Faral-Tello Paula, Greif Gonzalo, Romero Selva, Cabrera Andrés, Oviedo Cristina, González Telma, Libisch Gabriela, Arévalo Ana Paula, Varela Belén, Verdes José Manuel, Crispo Martina, Basmadjián Yester, Robello Carlos
Laboratorio de Interacciones Hospedero Patógeno/UBM, Institut Pasteur de Montevideo, Montevideo, Uruguay.
Departamento de Parasitología y Micología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
Microbiol Spectr. 2023 Feb 14;11(2):e0250422. doi: 10.1128/spectrum.02504-22.
Chagas disease is mainly transmitted by vertical transmission (VT) in nonendemic areas and in endemic areas where vector control programs have been successful. For the present study, we isolated natural Trypanosoma cruzi strains vertically transmitted through three generations and proceeded to study their molecular mechanism of VT using mice. No parasitemia was detected in immunocompetent mice, but the parasites were able to induce an immune response and colonize different organs. VT experiments revealed that infection with different strains did not affect mating, pregnancy, or resorption, but despite low parasitemia, VT strains reached the placenta and resulted in higher vertical transmission rates than strains of either moderate or high virulence. While the virulent strain modulated more than 2,500 placental genes, VT strains modulated 150, and only 29 genes are shared between them. VT strains downregulated genes associated with cell division and replication and upregulated immunomodulatory genes, leading to anti-inflammatory responses and tolerance. The virulent strain stimulated a strong proinflammatory immune response, and this molecular footprint correlated with histopathological analyses. We describe a unique placental response regarding the passage of T. cruzi VT isolates across the maternal-fetal interphase, challenging the current knowledge derived mainly from studies of laboratory-adapted or highly virulent strains. The main findings of this study are that we determined that there are Trypanosoma cruzi strains adapted to transplacental transmission and completely different from the commonly used laboratory reference strains. This implies a specific strategy for the vertical transmission of Chagas disease. It is impressive that the strains specialized for vertical transmission modify the gene expression of the placenta in a totally different way than the reference strains. In addition, we describe isolates of T. cruzi that cannot be transmitted transplacentally. Taken together, these results open up new insights into the molecular mechanisms of this insect vector-independent transmission form.
恰加斯病主要通过垂直传播（VT）在非流行地区以及病媒控制项目取得成功的流行地区传播。在本研究中，我们分离出经三代垂直传播的天然克氏锥虫菌株，并使用小鼠研究其垂直传播的分子机制。在免疫功能正常的小鼠中未检测到寄生虫血症，但这些寄生虫能够诱导免疫反应并在不同器官中定植。垂直传播实验表明，感染不同菌株并不影响交配、怀孕或吸收，但尽管寄生虫血症较低，垂直传播菌株仍可到达胎盘，且垂直传播率高于中等或高毒力菌株。虽然毒力菌株调节了超过2500个胎盘基因，但垂直传播菌株调节了150个，它们之间仅共享29个基因。垂直传播菌株下调了与细胞分裂和复制相关的基因，并上调了免疫调节基因，从而导致抗炎反应和耐受性。毒力菌株刺激了强烈的促炎免疫反应，这种分子特征与组织病理学分析相关。我们描述了关于克氏锥虫垂直传播分离株穿过母胎界面的独特胎盘反应，挑战了目前主要来自对实验室适应株或高毒力菌株研究的知识。本研究的主要发现是，我们确定存在适应经胎盘传播的克氏锥虫菌株，且与常用的实验室参考菌株完全不同。这意味着恰加斯病垂直传播的一种特定策略。令人印象深刻的是，专门用于垂直传播的菌株以与参考菌株完全不同的方式改变胎盘的基因表达。此外，我们描述了不能经胎盘传播的克氏锥虫分离株。综上所述，这些结果为这种不依赖昆虫媒介的传播形式的分子机制开辟了新的见解。
