Peroxidasin contributes to lung host defense by direct binding and killing of gram-negative bacteria

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.固有免疫识别（innate immune recognition）经典上由宿主模式识别受体（pattern-recognition receptors）与病原体相关分子模式（pathogen-associated molecular patterns）的相互作用所介导，该过程可触发一系列下游信号事件，促进入侵病原体的杀灭与清除。在本研究中，我们首次提供证据表明，过氧化物酶（peroxidasin，PXDN，又称血管过氧化物酶1）可直接结合革兰氏阴性菌（gram-negative bacteria）并介导杀菌活性（bactericidal activity），从而参与肺部宿主防御。PXDN包含5个亮氨酸重复序列（leucine-rich repeats）与4个免疫球蛋白结构域（immunoglobulin domains），这使其能够与革兰氏阴性菌的膜组分脂多糖（lipopolysaccharide）相结合。PXDN的杀菌活性通过其生成次卤酸（hypohalous acids）的能力实现。在铜绿假单胞菌（Pseudomonas aeruginosa）肺部感染的小鼠模型中，PXDN的缺失会导致无法清除该病原体，并使小鼠死亡率升高。上述观察结果表明，PXDN介导了此前未被发现的抗革兰氏阴性菌病原体的宿主防御功能。