 + macrophages) (Bost et al., 2020; Chua et al., 2020).”
From COVID-19 and the human innate immune system (2021) · cites this paper as Chua et al., 2020
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Detection of differentially abundant cell subpopulations in scRNA-seq data
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COVID-19 and cellular senescence
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- Authors
- Chua, R. L., Lukassen, S., Trump, S., Hennig, B. P., Wendisch, D., Pott, F., Debnath, O., Thürmann, L., Kurth, F., Völker, M. T., Kazmierski, J., Timmermann, B., Twardziok, S., Schneider, S., Machleidt, F., Müller-Redetzky, H., Maier, M., Krannich, A., Schmidt, S., Balzer, F., Liebig, J., Loske, J., Suttorp, N., Eils, J., Ishaque, N., Liebert, U. G., von Kalle, C., Hocke, A., Witzenrath, M., Goffinet, C., Drosten, C., Laudi, S., Lehmann, I., Conrad, C., Sander, L.-E., & Eils, R.
- Affiliations
- Humboldt-Universität zu Berlin (DE)
- University Hospital Leipzig (DE)
- Max Planck Institute for Molecular Genetics (DE)
- University Hospital Heidelberg (DE)
- Corresponding author
- Laudi, Sven
- Lehmann, Irina
- Conrad, Christian
- Sander, Leif-Erik
- Eils, Roland
- ORCID
- Chua, Robert Lorenz
- Lukassen, Soeren
- Trump, Saskia
- Hennig, Bianca P.
- Wendisch, Daniel
- Pott, Fabian
- Debnath, Olivia
- Thürmann, Loreen
- Kurth, Florian
- Kazmierski, Julia
- Twardziok, Sven
- Schneider, Stefan
- Machleidt, Felix
- Müller-Redetzky, Holger
- Maier, Melanie
- Krannich, Alexander
- Schmidt, Sein
- Balzer, Felix
- Liebig, Johannes
- Loske, Jennifer
- Suttorp, Norbert
- Ishaque, Naveed
- Liebert, Uwe Gerd
- Hocke, Andreas
- Witzenrath, Martin
- Goffinet, Christine
- Drosten, Christian
- Laudi, Sven
- Lehmann, Irina
- Conrad, Christian
- Sander, Leif-Erik
- Eils, Roland
- Venue
- Nature Biotechnology
- Published
- 2020-06-26
- Volume
- 38
- Issue
- 8
- Pages
- 970-979
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- OpenAlex
- W3037544553
- Cited by
- 1,035
- References
- 68
- Citations by year
- 2026: 38 · 2025: 60 · 2024: 113 · 2023: 169 · 2022: 243 · 2021: 312 · 2020: 99 · 2019: 1
- FWCI
- 27.10
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature Biotechnology (publishedVersion)
- medRxiv (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Funders
- European Commission (874710)
- Bundesministerium für Bildung und Forschung (031A537B, 031A533A, 031A538A, 031A533B, 031A535A, 031A537C, 031A534A, 031A532B, 01ZX1304B, FKZ 01KI20160A)
- Deutsche Forschungsgemeinschaft (114933180)
- Topics
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- COVID-19 pandemic, SARS-CoV-2, disease severity, airway epithelium, ACE2, interferon signaling, macrophage activation, chemokines, CCR1, CCR5, immune hyperactivation, lung injury, respiratory failure, nasopharynx, bronchi, single-cell RNA sequencing
- MeSH terms
- Angiotensin-Converting Enzyme 2, COVID-19, Adult, Aged, Bronchoalveolar Lavage Fluid, Cell Communication, Cell Differentiation, Epithelial Cells, Female, Humans, Immune System, Inflammation, Peptidyl-Dipeptidase A, Longitudinal Studies, Male, Middle Aged, Nasopharynx, Pneumonia, Viral, Respiratory System, Severity of Illness Index, Coronavirus Infections, Pandemics, Single-Cell Analysis, Transcriptome
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