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首页> 外文期刊>Infection and immunity >Epithelial Anion Transporter Pendrin Contributes to Inflammatory Lung Pathology in Mouse Models of Bordetella pertussis Infection
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Epithelial Anion Transporter Pendrin Contributes to Inflammatory Lung Pathology in Mouse Models of Bordetella pertussis Infection

机译：百日咳博德特氏菌感染小鼠模型中上皮阴离子转运蛋白Pendrin有助于炎症性肺病理

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Pertussis disease, characterized by severe and prolonged coughing episodes, can progress to a critical stage with pulmonary inflammation and death in young infants. However, there are currently no effective treatments for pertussis. We previously studied the role of pertussis toxin (PT), an important Bordetella pertussis virulence factor, in lung transcriptional responses to B. pertussis infection in mouse models. One of the genes most highly upregulated in a PT-dependent manner encodes an epithelial transporter of bicarbonate, chloride, and thiocyanate, named pendrin, that contributes to asthma pathology. In this study, we found that pendrin expression is upregulated at both gene and protein levels in the lungs of B. pertussis-infected mice. Pendrin upregulation is associated with PT production by the bacteria and with interleukin-17A (IL-17A) production by the host. B. pertussis-infected pendrin knockout (KO) mice had higher lung bacterial loads than infected pendrin-expressing mice but had significantly reduced levels of lung inflammatory pathology. However, reduced pathology did not correlate with reduced inflammatory cytokine expression. Infected pendrin KO mice had higher levels of inflammatory cytokines and chemokines than infected pendrin-expressing mice, suggesting that these inflammatory mediators are less active in the airways in the absence of pendrin. In addition, treatment of B. pertussis-infected mice with the carbonic anhydrase inhibitor acetazolamide reduced lung inflammatory pathology without affecting pendrin synthesis or bacterial loads. Together these data suggest that PT contributes to pertussis pathology through the upregulation of pendrin, which promotes conditions favoring inflammatory pathology. Therefore, pendrin may represent a novel therapeutic target for treatment of pertussis disease.
机译：百日咳病的特征是剧烈和长时间的咳嗽发作，可发展到婴儿发炎和死亡的关键阶段。但是，目前尚无有效的百日咳治疗方法。我们先前研究了百日咳毒素（PT），一种重要的百日咳博德特氏菌致病因子，在小鼠模型中对百日咳博德特氏菌感染的肺转录反应中的作用。以PT依赖性方式最上调的基因之一编码碳酸氢盐，氯化物和硫氰酸盐的上皮转运蛋白，称为pendrin，其有助于哮喘病理。在这项研究中，我们发现在百日咳博德特氏菌感染小鼠的肺中，在基因和蛋白质水平上，Pendrin表达均被上调。酚的上调与细菌产生的PT和宿主产生的白介素17A（IL-17A）有关。百日咳杆菌感染的Pendrin基因敲除（KO）小鼠比感染Pendrin的小鼠具有更高的肺细菌负荷，但肺炎性病理水平明显降低。但是，病理学降低与炎性细胞因子表达降低无关。感染的Pendrin KO小鼠的炎症细胞因子和趋化因子水平高于感染的Pendrin表达的小鼠，这表明在缺少Pendrin的情况下，这些炎症介质在气道中的活性较低。另外，用碳酸酐酶抑制剂乙酰唑胺治疗感染百日咳博德特氏菌的小鼠可减少肺部炎症，而不会影响Pendrin的合成或细菌载量。这些数据加在一起表明PT通过上调Pendrin促进百日咳病理，这促进了有利于炎症病理的疾病。因此，Pendrin可能代表一种治疗百日咳疾病的新型治疗靶标。

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