Toward precision medicine: Inflammatory nasal epithelial transcriptomic profiles in long COVID

Nadia Baalbaki; Jelle M. Blankestijn; Samuel W. Kazer; Mahmoud I. Abdel-Aziz; Lizan D. Bloemsma; Harm Jan Bogaard; Merel E. B. Cornelissen; Cornelis M. van Drunen; Daniëlle van Egmond; Esther J. Nossent; Jaclyn M. L. Walsh; P4O2 consortium

doi:10.1016/j.jaci.2025.05.023

Toward precision medicine: Inflammatory nasal epithelial transcriptomic profiles in long COVID

Amsterdam UMC
Boston Children's Hospital
Harvard University
Broad Institute of MIT and Harvard
Massachusetts Institute of Technology
Assiut University
University of Amsterdam

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Background: Little is known about the role of the nasal epithelium in long COVID (LC). Objective: We sought to assess nasal epithelial transcriptomes of patients with LC to unravel pathophysiological mechanisms for disease management. Methods: Medical data and transcriptomes were obtained from participants in the Precision Medicine for More Oxygen COVID-19 cohort at 3 to 6 months (n = 40) and at 12 to 18 months (n = 15) post-COVID. Cell-type frequencies were estimated by deconvolution from a single-cell data set. Hierarchical clustering identified transcriptomic clusters and cellular clusters from which differences in gene expression, gene set enrichment, and pulmonary phenotypes were assessed. Functional validation was performed using CRISPR/Cas9 gene editing and in vitro assays in primary mutant nasal epithelium, and gene expression comparisons were made with healthy controls (n = 51). Results: At 3 to 6 and 12 to 18 months, transcriptomes associated with inflammatory pathways (P_adj < .05). Transcriptomic and cellular clusters were identified and were related to inflammation and ciliogenesis (P_adj < .05). Comparison of transcriptomes of patients with and without pulmonary radiological abnormalities resulted in 613 significant differentially expressed genes (P_adj < .05). Upregulated inflammatory genes were observed in patients with abnormalities. SMURF1 expression was significantly increased in patients with abnormalities compared with those without abnormalities and healthy controls. SMURF1^−/− mutant nasal epithelial cells produced significantly lower levels (P < .05) of proinflammatory cytokines on virus exposure compared with controls. Conclusions: Nasal epithelium in LC exhibits persistent inflammatory states. SMURF1 upregulation potentially contributes to an exacerbated inflammatory state in nasal epithelium of patients with radiological abnormalities. This study demonstrates the importance of understanding these inflammatory profiles within a clinical context and emphasizes the need for further assessment and validation of SMURF1’s role in LC.

Original language	English
Pages (from-to)	790-802
Number of pages	13
Journal	Journal of allergy and clinical immunology
Volume	156
Issue number	3
Early online date	2025
DOIs	https://doi.org/10.1016/j.jaci.2025.05.023
Publication status	Published - Sept 2025

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Long COVID
inflammatory airway disease
nasal epithelium
post–acute COVID-19 syndrome
post–acute sequelae of COVID-19
post–viral condition
transcriptomics

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10.1016/j.jaci.2025.05.023

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Baalbaki, N., Blankestijn, J. M., Kazer, S. W., Abdel-Aziz, M. I., Bloemsma, L. D., Bogaard, H. J., Cornelissen, M. E. B., van Drunen, C. M., van Egmond, D., Nossent, E. J., Walsh, J. M. L., & P4O2 consortium (2025). Toward precision medicine: Inflammatory nasal epithelial transcriptomic profiles in long COVID. Journal of allergy and clinical immunology, 156(3), 790-802. https://doi.org/10.1016/j.jaci.2025.05.023

