scRNA-seq reveals persistent aberrant differentiation of nasal epithelium driven by TNFα and TGFβ in post-COVID syndrome

Post-COVID syndrome (PCS) affects approximately 3-17% of individuals following acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and poses a potential global health burden. While improved assessment strategies are emerging, mechanistic insights and treatment options remain limited. This study investigates molecular mechanisms underlying PCS using single-cell RNA (scRNA) transcriptomics combined with in vitro validation. scRNA analysis is performed on nasal biopsies from 25 patients with moderate or severe PCS to investigate differential cell types, signalling pathways, and cell-cell communication. Air-liquid interface cultures are used to validate findings, focusing on the TNFα-TGFβ axis. Severe PCS shows reduced numbers of ciliated cells, increased immune cell infiltration, and heightened inflammatory signaling that drives TGFβ and TNFα upregulation, in the absence of a detectable viral load. These changes trigger epithelial-mesenchymal transition, basal cell expansion and a mis-stratified nasal epithelium. In vitro experiments confirm TGFβ and TNFα as causal cytokines promoting ciliated cell loss and increased basal cell abundance. These findings indicate a sustained severe PCS is not driven by ongoing viral load but by immune cell activity and chronic cytokine production. Targeting the TNFα-TGFβ axis may mitigate immune-mediated nasal tissue damage and support epithelium restoration, offering a potential therapeutic strategy for PCS.

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Publication Details

Journal
Nature Communications
Published
2025-10-28
DOI
https://doi.org/10.1038/s41467-025-64778-0
Primary Topic
Sinusitis and nasal conditions
Type
article
Field-Weighted Citation Impact
0.00

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article

scRNA-seq reveals persistent aberrant differentiation of nasal epithelium driven by TNFα and TGFβ in post-COVID syndrome

Shauni B. Biedermann, Rochi Saurabh, Thomas Bahmer, Anke Fähnrich et al.
Nature Communications
Sinusitis and nasal conditions
article

scRNA-seq reveals persistent aberrant differentiation of nasal epithelium driven by TNFα and TGFβ in post-COVID syndrome

Shauni B. Biedermann, Rochi Saurabh, Thomas Bahmer, Anke Fähnrich, Folke Brinkmann, Wolfgang Lieb, Matthias Kopp, Fabian Ott, B. Voß, Klaus F. Rabe, Nicole Maison, Anna‐Maria Dittrich, Erika von Mutius, Jan Heyckendorf, Bianca Schaub, Constanze A. Jakwerth, Karri V. V. S. Narayana Reddy, Markus Weckmann, Gesine Hansen, Astrid Schaaf, A. Bohnhorst, Martin Laudien, Carsten B. Schmidt‐Weber, Hauke Busch, S Schreiber, Yamil Maluje, S. Winkelmann, J. Pierstorf
article en

Abstract

Post-COVID syndrome (PCS) affects approximately 3-17% of individuals following acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and poses a potential global health burden. While improved assessment strategies are emerging, mechanistic insights and treatment options remain limited. This study investigates molecular mechanisms underlying PCS using single-cell RNA (scRNA) transcriptomics combined with in vitro validation. scRNA analysis is performed on nasal biopsies from 25 patients with moderate or severe PCS to investigate differential cell types, signalling pathways, and cell-cell communication. Air-liquid interface cultures are used to validate findings, focusing on the TNFα-TGFβ axis. Severe PCS shows reduced numbers of ciliated cells, increased immune cell infiltration, and heightened inflammatory signaling that drives TGFβ and TNFα upregulation, in the absence of a detectable viral load. These changes trigger epithelial-mesenchymal transition, basal cell expansion and a mis-stratified nasal epithelium. In vitro experiments confirm TGFβ and TNFα as causal cytokines promoting ciliated cell loss and increased basal cell abundance. These findings indicate a sustained severe PCS is not driven by ongoing viral load but by immune cell activity and chronic cytokine production. Targeting the TNFα-TGFβ axis may mitigate immune-mediated nasal tissue damage and support epithelium restoration, offering a potential therapeutic strategy for PCS.

Nature CommunicationsVol. 16(1)
University of Bern (CH), University Hospital of Bern (CH), Helmholtz Zentrum München (DE), Christian-Albrechts-Universität zu Kiel (DE), Medizinische Hochschule Hannover (DE), German Center for Pediatric and Adolescent Rheumatology (DE), Institute for Integrative and Experimental Genomics (DE), Universitäres Kinderwunschzentrum Lübeck (DE), University Hospital Schleswig-Holstein (DE), University Children’s Hospital Bern (CH), Research Center Borstel - Leibniz Lung Center (DE), German Center for Lung Research (DE), LungenClinic Grosshansdorf (DE), Ludwig-Maximilians-Universität München (DE), Deutsche Forschungsgemeinschaft (DE), University of Lübeck (DE)
Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Christian-Albrechts-Universität zu Kiel, Universität zu Lübeck, Deutsches Zentrum für Lungenforschung, Leibniz-Gemeinschaft, International Graduate School of Science and Engineering
Openalex Percentile: Top 59%
Sinusitis and nasal conditions
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