Age-related differences in IL-1 signaling and capsule serotype affect persistence of Streptococcus pneumoniae colonization
Age-related differences in IL-1 signaling and capsule serotype affect persistence of Streptococcus pneumoniae colonization
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DOI：
10.1371/journal.ppat.1007396
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发表时间：
2018-10-01
期刊：
影响因子：
6.7
通讯作者：
Weiser, Jeffrey N.
中科院分区：
文献类型：
--
作者：
Kuipers, Kirsten;Lokken, Kristen L.;Weiser, Jeffrey N.
年轻是居住在上呼吸道（URT）的常见病原体长期定植的危险因素。为什么儿童呈现更持久的定植是未知的，并且相对而言，对导致持续定植的宿主-病原体相互作用的了解较少。为了确定婴儿期允许持续定植的因素，我们使用了肺炎链球菌定植的婴儿小鼠模型，其中上呼吸道粘膜表面的清除需要数周至数月。单一细菌因子，成孔毒素溶血素（Ply）的缺失，以及单一宿主因子，IL-1 α的缺失，导致更持久的定植。外源性给药Ply促进了IL-1的反应和清除，而IL-1 α经鼻处理足以降低定植密度。已知影响自然定植持续时间的主要因素包括宿主年龄和肺炎球菌荚膜血清型。未感染上呼吸道粘膜的qRT-PCR分析显示，与成年小鼠相比，幼鼠IL-1信号相关基因的基线表达降低。与这一观察结果一致，IL-1信号在成年小鼠的清除中起重要作用，但对幼鼠的早期定植没有影响。与年龄的影响相反，不同荚膜血清型的等基因构建体在定殖持久性方面存在差异，但诱导的IL-1反应相似。总之，这项工作强调了毒素诱导的IL-1 α反应在决定定植、清除和持续结果中的重要性。我们关于IL-1信号作为宿主年龄的功能的发现可能为儿童早期增加的易感性和更长时间的定植提供了解释。
Young age is a risk factor for prolonged colonization by common pathogens residing in their upper respiratory tract (URT). Why children present with more persistent colonization is unknown and there is relatively little insight into the host-pathogen interactions that contribute to persistent colonization. To identify factors permissive for persistent colonization during infancy, we utilized an infant mouse model of Streptococcus pneumoniae colonization in which clearance from the mucosal surface of the URT requires many weeks to months. Loss of a single bacterial factor, the pore-forming toxin pneumolysin (Ply), and loss of a single host factor, IL-1 alpha, led to more persistent colonization. Exogenous administration of Ply promoted IL-1 responses and clearance, and intranasal treatment with IL-1 alpha was sufficient to reduce colonization density. Major factors known to affect the duration of natural colonization include host age and pneumococcal capsular serotype. qRT-PCR analysis of the uninfected URT mucosa showed reduced baseline expression of genes involved in IL-1 signaling in infant compared to adult mice. In line with this observation, IL-1 signaling was important in initiating clearance in adult mice but had no effect on early colonization of infant mice. In contrast to the effect of age, isogenic constructs of different capsular serotype showed differences in colonization persistence but induced similar IL-1 responses. Altogether, this work underscores the importance of toxin-induced IL-1 alpha responses in determining the outcome of colonization, clearance versus persistence. Our findings about IL-1 signaling as a function of host age may provide an explanation for the increased susceptibility and more prolonged colonization during early childhood.