Alveolar Macrophages in Neonatal Mice Are Inherently Unresponsive to Pneumocystis murina Infection
Alveolar Macrophages in Neonatal Mice Are Inherently Unresponsive to Pneumocystis murina Infection
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DOI：
10.1128/iai.05707-11
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发表时间：
2012-08-01
影响因子：
3.1
通讯作者：
Garvy, Beth A.
中科院分区：
文献类型：
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作者：
Kurkjian, Cathryn;Hollifield, Melissa;Garvy, Beth A.
肺孢子虫肺炎最初在营养不良的儿童中被诊断出来，最近在有上呼吸道症状的儿童中被发现。我们先前报道，与成年小鼠相比，感染肺孢子虫的新生小鼠的免疫应答显著延迟（Garvy BA，Harmsen AG，Infect. Immun. 64：3987-3992，1996和Garvy BA，Qureshi M，J. Immunol·165：6480-6486，2000）。这种延迟的特征在于新生儿肺不能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，无论我们感染小鼠的年龄如何，它们都未能在肺泡腔中产生炎症反应，直到它们21天或更大。抗炎性细胞因子在抑制炎症方面具有一定作用，因为白细胞介素-10（IL-10）缺陷的幼仔比野生型幼仔更快地清除肺孢子虫，并且用特异性抗体中和转化生长因子β（TGF-β）在稍后的时间点增强T细胞迁移到肺部。然而，清除动力学与对照组幼仔相似，表明先天免疫控制肺孢子虫的能力存在内在缺陷。我们发现，采用过继转移策略，肺环境有助于肺孢子虫与肺泡巨噬细胞的结合，这意味着新生儿巨噬细胞对肺孢子虫的结合没有内在缺陷。使用在体内和体外试验，我们发现，肺孢子虫生物体能够刺激NF-κ B B易位到新生小鼠肺泡巨噬细胞的细胞核。这些数据表明，新生儿肺泡巨噬细胞对肺孢子虫感染的早期无反应性，这既是内在的，也与新生儿肺中发现的免疫抑制环境有关。
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 wildtype pups and the neutralization of transforming growth factor beta (TGF-beta) 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-kappa B 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.