Abstract
Respiratory disease is a major cause of morbidity and mortality in patients with ataxia-telangiectasia (A-T) who are prone to recurrent sinopulmonary infections, bronchiectasis, pulmonary fibrosis, and pulmonary failure. Upper airway infections are common in patients and S. pneumoniae is associated with these infections. We demonstrate here that the upper airway microbiome in patients with A-T is different from that to healthy controls, with S. pneumoniae detected largely in patients only. Patient-specific airway epithelial cells and differentiated air-liquid interface cultures derived from these were hypersensitive to infection which was at least in part due to oxidative damage since it was partially reversed by catalase. We also observed increased levels of the pro-inflammatory cytokines IL-8 and TNF-α (inflammasome-independent) and a decreased level of the inflammasome-dependent cytokine IL-β in patient cells. Further investigation revealed that the ASC-Caspase 1 signalling pathway was defective in A-T airway epithelial cells. These data suggest that the heightened susceptibility of these cells to S. pneumoniae infection is due to both increased oxidative damage and a defect in inflammasome activation, and has implications for lung disease in these patients.
Highlights
Respiratory disease is a major cause of morbidity and mortality in patients with ataxia-telangiectasia (A-T) who are prone to recurrent sinopulmonary infections, bronchiectasis, pulmonary fibrosis, and pulmonary failure
We have previously demonstrated that the ataxia-telangiectasia mutated (ATM) kinase is activated by H2O2, that generates reactive oxygen species (ROS), by a mechanism that is distinct from that caused by DNA double strand breaks (DSB), providing evidence that it is central to cellular antioxidant defence[13]
No significant differences were detected in the Streptococceae family between A-T and healthy control samples (Fig. 1B), the presence of S. pneumoniae was detected by PCR in all ten patients with A-T and was largely undetected in controls being evident at this level of detection in only three healthy controls out of ten (Fig. 1C)
Summary
Respiratory disease is a major cause of morbidity and mortality in patients with ataxia-telangiectasia (A-T) who are prone to recurrent sinopulmonary infections, bronchiectasis, pulmonary fibrosis, and pulmonary failure. Further investigation revealed that the ASC-Caspase 1 signalling pathway was defective in A-T airway epithelial cells These data suggest that the heightened susceptibility of these cells to S. pneumoniae infection is due to both increased oxidative damage and a defect in inflammasome activation, and has implications for lung disease in these patients. We have previously demonstrated that the ATM kinase is activated by H2O2, that generates ROS, by a mechanism that is distinct from that caused by DNA double strand breaks (DSB), providing evidence that it is central to cellular antioxidant defence[13] These data suggest that A-T cells would show increased sensitivity to oxidative stress but this was not directly demonstrated until recently. We describe the effects of S. pneumoniae infection in differentiated ALI cells from patients with A-T of and investigated the mechanism of cell killing after infection of these cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
