Understanding and manipulating how Trypanosoma cruzi infects its triatomine insect hosts

了解和操纵克氏锥虫如何感染其锥蝽昆虫宿主

• 批准号: BB/Y001125/1
• 负责人: Paul Dyson
• 金额: $ 49.71万
• 依托单位: Swansea University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FY001125%2F1
• 关键词: Understanding; manipulating; how; Trypanosoma; cruzi

Chagas disease, also known as American trypanosomiasis, results in approximately 10,000 deaths annually. It is caused by the protozoan parasite Trypanosoma cruzi. An estimated 6 to 7 million people worldwide are infected with T. cruzi but, despite these large numbers, Chagas disease is a neglected tropical disease for which there are no successful vaccines. The disease is endemic to 21 continental Latin American countries and is mostly transmitted when humans come into contact with faeces and/or urine of infected blood-sucking triatomine bugs, primarily Rhodnius prolixus and Triatoma infestans (vector-borne transmission). We know that the parasite utilises various mechanisms to evade the mammalian host immune system including producing signalling molecules termed lipid mediators that serve to dampen the host immune response. However, just how the parasite establishes itself in the insect host has not been elucidated. Our preliminary data indicates that the production of lipid mediators by insect-infective forms of the parasite likely plays a vital role and exploring this is a focus of the current proposal. We will identify these lipid mediators and investigate how they regulate insect immunity. A critical step is the initial stage of infection, when the parasite establishes itself in the insect gut. Competing gut bacteria create a hostile environment for the parasite. To counter this, the parasite hacks the insect immune system so that the insect produces antimicrobial proteins to reduce the bacterial population in the gut. With BBSRC support, we previously developed and patented a novel technology to repurpose gut bacteria from these insects so that they continuously produce genetic information that can silence specific genes of the insect host. We now intend to apply this technology to target how the insect immune system is regulated. Our goal is to exploit this to counter how the parasite hacks the insect immune response. If successful, this approach will reduce parasite numbers in the insect which will, in turn, lower disease transmission by the vector. The project will demonstrate whether this approach has potential to be used as part of our response to combat climate-change associated increases in vector-borne disease transmission in general.

恰加斯病，也称为美洲锥虫病，每年导致约 10,000 人死亡。它是由原生动物寄生虫克氏锥虫引起的。据估计，全世界有 6 至 700 万人感染克氏锥虫，但尽管感染人数众多，南美锥虫病仍是一种被忽视的热带疾病，目前还没有成功的疫苗。该疾病是 21 个拉丁美洲大陆国家的地方病，主要是在人类接触受感染的吸血锥蝽（主要是长红锥蝽和致病锥蝽）的粪便和/或尿液时传播（媒介传播）。我们知道，寄生虫利用各种机制来逃避哺乳动物宿主免疫系统，包括产生称为脂质介质的信号分子，用于抑制宿主免疫反应。然而，寄生虫如何在昆虫宿主中定居尚不清楚。我们的初步数据表明，昆虫感染形式的寄生虫产生的脂质介质可能发挥着至关重要的作用，探索这一点是当前提案的重点。我们将鉴定这些脂质介质并研究它们如何调节昆虫免疫力。关键的一步是感染的初始阶段，此时寄生虫在昆虫肠道中扎根。相互竞争的肠道细菌为寄生虫创造了一个敌对的环境。为了解决这个问题，寄生虫会攻击昆虫的免疫系统，使昆虫产生抗菌蛋白，以减少肠道中的细菌数量。在 BBSRC 的支持下，我们之前开发了一项新技术并获得了专利，该技术可以重新利用这些昆虫的肠道细菌，使其不断产生可以沉默昆虫宿主特定基因的遗传信息。我们现在打算应用这项技术来研究昆虫免疫系统的调节方式。我们的目标是利用这一点来对抗寄生虫如何破坏昆虫的免疫反应。如果成功，这种方法将减少昆虫体内的寄生虫数量，从而减少媒介的疾病传播。该项目将证明这种方法是否有可能被用作我们应对气候变化相关的媒介传播疾病传播增加的应对措施的一部分。