Identification and function of mechanosensitive channels in Trypanosoma cruzi

摘要 查加斯病是一种人畜共患的热带疾病，由原生动物寄生虫克氏锥虫引起。 它在拉丁美洲流行，是世界上充血性心力衰竭的主要原因之一。历史上 与农村地区的贫困有关，病媒的移民和迁移正在改变流行病学， 这种疾病的发病率，美国的病例数量大幅增加就是证明。治疗受到限制 硝呋替莫和苄硝哒唑，这两种药物都是相对有毒的，疗效有限， FDA用于一般用途。 研究寄生虫的感知、适应和生存机制对防治寄生虫病具有重要意义。 确定选择性药物靶点，可导致消除寄生虫而不影响宿主 细胞在向不同生命阶段转化的过程中，T.克鲁兹发现， 它必须适应这些条件才能生存。机械敏感通道是阳离子通道，能够 检测膜张力的变化，并且通常由脂质双层的拉伸激活。他们 被认为是多种细胞和生物体中张力变化的主要传感器， 信号传导途径，驱动剪切调节、剪切应力感应和分化。虽然T.克鲁兹有一个 强大的能力，在各种环境中生存，分子的身份检测变化和引发 寄生虫的适应性反应仍然是未知的。先前的计算机模拟研究表明， T.克鲁兹我们的工作集中在两种类型的蛋白质：TcMscS，a 具有细菌小电导机械敏感通道所共有的结构特征的通道;和压电 通道，调节功能如细胞体积、剪切应力传感和运动性的大蛋白质。 我们认为，机械激活通道在感知和适应中起着重要作用， 环境条件T. cruzi，确定宿主细胞入侵的成功和宿主细胞的存活， 寄生虫分析了T. cruzi机械敏感通道表达谱和定位，补充 与电生理学研究将阐明激活和调制的机制，这些 proteins.此外，我们将探索与通道激活相关的信号通路的激活。 体内表达水平的遗传操作和表型分析将证明生理学上的差异。 TcMscS和TcPiezo通道在寄生虫中的作用，并将有助于建立其作为治疗药物的潜力 目标的

Abstract Chagas disease is a zoonotic tropical pathology, caused by the protozoan parasite Trypanosoma cruzi. Endemic in Latin America, it is one of the leading causes of congestive heart failure in the world. Historically associated with poverty in rural areas, immigration and relocation of the vectors are changing the epidemiology of the disease, as evidenced by a substantial increase in the number of cases in the US. Treatment is restricted to nifurtimox and benznidazole, both of which are relatively toxic, have limited efficacy and are not approved by the FDA for general use. The study of the mechanisms of sensing, adaptation and survival of the parasite is important for the identification of selective drug targets that can lead to the elimination of the parasite without affecting the host cells. During the transformation into different life stages, T. cruzi finds extreme fluctuations in environmental conditions to which it must adapt in order to survive. Mechanosensitive channels are cation channels able to detect changes in the tension of the membranes and are usually activated by stretch of the lipid bilayer. They are considered the primary sensors of tension changes in a multiplicity of cells and organisms, triggering signaling pathways that drive osmoregulation, shear stress sensing and differentiation. Although T. cruzi has a robust capacity to survive in various environments, the identity of the molecules detecting changes and eliciting adaptive responses in the parasites is still unknown. Previous in silico studies suggest the presence of several putative mechanosensitive channels in T. cruzi. We are focusing our work in two types of proteins: TcMscS, a channel with structural features shared by bacterial small conductance mechanosensitive channels; and Piezo channels, large proteins that regulate functions such as cell volume, shear stress sensing and motility. We propose that mechanically activated channels play an important role in sensing and adaptation to environmental conditions in T. cruzi, determining the success of the host cell invasion and the survival of the parasite. Analysis of T. cruzi mechanosensitive channels expression profiles and localization, complemented with electrophysiological studies will shed light about the mechanism of activation and modulation of these proteins. Additionally, we will explore the activation of signaling pathways linked to the activation of the channels. Genetic manipulation of the level of expression and phenotypic analysis in vivo will demonstrate the physiological role of TcMscS and TcPiezo channels in the parasites and will help establishing their potential as therapeutic targets.