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首页> 美国卫生研究院文献>other >The Interaction of Pneumocystis with the C-Type Lectin Receptor Mincle Exerts a Significant Role in Host Defense Against Infection
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The Interaction of Pneumocystis with the C-Type Lectin Receptor Mincle Exerts a Significant Role in Host Defense Against Infection

机译：肺囊虫与C型凝集素受体微粒的相互作用在宿主抗感染中发挥了重要作用

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Pneumocystis pneumonia (PCP) remains a major cause of morbidity and mortality within immunocompromised patients. In this study, we examined the potential role of Mincle (Macrophage inducible C-type lectin) for host defense against Pneumocystis. Binding assays implementing soluble Mincle Carbohydrate Recognition Domain (CRD) fusion proteins demonstrated binding to intact Pneumocystis carinii (Pc) as well as to organism homogenates, and purified major surface glycoprotein/glycoprotein A derived from the organism. Additional experiments showed that rats with Pneumocystis pneumonia (PCP) expressed increased Mincle mRNA levels. Mouse macrophages over-expressing Mincle displayed increased binding to Pc life forms and enhanced protein tyrosine phosphorylation. The binding of Pc to Mincle resulted in activation of Fc receptor γ (FcRγ) mediated cell signaling. RNA silencing of Mincle in mouse macrophages resulted in decreased activation of Syk kinase after Pc challenge, critical in downstream inflammatory signaling. Mincle deficient CD-4 depleted (Mincle−/−) mice showing a significant defect in organism clearance from the lungs with higher organism burdens and altered lung cytokine responses during Pneumocystis murina (Pm) pneumonia. Interestingly, Mincle−/− did not demonstrate worsened survival during PCP compared to wild type mice, despite the markedly increased organism burdens. This may be related to increased expression of anti-inflammatory factors such as IL-1Ra during infection in the Mincle−/− mice. Of note, the Pm infected Mincle−/− mice demonstrated increased expression of known C-type lectin receptors Dectin-1, Dectin-2, and MCL compared to infected wild type mice. Taken together, these data support a significant role for Mincle in Pneumocystis modulating host defense during infection.
机译：肺囊虫性肺炎（PCP）仍然是免疫功能低下患者发病和死亡的主要原因。在这项研究中，我们检查了Mincle（巨噬细胞诱导型C型凝集素）在抵抗肺孢子虫的宿主防御中的潜在作用。实施可溶性Mincle碳水化合物识别域（CRD）融合蛋白的结合试验证明与完整的卡氏肺孢子虫（Pc）以及与生物匀浆的结合，以及纯化自该生物的主要表面糖蛋白/糖蛋白A。其他实验表明，患有肺孢子虫肺炎（PCP）的大鼠表达的Mincle mRNA水平升高。过表达Mincle的小鼠巨噬细胞显示出与Pc生命形式的结合增加，蛋白质酪氨酸磷酸化增强。 Pc与Mincle的结合导致Fc受体γ（FcRγ）介导的细胞信号传导的激活。小鼠巨噬细胞中Mincle的RNA沉默导致Pc攻击后Syk激酶的激活减少，这对下游炎症信号传导至关重要。缺乏Mincle的CD-4耗竭的（Mincle -// ）小鼠表现出明显的缺陷，其肺部微生物清除能力较高，而肺炎单胞菌（Pm）肺炎时肺细胞因子的响应发生了变化。有趣的是，尽管生物体负担明显增加，但与野生型小鼠相比，Mincle -/-在PCP期间并未表现出恶化的生存。这可能与Mincle -/-小鼠感染期间抗炎因子（例如IL-1Ra）的表达增加有关。值得注意的是，与受感染的野生型小鼠相比，经Pm感染的Mincle -/-小鼠表现出已知C型凝集素受体Dectin-1，Dectin-2和MCL的表达增加。综上所述，这些数据支持Mincle在肺孢子菌感染期间调节宿主防御的重要作用。

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