CFTR Protects against Mycobacterium abscessus Infection by Fine-Tuning Host Oxidative Defenses.
CFTR Protects against Mycobacterium abscessus Infection by Fine-Tuning Host Oxidative Defenses.
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DOI：
10.1016/j.celrep.2019.01.071
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发表时间：
2019-02-12
期刊：
影响因子：
8.8
通讯作者：
Kremer, Laurent
中科院分区：
文献类型：
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作者：
Bernut, Audrey;Dupont, Christian;Kremer, Laurent
囊性纤维化（CF）是一种由缺陷性CF跨膜传导调节因子（CFTR）引起的遗传性疾病，由快速生长的分枝杆菌（Mycobacterium dumessus）引起的感染在CF中越来越普遍。然而，功能失调的CFTR和易感染猪支原体之间的潜在联系仍然未知。在此，我们利用CFTR缺失的斑马鱼模型，重现CF免疫发病机制，以研究CFTR在先天免疫中对M. messusus感染的贡献。CFTR的缺失通过受损的NADPH氧化酶依赖性细胞内生长限制和减少的中性粒细胞趋化性增加对感染的易感性，这两者共同损害肉芽肿形成和完整性。因此，巨噬细胞的细胞外增殖迅速扩大，诱导脓肿形成并引起致命感染。由于这些表型在其他分枝杆菌中没有观察到，我们的研究结果强调了CFTR通过建立有效的氧化反应在分枝杆菌免疫控制中的关键和特定作用。
Infection by rapidly growing Mycobacterium abscessus is increasingly prevalent in cystic fibrosis (CF), a genetic disease caused by a defective CF transmembrane conductance regulator (CFTR). However, the potential link between a dysfunctional CFTR and vulnerability to M.abscessus infection remains unknown. Herein, we exploit a CFTR-depleted zebrafish model, recapitulating CF immuno-pathogenesis, to study the contribution of CFTR in innate immunity against M.abscessus infection. Loss of CFTR increases susceptibility to infection through impaired NADPH oxidase-dependent restriction of intracellular growth and reduced neutrophil chemotaxis, which together compromise granuloma formation and integrity. As a consequence, extracellular multiplication of M.abscessus expands rapidly, inducing abscess formation and causing lethal infections. Because these phenotypes are not observed with other mycobacteria, our findings highlight the crucial and specific role of CFTR in the immune control of M.abscessus by mounting effective oxidative responses.