Diurnal differences in intracellular replication within splenic macrophages correlates with the outcome of pneumococcal infection
Diurnal differences in intracellular replication within splenic macrophages correlates with the outcome of pneumococcal infection
复制标题
脾巨噬细胞内细胞内复制的昼夜差异与肺炎球菌感染的结果相关
DOI：
10.1101/2022.01.30.478422
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Hames R
中科院分区：
文献类型：
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作者：
Hames R
昼夜节律影响细菌感染的进展和严重程度，包括由肺炎链球菌引起的感染，但造成这种现象的机制在很大程度上仍然难以捉摸。随着我们对s的复制作用的理解的进展。脾巨噬细胞内的肺炎，我们试图研究脾脏内的事件是否与侵袭性肺炎球菌感染的不同结果相关。利用小鼠侵袭性肺炎球菌病（IPD）模型，我们报告了小鼠活跃期（zeitgeber时间15；光照周期开始后15h，暗周期开始后3h）感染导致败血症发作明显快于静息期（zeitgeber时间3；光照周期开始后3h）感染。这与活动期感染小鼠在早期时间点脾脏内的肺炎球菌负荷明显高于静止期感染小鼠相关。这些脾脏的全切片共聚焦显微镜分析显示，肺炎球菌的数量明显高于边缘区嗜金属巨噬细胞（MMMs），已知其允许细胞内肺炎球菌复制，这是败血症发病的先决条件。与休眠期感染小鼠相比，活跃期感染小鼠mmmm内的肺炎球菌簇更丰富，并且随着时间的推移，其大小会增加，而休眠期感染小鼠的大小会减少，并且在mmmm中存在的比例较低。在将肺炎球菌重新注入血液后，活跃期感染小鼠的血清IL-6和TNF-α浓度显著升高，这一现象发生在此之前。这些数据通过将侵袭性肺炎球菌感染的易感性与MMMs允许被吞噬细菌持续和复制的倾向变化联系起来，极大地提高了我们对肺炎球菌感染的基础知识。这些发现还概述了一种罕见的情况，即生物体昼夜节律周期的活跃阶段在控制侵袭性感染方面起着看似适得其反的作用。
Circadian rhythms affect the progression and severity of bacterial infections including those caused byStreptococcus pneumoniae, but the mechanisms responsible for this phenomenon remain largely elusive. Following advances in our understanding of the role of replication ofS. pneumoniaewithin splenic macrophages, we sought to investigate whether events within the spleen correlate with differential outcomes of invasive pneumococcal infection. Utilising murine invasive pneumococcal disease (IPD) models, here we report that infection during the murine active phase (zeitgeber time 15; 15h after start of light cycle, 3h after start of dark cycle) resulted in significantly faster onset of septicaemia compared to rest phase (zeitgeber time 3; 3h after start of light cycle) infection. This correlated with significantly higher pneumococcal burden within the spleen of active phase-infected mice at early time points compared to rest phase-infected mice. Whole-section confocal microscopy analysis of these spleens revealed that the number of pneumococci is significantly higher exclusively within marginal zone metallophilic macrophages (MMMs) known to allow intracellular pneumococcal replication as a prerequisite step to the onset of septicaemia. Pneumococcal clusters within MMMs were more abundant and increased in size over time in active phase-infected mice compared to those in rest phase-infected mice which decreased in size and were present in a lower percentage of MMMs. This phenomenon preceded significantly higher levels of bacteraemia alongside serum IL-6 and TNF-α concentrations in active phase-infected mice following re-seeding of pneumococci into the blood. These data greatly advance our fundamental knowledge of pneumococcal infection by linking susceptibility to invasive pneumococcal infection to variation in the propensity of MMMs to allow persistence and replication of phagocytosed bacteria. These findings also outline a somewhat rare scenario whereby the active phase of an organism’s circadian cycle plays a seemingly counterproductive role in the control of invasive infection.