@article{0cbfe15ed38747c69aa1238024434a7c,

title = "Toward precision medicine: Inflammatory nasal epithelial transcriptomic profiles in long COVID",

abstract = "Background: Little is known about the role of the nasal epithelium in long COVID (LC). Objective: We sought to assess nasal epithelial transcriptomes of patients with LC to unravel pathophysiological mechanisms for disease management. Methods: Medical data and transcriptomes were obtained from participants in the Precision Medicine for More Oxygen COVID-19 cohort at 3 to 6 months (n = 40) and at 12 to 18 months (n = 15) post-COVID. Cell-type frequencies were estimated by deconvolution from a single-cell data set. Hierarchical clustering identified transcriptomic clusters and cellular clusters from which differences in gene expression, gene set enrichment, and pulmonary phenotypes were assessed. Functional validation was performed using CRISPR/Cas9 gene editing and in vitro assays in primary mutant nasal epithelium, and gene expression comparisons were made with healthy controls (n = 51). Results: At 3 to 6 and 12 to 18 months, transcriptomes associated with inflammatory pathways (Padj < .05). Transcriptomic and cellular clusters were identified and were related to inflammation and ciliogenesis (Padj < .05). Comparison of transcriptomes of patients with and without pulmonary radiological abnormalities resulted in 613 significant differentially expressed genes (Padj < .05). Upregulated inflammatory genes were observed in patients with abnormalities. SMURF1 expression was significantly increased in patients with abnormalities compared with those without abnormalities and healthy controls. SMURF1−/− mutant nasal epithelial cells produced significantly lower levels (P < .05) of proinflammatory cytokines on virus exposure compared with controls. Conclusions: Nasal epithelium in LC exhibits persistent inflammatory states. SMURF1 upregulation potentially contributes to an exacerbated inflammatory state in nasal epithelium of patients with radiological abnormalities. This study demonstrates the importance of understanding these inflammatory profiles within a clinical context and emphasizes the need for further assessment and validation of SMURF1{\textquoteright}s role in LC.",

keywords = "Long COVID, inflammatory airway disease, nasal epithelium, post–acute COVID-19 syndrome, post–acute sequelae of COVID-19, post–viral condition, transcriptomics",

author = "Nadia Baalbaki and Blankestijn, \{Jelle M.\} and Kazer, \{Samuel W.\} and Abdel-Aziz, \{Mahmoud I.\} and Bloemsma, \{Lizan D.\} and Bogaard, \{Harm Jan\} and Cornelissen, \{Merel E. B.\} and \{van Drunen\}, \{Cornelis M.\} and \{van Egmond\}, Dani{\"e}lle and Nossent, \{Esther J.\} and Walsh, \{Jaclyn M. L.\} and \{P4O2 consortium\} and Jose Ordovas-Montanes and Korneliusz Golebski and \{Maitland-van der Zee\}, \{Anke H.\}",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors",

year = "2025",

month = sep,

doi = "10.1016/j.jaci.2025.05.023",

language = "English",

volume = "156",

pages = "790--802",

journal = "Journal of allergy and clinical immunology",

issn = "0091-6749",

publisher = "Mosby Inc.",

number = "3",

}

Baalbaki, N , Blankestijn, JM, Kazer, SW, Abdel-Aziz, MI , Bloemsma, LD , Bogaard, HJ , Cornelissen, MEB , van Drunen, CM , van Egmond, D , Nossent, EJ, Walsh, JML & P4O2 consortium 2025, 'Toward precision medicine: Inflammatory nasal epithelial transcriptomic profiles in long COVID', Journal of allergy and clinical immunology, vol. 156, no. 3, pp. 790-802. https://doi.org/10.1016/j.jaci.2025.05.023

TY - JOUR

T1 - Toward precision medicine

T2 - Inflammatory nasal epithelial transcriptomic profiles in long COVID

AU - Baalbaki, Nadia

AU - Blankestijn, Jelle M.

AU - Kazer, Samuel W.

AU - Abdel-Aziz, Mahmoud I.

AU - Bloemsma, Lizan D.

AU - Bogaard, Harm Jan

AU - Cornelissen, Merel E. B.

AU - van Drunen, Cornelis M.

AU - van Egmond, Daniëlle

AU - Nossent, Esther J.

AU - Walsh, Jaclyn M. L.

AU - P4O2 consortium

AU - Ordovas-Montanes, Jose

AU - Golebski, Korneliusz

AU - Maitland-van der Zee, Anke H.

