Impaired Innate and Adaptive Immunity to Streptococcus pneumoniae and Its Effect on Colonization in an Infant Mouse Model
Impaired Innate and Adaptive Immunity to Streptococcus pneumoniae and Its Effect on Colonization in an Infant Mouse Model
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DOI：
10.1128/iai.00871-08
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发表时间：
2009-04-01
影响因子：
3.1
通讯作者：
Malley, Richard
中科院分区：
文献类型：
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作者：
Bogaert, Debby;Weinberger, Daniel;Malley, Richard
肺炎链球菌的定植和侵袭性疾病分别在三岁和一岁左右达到高峰，此后下降。虽然这些下降部分归因于通过自然暴露获得的免疫力，但先天免疫反应的成熟也可能涉及。一种粘膜给药的候选全细胞肺炎球菌疫苗（WCV）含有杀死的肺炎球菌抗原（WCA）和霍乱毒素佐剂，通过抗体独立和CD4(+) TH17细胞依赖的机制防止鼻内携带肺炎球菌。由于婴儿和儿童是该疫苗的关键目标人群，我们试图评估新生儿和婴儿小鼠对肺炎链球菌的免疫反应，并评估WCV是否对这些小鼠有效。与人类婴儿一样，幼鼠对肺炎链球菌鼻咽部定植的清除能力受损。在体外被杀死的肺炎球菌刺激的新生小鼠和幼龄小鼠的巨噬细胞中，细胞因子的产生显著减少，包括KC、粒细胞集落刺激因子、粒细胞-巨噬细胞集落刺激因子、巨噬细胞趋化蛋白1、白细胞介素-6 （IL-6）、IL-1 α、肿瘤坏死因子α和γ干扰素，而IL-10的表达与成年小鼠的巨噬细胞相比显著增加。当使用新生儿巨噬细胞代替成人巨噬细胞作为抗原提呈细胞时，成人免疫CD4(+) T细胞产生IL-17A的时间明显延迟。此外，与成年免疫小鼠的血液相比，在WCA刺激后，新生儿免疫小鼠的全血产生的IL-17A明显减少。尽管如此，单次免疫新生小鼠WCV可显著降低定植密度。总的来说，我们的数据表明新生儿和婴儿小鼠的先天和获得性细胞免疫反应都有损伤。然而，WCV在肺炎球菌攻击后可显著减少定植，这表明它在未成熟的免疫应答中可能仍然有效。
Streptococcus pneumoniae colonization and invasive disease peak around the third and first birthdays, respectively, and decline thereafter. While these declines are attributable in part to immunity acquired via natural exposure, maturation of innate immune responses may also be involved. A mucosally administered candidate whole-cell pneumococcal vaccine (WCV) containing killed pneumococcal antigen (WCA) plus a cholera toxin adjuvant protects against intranasal carriage of pneumococci by a mechanism that is antibody independent and CD4(+) TH17 cell dependent. Because infants and children are a key target population for this vaccine, we sought to evaluate the immune responses of neonatal and infant mice to S. pneumoniae and to assess whether the WCV would be effective in these mice. Like human infants, infant mice showed impaired clearance of nasopharyngeal colonization with S. pneumoniae. Macrophages from neonatal and infant mice stimulated with killed pneumococci in vitro showed significantly reduced cytokine production, including that of KC, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, macrophage chemoattractant protein 1, interleukin-6 (IL-6), IL-1 alpha, tumor necrosis factor alpha, and gamma interferon, whereas IL-10 expression was significantly increased compared to that in macrophages from adult mice. IL-17A production from adult immune CD4(+) T cells was significantly delayed when neonatal macrophages instead of adult macrophages were used as antigen-presenting cells. Moreover, whole blood from mice immunized as neonates with WCV produced significantly less IL-17A after stimulation with WCA than did blood from mice immunized as adults. Nonetheless, a single immunization of neonatal mice with WCV significantly reduced colonization density. Overall, our data suggest an impairment of both innate and acquired cellular immune responses in neonatal and infant mice. However, WCV confers a significant reduction in colonization following pneumococcal challenge, suggesting that it may still be effective in the setting of immature immune responses.