Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, Kentucky, USA.
Infect Immun. 2012 Aug;80(8):2835-46. doi: 10.1128/IAI.05707-11. Epub 2012 Jun 4.
Pneumocystis pneumonia was first diagnosed in malnourished children and has more recently been found in children with upper respiratory symptoms. We previously reported that there is a significant delay in the immune response in newborn mice infected with Pneumocystis compared to adults (Garvy BA, Harmsen AG, Infect. Immun. 64:3987-3992, 1996, and Garvy BA, Qureshi M, J. Immunol. 165:6480-6486, 2000). This delay is characterized by the failure of neonatal lungs to upregulate proinflammatory cytokines and attract T cells into the alveoli. Here, we report that regardless of the age at which we infected the mice, they failed to mount an inflammatory response in the alveolar spaces until they were 21 days of age or older. Anti-inflammatory cytokines had some role in dampening inflammation, since interleukin-10 (IL-10)-deficient pups cleared Pneumocystis faster than wild-type pups and the neutralization of transforming growth factor beta (TGF-β) with specific antibody enhanced T cell migration into the lungs at later time points. However, the clearance kinetics were similar to those of control pups, suggesting that there is an intrinsic deficiency in the ability of innate immunity to control Pneumocystis. We found, using an adoptive transfer strategy, that the lung environment contributes to association of Pneumocystis organisms with alveolar macrophages, implying no intrinsic deficiency in the binding of Pneumocystis by neonatal macrophages. Using both in vivo and in vitro assays, we found that Pneumocystis organisms were less able to stimulate translocation of NF-κB to the nucleus of alveolar macrophages from neonatal mice. These data indicate that there is an early unresponsiveness of neonatal alveolar macrophages to Pneumocystis infection that is both intrinsic and related to the immunosuppressive environment found in neonatal lungs.
卡氏肺孢子虫肺炎最初被诊断于营养不良的儿童中，近来在出现上呼吸道症状的儿童中也被发现。我们之前曾报道过，与成年鼠相比，新生鼠感染卡氏肺孢子虫后，其免疫反应存在显著延迟（Garvy BA, Harmsen AG, Infect. Immun. 64:3987-3992, 1996，和 Garvy BA, Qureshi M, J. Immunol. 165:6480-6486, 2000）。这种延迟的特征是新生鼠肺部无法上调促炎细胞因子，并将 T 细胞吸引到肺泡中。在这里，我们报告说，无论我们何时感染这些小鼠，它们在 21 日龄或更老时都无法在肺泡空间中引发炎症反应。抗炎细胞因子在抑制炎症方面发挥了一定作用，因为白细胞介素-10（IL-10）缺陷型幼鼠比野生型幼鼠清除卡氏肺孢子虫的速度更快，并且用特异性抗体中和转化生长因子-β（TGF-β）可以在稍后的时间点增强 T 细胞向肺部的迁移。然而，清除动力学与对照幼鼠相似，这表明固有免疫控制卡氏肺孢子虫的能力存在内在缺陷。我们使用过继转移策略发现，肺部环境有助于卡氏肺孢子虫与肺泡巨噬细胞的结合，这表明新生巨噬细胞结合卡氏肺孢子虫不存在固有缺陷。通过体内和体外测定，我们发现卡氏肺孢子虫对新生鼠肺泡巨噬细胞 NF-κB 核易位的刺激作用较弱。这些数据表明，新生肺泡巨噬细胞对卡氏肺孢子虫感染的早期反应存在内在缺陷，且与新生肺部中发现的免疫抑制环境有关。
