Department of Infection Biology, London School of Hygiene and Tropical Medicine, London, United Kingdom.
Stem Cells and Regenerative Medicine, University College London, Institute of Child Health, London, United Kingdom.
PLoS Pathog. 2021 Aug 23;17(8):e1009864. doi: 10.1371/journal.ppat.1009864. eCollection 2021 Aug.
Digestive Chagas disease (DCD) is an enteric neuropathy caused by Trypanosoma cruzi infection. The mechanism of pathogenesis is poorly understood and the lack of a robust, predictive animal model has held back research. We screened a series of mouse models using gastrointestinal tracer assays and in vivo infection imaging systems to discover a subset exhibiting chronic digestive transit dysfunction and significant retention of faeces in both sated and fasted conditions. The colon was a specific site of both tissue parasite persistence, delayed transit and dramatic loss of myenteric neurons as revealed by whole-mount immunofluorescence analysis. DCD mice therefore recapitulated key clinical manifestations of human disease. We also exploited dual reporter transgenic parasites to home in on locations of rare chronic infection foci in the colon by ex vivo bioluminescence imaging and then used fluorescence imaging in tissue microdomains to reveal co-localisation of infection and enteric nervous system lesions. This indicates that long-term T. cruzi-host interactions in the colon drive DCD pathogenesis, suggesting that the efficacy of anti-parasitic chemotherapy against chronic disease progression warrants further pre-clinical investigation.
消化道恰加斯病（DCD）是一种由克氏锥虫感染引起的肠神经病。发病机制尚不清楚，缺乏强大的、可预测的动物模型阻碍了研究的进展。我们使用胃肠道示踪剂检测和体内感染成像系统筛选了一系列小鼠模型，发现了一部分小鼠在饱腹和禁食状态下均表现出慢性消化道转运功能障碍和粪便明显滞留。通过全组织免疫荧光分析显示，结肠是组织寄生虫持续存在、转运延迟以及肠神经元大量丢失的特定部位。因此，DCD 小鼠再现了人类疾病的关键临床表现。我们还利用双报告基因转基因寄生虫通过离体生物发光成像来定位结肠中罕见的慢性感染灶，并在组织微区利用荧光成像来揭示感染与肠神经系统病变的共定位。这表明结肠中寄生虫与宿主的长期相互作用导致了 DCD 的发病机制，提示抗寄生虫化疗对慢性疾病进展的疗效值得进一步进行临床前研究。
