Peroxidasin contributes to lung host defense by direct binding and killing of gram-negative bacteria.
Peroxidasin contributes to lung host defense by direct binding and killing of gram-negative bacteria.
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DOI：
10.1371/journal.ppat.1007026
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发表时间：
2018-05
期刊：
影响因子：
6.7
通讯作者：
Cheng G
中科院分区：
文献类型：
--
作者：
Shi R;Cao Z;Li H;Graw J;Zhang G;Thannickal VJ;Cheng G
先天免疫识别通常由宿主模式识别受体和病原体相关分子模式的相互作用介导;这触发了一系列下游信号传导事件，促进杀死和消除入侵病原体。在这份报告中，我们提供了第一个证据表明，过氧化物酶（PXDN;也称为血管过氧化物酶-1）直接结合到革兰氏阴性菌和介导杀菌活性，从而有助于肺部宿主防御。PXDN含有五个富含亮氨酸的重复序列和四个免疫球蛋白结构域，这允许其与革兰氏阴性菌的膜组分脂多糖相互作用。PXDN的杀菌活性通过其产生次卤酸的能力介导。在假单胞菌肺部感染的鼠模型中，PXDN的缺乏导致不能根除铜绿假单胞菌并增加死亡率。这些观察结果表明，PXDN介导以前未被认识到的宿主防御功能，对革兰氏阴性细菌病原体。多细胞生物已经进化出多种多样的宿主防御机制，以抵抗入侵的病原体。在这些机制中，对病原体的识别经典地由宿主和病原体的相互作用介导，其触发一系列下游反应以消除病原体。选择性和直接与病原体相互作用并杀死病原体的蛋白质尚未得到很好的鉴定。在本研究中，我们已经确定了PXDN介导的细菌杀伤的双重功能机制。我们提供了PXDN直接结合革兰氏阴性菌和介导杀菌活性的新作用的第一个证据。PXDN在肺组织中高表达，并分泌到肺上皮衬里液中，由LPS和TNF-α诱导。PXDN突变小鼠在铜绿假单胞菌的急性肺部感染模型中显示肺宿主防御受损。PXDN是一类具有识别和杀灭病原体双重功能的新型杀菌酶。具有双重功能的酶的这一发现对于先天免疫的新概念理解以及治疗开发具有重要意义。
Innate immune recognition is classically mediated by the interaction of host pattern-recognition receptors and pathogen-associated molecular patterns; this triggers a series of downstream signaling events that facilitate killing and elimination of invading pathogens. In this report, we provide the first evidence that peroxidasin (PXDN; also known as vascular peroxidase-1) directly binds to gram-negative bacteria and mediates bactericidal activity, thus, contributing to lung host defense. PXDN contains five leucine-rich repeats and four immunoglobulin domains, which allows for its interaction with lipopolysaccharide, a membrane component of gram-negative bacteria. Bactericidal activity of PXDN is mediated via its capacity to generate hypohalous acids. Deficiency of PXDN results in a failure to eradicate Pseudomonas aeruginosa and increased mortality in a murine model of Pseudomonas lung infection. These observations indicate that PXDN mediates previously unrecognized host defense functions against gram-negative bacterial pathogens. Multicellular organisms have evolved diversified host defense mechanisms for survival against invading pathogens. Of the mechanisms, the recognition of pathogens is classically mediated by the interaction of host and pathogen, which triggers a series of downstream responses to eliminate pathogens. Proteins that both selectively and directly interact with and kill pathogens are not well identified. In current study, we have determined the dual-function mechanisms of PXDN -mediated bacteria killing. We provide the first evidence for a novel role of PXDN in directly binding to gram-negative bacteria and mediating bactericidal activity. PXDN is highly expressed in the lung and secreted into epithelial lining fluid of the lung, and is induced by LPS and TNF-α. PXDN mutant mice reveal impaired lung host defense in acute lung infection model of P. aeruginosa. PXDN is a new class of bactericidal enzyme with dual function of recognizing and killing pathogens. This finding of an enzyme with dual function has important implications for new conceptual understanding of the innate immunity as well as for therapeutic development.
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DOI：
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发表时间：
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影响因子：
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