Local association of Trypanosoma cruzi chronic infection foci and enteric neuropathic lesions at the tissue micro-domain scale.
Local association of Trypanosoma cruzi chronic infection foci and enteric neuropathic lesions at the tissue micro-domain scale.
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DOI：
10.1371/journal.ppat.1009864
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发表时间：
2021-08
期刊：
影响因子：
6.7
通讯作者：
Lewis MD
中科院分区：
文献类型：
--
作者：
Khan AA;Langston HC;Costa FC;Olmo F;Taylor MC;McCann CJ;Kelly JM;Lewis MD
消化性恰加斯病（DCD）是由克氏锥虫感染引起的肠道神经病。发病机制知之甚少，缺乏一个强大的，预测性的动物模型阻碍了研究。我们筛选了一系列的小鼠模型，使用胃肠示踪剂测定和体内感染成像系统，以发现一个子集，表现出慢性消化道运输功能障碍和显着保留粪便在饱腹和禁食条件。结肠是一个特定的网站，这两个组织寄生虫的持久性，延迟运输和肌间神经元的戏剧性损失所揭示的整装免疫荧光分析。因此，DCD小鼠重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慢性感染病灶的位置，然后在组织微区中使用荧光成像来揭示感染和肠神经系统病变的共定位。这表明T.结肠中的cruzi-宿主相互作用驱动DCD发病机制，表明抗寄生虫化疗对慢性疾病进展的疗效值得进一步临床前研究。查加斯病（美洲锥虫病）是由原生动物寄生虫克氏锥虫引起的。查加斯病有两种类型，心脏型和消化型;有些患者有两种症状。这种寄生虫是如何引起消化系统疾病的，目前还知之甚少。众所周知，肠道神经系统的损伤是一个重要因素，但目前尚不清楚这种损伤在感染过程中何时何地发生，以及为什么只有一部分感染者会出现这种结果。我们研究了小鼠的感染，发现了寄生虫和小鼠的某些组合，这些组合表现出与人类消化恰加斯病患者相似的症状，包括专门局限于结肠的寄生虫病问题。使用经过基因工程改造的寄生虫，可以发出生物发光和荧光，我们随着时间的推移跟踪感染，并能够分析结肠壁肌肉组织深处的罕见感染细胞。我们发现在最初感染后6个月，在与这些感染灶相同的位置有受损神经元的证据。我们的研究结果表明，消化性恰加斯病可能是由于慢性感染和炎症而发生的，这可能会改变治疗方法。
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. Chagas disease (American trypanosomiasis) is caused by the protozoan parasite Trypanosoma cruzi. Chagas disease has two types, the cardiac form and the digestive form; some patients have symptoms of both. How the parasite causes digestive disease is poorly understood. It is known that damage to the gut’s nervous system is an important factor, but it has been unclear exactly where and when this damage occurs during the course of an infection and also why only a subset of infected people suffer from this outcome. We studied infections in mice and found certain combinations of strains of parasites and mice that exhibited symptoms similar to human digestive Chagas patients, including a problem with peristalsis that localised specifically to the colon. Using parasites that were genetically engineered to emit both bioluminescent and fluorescent light, we tracked infections over time and were able to analyse rare infected cells deep within the muscle tissue of the wall of the colon. We found evidence of damaged neurons in the same location as these infection foci over 6 months after initial infection. Our results show that digestive Chagas disease probably develops as a result of chronic infection and inflammation, which potentially changes approaches to treatment.
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影响因子：
3.7
作者：
do Carmo Neto JR;Vinicius da Silva M;Braga YLL;Florencio da Costa AW;Fonseca SG;Nagib PRA;Nunes Celes MR;Oliveira MAP;Machado JR
通讯作者：
Machado JR
影响因子：
3.8
作者：
Costa FC;Francisco AF;Jayawardhana S;Calderano SG;Lewis MD;Olmo F;Beneke T;Gluenz E;Sunter J;Dean S;Kelly JM;Taylor MC
通讯作者：
Taylor MC
影响因子：
2
作者：
de Souza AP;Sieberg R;Li H;Cahill HR;Zhao D;Araújo-Jorge TC;Tanowitz HB;Jelicks LA
通讯作者：
Jelicks LA
影响因子：
2.4
作者：
da Silveira, ABM;Arantes, RME;Reis, DD
通讯作者：
Reis, DD
影响因子：
2
作者：
Florez, Oscar;Esper, Jhonatan;Gonzalez Rugeles, Clara Isabel
通讯作者：
Gonzalez Rugeles, Clara Isabel