Neurogenômica, Imunopatologia, Instituto René Rachou (IRR), Fiocruz, Belo Horizonte, Brazil.
Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.
Front Immunol. 2024 Oct 14;15:1429157. doi: 10.3389/fimmu.2024.1429157. eCollection 2024.
Pneumococcal meningitis (PM) triggers apoptotic neuronal and progenitor cell death in the hippocampal dentate gyrus (DG), resulting in subsequent cognitive impairment. Microglia play a crucial role in PM-induced hippocampal damage. While the lasting effects of neonatal nutrition on health are well documented, the influence of early-life overfeeding on the host response to neuroinfections remains uncertain. This study aimed to examine whether neonatal overfeeding affects the outcome of PM in the hippocampus (HC).
Overfeeding was induced by adjusting litter size immediately after birth. On the eleventh day of life, rats were intracisternally injected with or saline, followed by euthanasia after 24 hours for brain dissection. Histological analysis evaluated apoptosis in the DG and the extent of inflammatory infiltrate in the hippocampal fissure, while microgliosis was assessed by immunohistochemistry. The hippocampal transcriptome was analyzed using RNAseq, and the mRNA levels of specific inflammatory biomarkers were evaluated via RT-qPCR.
Overfed rats exhibited 40.5% greater body mass compared to their normal-fed counterparts. Intriguingly, PM-induced apoptosis in the DG was 50% lower in overfed rats. This effect was accompanied by significant alterations in the hippocampal transcriptional profile, particularly the lack of activation of the pathway in overfed infected animals. RT-qPCR analysis of and examination of Iba1-immunostained cells revealed mild microgliosis in the HC of infected-overfed animals. This reduced microglial reaction may be attributed to the diminished activation of interferon signaling pathways, as disclosed by the transcriptome analysis, potentially preventing microglial priming. Additionally, evidence of reduced neuroinflammation in overfed rats with PM was observed through the milder activation of pathways associated with Toll-like receptors, interleukins, and chemokine signaling. Furthermore, overfed animals exhibited increased transcription of proinflammatory and anti-inflammatory genes, with the latter showing higher expression even in the absence of PM, suggesting a priming effect of overfeeding on hippocampal immune cells.
This study sheds light on the complex interplay between early-life overfeeding, immune response, and neuroprotection in infant rats with PM. The findings demonstrate the neuroprotective impact of early-life overfeeding in the context of PM, linked to the modulation of microglial function.
肺炎球菌性脑膜炎（PM）可在海马齿状回（DG）引发凋亡性神经元和祖细胞死亡，从而导致随后的认知障碍。小胶质细胞在 PM 诱导的海马损伤中起着至关重要的作用。虽然新生儿营养对健康的持久影响已有充分记录，但早期过度喂养对宿主对神经感染反应的影响仍不确定。本研究旨在探讨新生儿过度喂养是否会影响 PM 在海马（HC）中的结果。
通过在出生后立即调整窝仔数来诱导过度喂养。在第 11 天，大鼠经脑室内注射 或生理盐水，24 小时后安乐死进行脑解剖。组织学分析评估 DG 中的细胞凋亡和海马裂中的炎症浸润程度，而通过免疫组织化学评估小胶质细胞增生。使用 RNAseq 分析海马转录组，并通过 RT-qPCR 评估特定炎症生物标志物的 mRNA 水平。
与正常喂养的大鼠相比，过度喂养的大鼠体重增加了 40.5%。有趣的是，PM 诱导的 DG 细胞凋亡在过度喂养的大鼠中降低了 50%。这种影响伴随着海马转录谱的显著改变，特别是在感染过度喂养动物中缺乏 途径的激活。感染过度喂养动物的 和 Iba1 免疫染色细胞的 RT-qPCR 分析显示 HC 中的小胶质细胞轻度增生。这种减少的小胶质细胞反应可能归因于干扰素信号通路的激活减少，正如转录组分析所揭示的那样，这可能防止了小胶质细胞的启动。此外，通过观察与 Toll 样受体、白细胞介素和趋化因子信号相关的途径的轻度激活，在患有 PM 的过度喂养大鼠中观察到神经炎症减轻。此外，过度喂养的动物表现出促炎 和抗炎 基因的转录增加，即使在没有 PM 的情况下，后者的表达也更高，这表明过度喂养对海马免疫细胞具有启动作用。
本研究阐明了新生儿期过度喂养、免疫反应和婴儿期 PM 大鼠神经保护之间的复杂相互作用。研究结果表明，PM 背景下早期过度喂养具有神经保护作用，与小胶质细胞功能的调节有关。
