College of Medical, Veterinary and Life Sciences, Institute of Infection, Immunity and Inflammation, Glasgow, United Kingdom.
Institute of Biodiversity, Animal Health and Comparative Medicine, Glasgow, United Kingdom.
PLoS Negl Trop Dis. 2021 Nov 11;15(11):e0009892. doi: 10.1371/journal.pntd.0009892. eCollection 2021 Nov.
Human African trypanosomiasis (HAT), also known as sleeping sickness, is a major cause of mortality and morbidity in sub-Saharan Africa. We hypothesised that recent findings of neurological features and parasite brain infiltration occurring at much earlier stages in HAT than previously thought could be explained by early activation of host genetic programmes controlling CNS disease. Accordingly, a transcriptomal analysis was performed on brain tissue at 0, 7, 14, 21 and 28dpi from the HAT CD1/GVR35 mouse model. Up to 21dpi, most parasites are restricted to the blood and lymphatic system. Thereafter the trypanosomes enter the brain initiating the encephalitic stage. Analysis of ten different time point Comparison pairings, revealed a dynamic transcriptome comprising four message populations. All 7dpi Comparisons had by far more differentially expressed genes compared to all others. Prior to invasion of the parenchyma, by 7dpi, ~2,000 genes were up-regulated, denoted [7dpi↑] in contrast to a down regulated population [7dpi↓] also numbering ~2,000. However, by 14dpi both patterns had returned to around the pre-infected levels. The third, [28dpi↑] featured over three hundred transcripts which had increased modestly up to14dpi, thereafter were significantly up-regulated and peaked at 28dpi. The fourth, a minor population, [7dpi↑-28dpi↑], had similar elevated levels at 7dpi and 28dpi. KEGG and GO enrichment analysis predicted a diverse phenotype by 7dpi with changes to innate and adaptive immunity, a Type I interferon response, neurotransmission, synaptic plasticity, pleiotropic signalling, circadian activity and vascular permeability without disruption of the blood brain barrier. This key observation is consistent with recent rodent model neuroinvasion studies and clinical reports of Stage 1 HAT patients exhibiting CNS symptoms. Together, these findings challenge the strict Stage1/Stage2 phenotypic demarcation in HAT and show that that significant neurological, and immune changes can be detected prior to the onset of CNS disease.
人类非洲锥虫病（HAT），也称为昏睡病，是撒哈拉以南非洲地区主要的死亡和发病原因。我们假设，最近发现的 HAT 中神经特征和寄生虫脑浸润发生在比以前认为的更早的阶段，可以通过控制中枢神经系统疾病的宿主遗传程序的早期激活来解释。因此，对 HAT CD1/GVR35 小鼠模型的脑组织在 0、7、14、21 和 28dpi 进行了转录组分析。在 21dpi 之前，大多数寄生虫局限于血液和淋巴系统。此后，锥虫进入大脑，引发脑炎阶段。对十个不同时间点比较配对的分析显示，存在一个包含四个信息群体的动态转录组。与所有其他比较相比，7dpi 的所有比较迄今为止都有更多的差异表达基因。在实质入侵之前，到 7dpi 时，约有 2000 个基因上调，与下调群体[7dpi↓]形成对比，下调群体的数量也约为 2000 个。然而，到 14dpi 时，两个模式都回到了感染前的水平。第三个[28dpi↑]有超过 300 个转录物，在 14dpi 之前适度增加，此后显著上调并在 28dpi 时达到峰值。第四个，一个较小的群体[7dpi↑-28dpi↑]，在 7dpi 和 28dpi 时有类似的升高水平。KEGG 和 GO 富集分析预测，到 7dpi 时会出现多种表型变化，包括先天和适应性免疫、I 型干扰素反应、神经传递、突触可塑性、多效信号、昼夜活动和血管通透性变化，而血脑屏障不会被破坏。这一关键观察结果与最近的啮齿动物模型神经入侵研究和 HAT 阶段 1 患者出现中枢神经系统症状的临床报告一致。总之，这些发现对 HAT 中严格的 1 期/2 期表型划分提出了挑战，并表明在中枢神经系统疾病发作之前，可以检测到显著的神经和免疫变化。
