Immune Dysfunction in Ataxia Telangiectasia Mutated Lung Disease

High levels of oxygen stimulate the production of mitochondrial-derived reactive oxygen species that damage DNA and other molecules.  We have shown how epithelial cells defend against oxygen-induced DNA damage via the sequential activation of hSMG-1, a large phosphatidylinositol 3-kinase-like kinase involved in nonsense mediated mRNA decay, and the related kinase Ataxia-telangiectasia mutated (ATM), which recognizes DNA strand breaks. These two kinases phosphorylate many downstream substrates during hyperoxia, including the tumor suppressor p53. The p53 protein in turn stimulates transcription of the cell cycle inhibitor p21 that promotes survival of cells exposed to hyperoxia.

Interestingly, individuals with mutations in ATM suffer chronically from progressive neurologic deterioration, immune deficiencies, and cancer, but frequently succumb to recurrent respiratory infections through poorly understood mechanisms. Since influenza A viruses (IAV) are a significant environmental threat to A-T individuals, we infected wildtype (WT) and Atm-null mice harboring an exon 4 deletion of Atm with IAV (HKx31, H3N2) and investigated how loss of Atm impacted the host response to primary IAV infection.

Persistent peribronchial inflammation, changes in the proportions of macrophages, lymphocytes, and neutrophils, and reduced influenza-specific antibodies were observed in infected Atm-null mice compared to infected WT mice. Airways that normally regenerate with Scgb1a1+ Club cells were now lined with undefined epithelial cells and Krt5+ basal cells. When re-infected with IAV 8 weeks later, Atm-null mice lost more weight than infected WT mice suggesting they failed to develop sterilizing immunity during the first infection.

We are currently identifying how loss of Atm impairs the host response to infection by conditionally deleting the Atm gene in specific lung epithelial cells or circulating immune cells using Cre-mediated recombination.