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Increased susceptibility of airway epithelial cells from ataxia-telangiectasia to S. pneumoniae infection due to oxidative damage and impaired innate immunity.

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-? (inflammasome-independent) and a decreased level of the inflammasome-dependent cytokine IL-? 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.

SUBMITTER: Yeo AJ

PROVIDER: S-EPMC6385340 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Increased susceptibility of airway epithelial cells from ataxia-telangiectasia to S. pneumoniae infection due to oxidative damage and impaired innate immunity.

Yeo Abrey J AJ Henningham Anna A Fantino Emmanuelle E Galbraith Sally S Krause Lutz L Wainwright Claire E CE Sly Peter D PD Lavin Martin F MF

Scientific reports 20190222 1

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. Patie ...[more]

PMID: 30796268

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Project description:Ataxia-telangiectasia (AT) and Nijmegen breakage syndrome (NBS) belong to a group of primary immunodeficiency diseases (PI) characterized by premature aging, cerebral degeneration, immunoglobulin deficiency and higher cancer susceptibility. Despite the fact that oxidative stress has been demonstrated in vitro and in animal models of AT and NBS, the involvement of redox homeostasis disorders is still unclear in the in vivo phenotype of AT and NBS patients. Our study is the first to compare both enzymatic and non-enzymatic antioxidants as well as oxidative damage between AT and NBS subjects. Twenty two Caucasian children with AT and twelve patients with NBS were studied. Enzymatic and non-enzymatic antioxidants - glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase-1 (SOD) and uric acid (UA); redox status-total antioxidant capacity (TAC) and ferric reducing ability of plasma (FRAP); and oxidative damage products-8-hydroxy-2'-deoxyguanosine (8-OHdG), advanced glycation end products (AGE), advanced oxidation protein products (AOPP), 4-hydroxynonenal (4-HNE) protein adducts, and 8-isoprostanes (8-isop) were evaluated in serum or plasma samples. We showed that CAT, SOD and UA were significantly increased, while TAC and FRAP levels were statistically lower in the plasma of AT patients compared to controls. In NBS patients, only CAT activity was significantly elevated, while TAC was significantly decreased as compared to healthy children. We also showed higher oxidative damage to DNA (↑8-OHdG), proteins (↑AGE, ↑AOPP), and lipids (↑4-HNE, ↑8-isop) in both AT and NBS patients. Interestingly, we did not demonstrate any significant differences in the antioxidant defense and oxidative damage between AT and NBS patients. However, in AT children, we showed a positive correlation between 8-OHdG and the α-fetoprotein level as well as a negative correlation between 8-OHdG and IgA. In NBS, AGE was positively correlated with IgM and negatively with the IgG level. Summarizing, we demonstrated an imbalance in cellular redox homeostasis and higher oxidative damage in AT and NBS patients. Despite an increase in the activity/concentration of some antioxidants, the total antioxidant capacity is overwhelmed in children with AT and NBS and predisposes them to more considerable oxidative damage. Oxidative stress may play a major role in AT and NBS phenotype.

Project description:Patients with ataxia-telangiectasia (A-T) suffer from progressive cerebellar ataxia, immunodeficiency, respiratory failure, and cancer susceptibility. From a clinical point of view, A-T patients with IgA deficiency show more symptoms and may have a poorer prognosis. In this study, we analyzed mortality and immunity data of 659 A-T patients with regard to IgA deficiency collected from the European Society for Immunodeficiencies (ESID) registry and from 66 patients with classical A-T who attended at the Frankfurt Goethe-University between 2012 and 2018. We studied peripheral B- and T-cell subsets and T-cell repertoire of the Frankfurt cohort and survival rates of all A-T patients in the ESID registry. Patients with A-T have significant alterations in their lymphocyte phenotypes. All subsets (CD3, CD4, CD8, CD19, CD4/CD45RA, and CD8/CD45RA) were significantly diminished compared to standard values. Patients with IgA deficiency (n = 35) had significantly lower lymphocyte counts compared to A-T patients without IgA deficiency (n = 31) due to a further decrease of naïve CD4 T-cells, central memory CD4 cells, and regulatory T-cells. Although both patient groups showed affected TCR-ß repertoires compared to controls, no differences could be detected between patients with and without IgA deficiency. Overall survival of patients with IgA deficiency was significantly diminished. For the first time, our data show that patients with IgA deficiency have significantly lower lymphocyte counts and subsets, which are accompanied with reduced survival, compared to A-T patients without IgA deficiency. IgA, a simple surrogate marker, is indicating the poorest prognosis for classical A-T patients. Both non-interventional clinical trials were registered at clinicaltrials.gov 2012 (Susceptibility to infections in ataxia-telangiectasia; NCT02345135) and 2017 (Susceptibility to Infections, tumor risk and liver disease in patients with ataxia-telangiectasia; NCT03357978).

Dataset Information

Increased susceptibility of airway epithelial cells from ataxia-telangiectasia to S. pneumoniae infection due to oxidative damage and impaired innate immunity.

Publications

Increased susceptibility of airway epithelial cells from ataxia-telangiectasia to S. pneumoniae infection due to oxidative damage and impaired innate immunity.

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