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首页> 外文期刊>Microbial Pathogenesis >Evidence for the requirement of T cell costimulation in the pathogenesis of natural Pneumocystis carinii pulmonary infection
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Evidence for the requirement of T cell costimulation in the pathogenesis of natural Pneumocystis carinii pulmonary infection

机译：在天然卡氏肺囊虫肺部感染的发病机理中需要T细胞共刺激的证据

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Pneumocystis carinii pneumonia (PCP) is a frequent and serious opportunistic infection in immunocompromized patients. Although the pathogenesis of PCP-mediated lung injury is poorly understood, a central involvement of host inflammatory responses has been implicated. We have found that while the loss of specific T cell costimulatory signals increases susceptibility to the spontaneous pneumocystis infection, PCP-induced pulmonary injury (and subsequent morbidity and mortality) involves other intact costimulatory pathways. Mice that are genetically deficient for the costimulatory receptor CD154 (CD154 knockout (ko) mice) spontaneously developed PCP, consistent with the increased susceptibility of X-linked hyper IgM syndrome patients (caused by CD154 gene mutations) to P. carinii infection. In these mice PCP was manifested by progressive weight loss, dyspnea and death. In contrast, CD154 ko mice also genetically lacking ICAM1 (CD154 ko x ICAM 1 ko) or CD28 (CD154 ko x CD28 ko) costimulatory receptors had later onset of weight loss and significantly prolonged survival. Although onset of infection and age-matched P. carinii organism burden were equivalent, the CD154 single knockout mice had evidence of greater pulmonary inflammation vs. the double ko's. These findings suggest that costimulation-dependent T cell-mediated inflammation plays an important role in both susceptibility to and pathogenesis of PCP, and may identify potential molecular targets for novel immunomodulatory treatment approaches.
机译：卡氏肺孢子虫肺炎（PCP）是免疫功能低下患者的一种频繁且严重的机会性感染。尽管对PCP介导的肺损伤的发病机理了解甚少，但已牵涉到宿主炎症反应的中心参与。我们已经发现，虽然特异性T细胞共刺激信号的丢失增加了对自发性肺孢子虫感染的敏感性，但PCP诱导的肺损伤（以及随后的发病率和死亡率）涉及其他完整的共刺激途径。遗传缺陷共刺激受体CD154（CD154基因敲除（ko）小鼠）的小鼠自发发展为PCP，这与X连锁性高IgM综合征患者（由CD154基因突变引起）对卡氏疟原虫感染的敏感性增加有关。在这些小鼠中，PCP表现为进行性的体重减轻，呼吸困难和死亡。相比之下，在基因上也缺乏ICAM1（CD154 ko x ICAM 1 ko）或CD28（CD154 ko x CD28 ko）共刺激受体的CD154 ko小鼠后来体重减轻且存活时间显着延长。尽管感染的发作和年龄匹配的卡氏疟原虫生物体的负担相当，但CD154单基因敲除小鼠的肺部炎症比双ko小鼠更大。这些发现表明，协同刺激依赖性T细胞介导的炎症在对PCP的易感性和发病机理中都起着重要作用，并且可能为新型免疫调节治疗方法确定潜在的分子靶标。

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