Ataxia telangiectasia mutated is required for efficient proximal airway epithelial cell regeneration following influenza A virus infection
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 01, 2022
- Source ID
- 10.1152/ajplung.00378.2021
Entities
People
- Andrew M. Dylag
- Luis Martinez-Sobrido
- Margot Mayer-pröschel
- Michael A O'Reilly
- Min Yee
- Molly Behan
- Rachel Warren
- William Domm
Organizations
- National Heart, Lung, and Blood Institute
- National Institute of Allergy and Infectious Diseases
- National Institute of Environmental Health Sciences
- National Institute of General Medical Sciences
- National Institute of Neurological Disorders and Stroke
- United States Department of Defense
- University of Rochester