Ataxia telangiectasia mutated is required for efficient proximal airway epithelial cell regeneration following influenza A virus infection

Author:

Warren Rachel1,Dylag Andrew M.2ORCID,Behan Molly2,Domm William2,Yee Min2,Mayer-Pröschel Margot3,Martinez-Sobrido Luis4,O’Reilly Michael A.2ORCID

Affiliation:

1. Department of Microbiology and Immunology, School of Medicine and Dentistry, University of Rochester, Rochester, New York

2. Department of Pediatrics, School of Medicine and Dentistry, University of Rochester, Rochester, New York

3. Biomedical Genetics, School of Medicine and Dentistry, University of Rochester, Rochester, New York

4. Disease Intervention and Prevention Program, Texas Biomedical Research Institute, San Antonio, Texas

Abstract

Children and young adults with mutant forms of ataxia telangiectasia mutated (ATM), a kinase involved in DNA damage signaling and mitochondrial homeostasis, suffer from recurrent respiratory infections, immune deficiencies, and obstructive airways disease associated with disorganized airway epithelium. We previously showed in mice how Atm was required to mount a protective immune memory response to influenza A virus [IAV; Hong Kong/X31 (HKx31), H3N2]. Here, Atm wildtype (WT) and knockout (Atm-null) mice were used to investigate how Atm is required to regenerate the injured airway epithelium following IAV infection. When compared with WT mice, naive Atm-null mice had increased airway resistance and reduced lung compliance that worsened during infection before returning to naïve levels by 56 days postinfection (dpi). Although Atm-null lungs appeared pathologically normal before infection by histology, they developed an abnormal proximal airway epithelium after infection that contained E-cadherin+, Sox2+, and Cyp2f2+ cells lacking secretoglobin family 1 A member 1 (Scgb1a1) protein expression. Patchy and low expression of Scgb1a1 were eventually observed by 56 dpi. Genetic lineage tracing in HKx31-infected mice revealed club cells require Atm to rapidly and efficiently restore Scgb1a1 expression in proximal airways. Since Scgb1a1 is an immunomodulatory protein that protects the lung against a multitude of respiratory challenges, failure to efficiently restore its expression may contribute to the respiratory diseases seen in individuals with ataxia telangiectasia.

Funder

HHS | NIH | National Institute of Allergy and Infectious Diseases

HHS | NIH | National Heart, Lung, and Blood Institute

HHS | NIH | National Institute of Environmental Health Sciences

Action for A-T

HHS | NIH | National Institute of General Medical Sciences

HHS | NIH | National Institute of Neurological Disorders and Stroke

U.S. Department of Defense

Publisher

American Physiological Society

Subject

Cell Biology,Physiology (medical),Pulmonary and Respiratory Medicine,Physiology

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