Department of Genetics and Genome Biology, University of Leicester, Leicester, United Kingdom.
Centre for Inflammation and Tissue Repair, UCL Respiratory, Division of Medicine, University College Medical School, London, United Kingdom.
Front Immunol. 2022 Jun 2;13:907461. doi: 10.3389/fimmu.2022.907461. eCollection 2022.
Circadian rhythms affect the progression and severity of bacterial infections including those caused by , but the mechanisms responsible for this phenomenon remain largely elusive. Following advances in our understanding of the role of replication of within 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.
昼夜节律会影响细菌感染的进展和严重程度，包括由 引起的感染，但导致这种现象的机制在很大程度上仍难以捉摸。在我们对 在内脏巨噬细胞中复制作用的理解取得进展之后，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，我们在此报告称，在小鼠活动期（ Zeitgeber 时间 15；光周期开始后 15 小时，暗周期开始后 3 小时）感染会导致菌血症更快发作，与休息期（ Zeitgeber 时间 3；光周期开始后 3 小时）感染相比。这与活动期感染小鼠脾脏内的肺炎球菌负荷在早期明显高于休息期感染小鼠相关。对这些脾脏进行全切片共聚焦显微镜分析显示，与休息期感染小鼠相比，活动期感染小鼠脾脏内的边缘区嗜金属巨噬细胞（MMM）中肺炎球菌数量明显更高，而 MMM 是允许肺炎球菌在细胞内复制的，这是菌血症发作的先决条件。与休息期感染小鼠相比，活动期感染小鼠的 MMM 内肺炎球菌簇的数量更多且随时间增加，体积增大，而休息期感染小鼠的 MMM 内肺炎球菌簇体积减小，并且存在于 MMM 的百分比降低。这一现象发生在活动期感染小鼠的菌血症水平、血清 IL-6 和 TNF-α 浓度显著升高之前，这些小鼠的肺炎球菌重新定植到血液中。这些数据通过将对侵袭性肺炎球菌感染的易感性与 MMM 允许吞噬细菌持续存在和复制的倾向的变化联系起来，极大地推进了我们对肺炎球菌感染的基本认识。这些发现还概述了一种罕见的情况，即生物体昼夜节律的活动期在控制侵袭性感染方面似乎起到了适得其反的作用。