PY - 2025/9

Y1 - 2025/9

N2 - Background: Little is known about the role of the nasal epithelium in long COVID (LC). Objective: We sought to assess nasal epithelial transcriptomes of patients with LC to unravel pathophysiological mechanisms for disease management. Methods: Medical data and transcriptomes were obtained from participants in the Precision Medicine for More Oxygen COVID-19 cohort at 3 to 6 months (n = 40) and at 12 to 18 months (n = 15) post-COVID. Cell-type frequencies were estimated by deconvolution from a single-cell data set. Hierarchical clustering identified transcriptomic clusters and cellular clusters from which differences in gene expression, gene set enrichment, and pulmonary phenotypes were assessed. Functional validation was performed using CRISPR/Cas9 gene editing and in vitro assays in primary mutant nasal epithelium, and gene expression comparisons were made with healthy controls (n = 51). Results: At 3 to 6 and 12 to 18 months, transcriptomes associated with inflammatory pathways (Padj < .05). Transcriptomic and cellular clusters were identified and were related to inflammation and ciliogenesis (Padj < .05). Comparison of transcriptomes of patients with and without pulmonary radiological abnormalities resulted in 613 significant differentially expressed genes (Padj < .05). Upregulated inflammatory genes were observed in patients with abnormalities. SMURF1 expression was significantly increased in patients with abnormalities compared with those without abnormalities and healthy controls. SMURF1−/− mutant nasal epithelial cells produced significantly lower levels (P < .05) of proinflammatory cytokines on virus exposure compared with controls. Conclusions: Nasal epithelium in LC exhibits persistent inflammatory states. SMURF1 upregulation potentially contributes to an exacerbated inflammatory state in nasal epithelium of patients with radiological abnormalities. This study demonstrates the importance of understanding these inflammatory profiles within a clinical context and emphasizes the need for further assessment and validation of SMURF1’s role in LC.

AB - Background: Little is known about the role of the nasal epithelium in long COVID (LC). Objective: We sought to assess nasal epithelial transcriptomes of patients with LC to unravel pathophysiological mechanisms for disease management. Methods: Medical data and transcriptomes were obtained from participants in the Precision Medicine for More Oxygen COVID-19 cohort at 3 to 6 months (n = 40) and at 12 to 18 months (n = 15) post-COVID. Cell-type frequencies were estimated by deconvolution from a single-cell data set. Hierarchical clustering identified transcriptomic clusters and cellular clusters from which differences in gene expression, gene set enrichment, and pulmonary phenotypes were assessed. Functional validation was performed using CRISPR/Cas9 gene editing and in vitro assays in primary mutant nasal epithelium, and gene expression comparisons were made with healthy controls (n = 51). Results: At 3 to 6 and 12 to 18 months, transcriptomes associated with inflammatory pathways (Padj < .05). Transcriptomic and cellular clusters were identified and were related to inflammation and ciliogenesis (Padj < .05). Comparison of transcriptomes of patients with and without pulmonary radiological abnormalities resulted in 613 significant differentially expressed genes (Padj < .05). Upregulated inflammatory genes were observed in patients with abnormalities. SMURF1 expression was significantly increased in patients with abnormalities compared with those without abnormalities and healthy controls. SMURF1−/− mutant nasal epithelial cells produced significantly lower levels (P < .05) of proinflammatory cytokines on virus exposure compared with controls. Conclusions: Nasal epithelium in LC exhibits persistent inflammatory states. SMURF1 upregulation potentially contributes to an exacerbated inflammatory state in nasal epithelium of patients with radiological abnormalities. This study demonstrates the importance of understanding these inflammatory profiles within a clinical context and emphasizes the need for further assessment and validation of SMURF1’s role in LC.

KW - Long COVID

KW - inflammatory airway disease

KW - nasal epithelium

KW - post–acute COVID-19 syndrome

KW - post–acute sequelae of COVID-19

KW - post–viral condition

KW - transcriptomics

UR - https://www.scopus.com/pages/publications/105009637888

U2 - 10.1016/j.jaci.2025.05.023

DO - 10.1016/j.jaci.2025.05.023

M3 - Article

C2 - 40482860

SN - 0091-6749

VL - 156

SP - 790

EP - 802

JO - Journal of allergy and clinical immunology

JF - Journal of allergy and clinical immunology

IS - 3

ER -

Toward precision medicine: Inflammatory nasal epithelial transcriptomic profiles in long COVID

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UN SDGs

Keywords

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