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Type 2 inflammation reduces SARS-CoV-2 replication in the airway epithelium in allergic asthma through functional alteration of ciliated epithelial cells - 05/07/23

Doi : 10.1016/j.jaci.2023.03.021 
Naresh Doni Jayavelu, PhD a, , Matthew C. Altman, MD a, b, , , Basilin Benson, MS b, Matthew J. Dufort, PhD a, Elizabeth R. Vanderwall, BS c, Lucille M. Rich, BS c, Maria P. White, BA c, Patrice M. Becker, MD d, Alkis Togias, MD d, Daniel J. Jackson, MD e, , Jason S. Debley, MD, MPH c, f,
a Systems Immunology Division, Benaroya Research Institute at Virginia Mason, Seattle, Wash 
b Division of Allergy and Infectious Diseases, University of Washington School of Medicine, Seattle, Wash 
c Center for Immunity and Immunotherapies, Seattle Children’s Research Institute, Seattle, Wash 
d National Institute of Allergy and Infectious Diseases/National Institutes of Health, Bethesda, Md 
e Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wis 
f Department of Pediatrics, Division of Pulmonary and Sleep Medicine, Seattle Children’s Hospital, University of Washington, Seattle, Wash 

∗∗Corresponding author: Matthew C. Altman, MD, Systems Immunology Division, Benaroya Research Institute, 1201 Ninth Ave, Seattle, WA 98101.Systems Immunology DivisionBenaroya Research Institute1201 Ninth AveSeattleWA98101

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Abstract

Background

Despite well-known susceptibilities to other respiratory viral infections, individuals with allergic asthma have shown reduced susceptibility to severe coronavirus disease 2019 (COVID-19).

Objective

We sought to identify mechanisms whereby type 2 inflammation in the airway protects against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by using bronchial airway epithelial cells (AECs) from aeroallergen-sensitized children with asthma and healthy nonsensitized children.

Methods

We measured SARS-CoV-2 replication and ACE2 protein and performed bulk and single-cell RNA sequencing of ex vivo infected AEC samples with SARS-CoV-2 infection and with or without IL-13 treatment.

Results

We observed that viral replication was lower in AECs from children with allergic asthma than those from in healthy nonsensitized children and that IL-13 treatment reduced viral replication only in children with allergic asthma and not in healthy children. Lower viral transcript levels were associated with a downregulation of functional pathways of the ciliated epithelium related to differentiation as well as cilia and axoneme production and function, rather than lower ACE2 expression or increases in goblet cells or mucus secretion pathways. Moreover, single-cell RNA sequencing identified specific subsets of relatively undifferentiated ciliated epithelium (which are common in allergic asthma and highly responsive to IL-13) that directly accounted for impaired viral replication.

Conclusion

Our results identify a novel mechanism of innate protection against SARS-CoV-2 in allergic asthma that provides important molecular and clinical insights during the ongoing COVID-19 pandemic.

El texto completo de este artículo está disponible en PDF.

Key words : SARS-CoV-2, COVID-19, asthma, airway epithelial cells, epithelium, IL-13, children

Abbreviations used : ACE2, AEC, ALI, BSL3, COVID-19, FDR, GEM, GO, Log2FC, MOI, qPCR, RNA-seq, SARS-CoV-2, scRNA-seq, SMEM, UMAP


Esquema


 Supported by the National Institutes of Health/National Institute of Allergy and Infectious Diseases (to N.D.J., M.C.A, B.B., M.D., E.R.V., L.M.R., M.P.W., D.J.J, and J.S.D.), including grants K24AI150991-01S1 (to J.S.D.) and R01AI163160-01A1 (to J.S.D.).
 Disclosure of potential conflict of interest: M. C. Altman reports personal fees from Sanofi-Regeneron and additional grant support from the National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases and the American Academy of Allergy, Asthma & Immunology outside the submitted work. D. J. Jackson reports personal fees from Novartis, Pfizer, Regeneron, AstraZeneca, Sanofi, and Vifor Pharma, as well as grants and personal fees from GlaxoSmithKline and grants from the NIH/National Heart, Lung and Blood Institute (NHLBI) outside the submitted work. J. S. Debley reports additional grant support from the NIH/NHLBI and the Bill and Melinda Gates Foundation outside the submitted work. The rest of the authors declare that they have no relevant conflicts of interest.


© 2023  Publicado por Elsevier Masson SAS.
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Vol 152 - N° 1

P. 56-67 - juillet 2023 Regresar al número
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