Targeting cattle-borne zoonoses and cattle pathogens using a novel trypanosomatid-based delivery system.
Targeting cattle-borne zoonoses and cattle pathogens using a novel trypanosomatid-based delivery system.
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DOI：
10.1371/journal.ppat.1002340
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发表时间：
2011-10
期刊：
影响因子：
6.7
通讯作者：
Matthews KR
中科院分区：
文献类型：
--
作者：
Mott GA;Wilson R;Fernando A;Robinson A;MacGregor P;Kennedy D;Schaap D;Matthews JB;Matthews KR
锥虫寄生虫因其在整个非洲和南美洲引起的人类疾病而臭名昭着。然而，非致病性锥虫也在世界范围内发现，感染广泛的宿主。一个例子是泰氏锥虫（Megatrypanum），一种普遍存在的原生动物牛科动物，分布于全球。利用致病性锥虫的知识，我们开发了泰氏锥虫作为一种新的载体，将疫苗抗原和其他蛋白质输送给牛。T.已经优化并表达了异源蛋白质，所述异源蛋白质被靶向用于分泌或使用来自布氏锥虫的运输信号在细胞内部或表面特异性定位。在牛中，工程车辆可以建立在预先存在的天然T。theileri群体，保持长期和产生特异性免疫反应的表达巴氏杆菌抗原在保护水平。建立在对锥虫病原体几十年的基础研究基础上，泰氏锥虫提供了针对多种感染的巨大潜力，包括主要的牛源性人畜共患病，如大肠杆菌，沙门氏菌属，流产布鲁氏菌和分枝杆菌属。它还具有向牛提供治疗的潜力，包括保护人类免受牛锥虫感染的溶解因子。这可以通过保护非洲土著牛免受非洲锥虫病的侵害来减轻贫困。动质体目的单细胞寄生虫是造成人类和动物毁灭性疾病的原因，包括非洲锥虫病、恰加斯病和利什曼病。然而，也有许多种类的锥虫不会引起疾病，并在全球范围内分布。一个例子是泰氏锥虫（Megatrypanum），它仅限于牛科动物，在世界各地的牛群中普遍存在。这种微生物在细胞外长期存在于血液和组织中，对宿主健康或生产力没有任何不良影响。利用致病性锥虫的基因表达和蛋白质运输的知识，我们已经成功地开发了，从第一原则，锥虫theileri作为疫苗抗原和治疗的传递系统。T. theileri，并在体内评价了源自分歧Babelidae的疫苗抗原的递送。我们的结果表明T. theileri作为一种灵活且易于操作的蛋白质递送系统，适用于控制牛病原体和牛传播的人畜共患病。在一个值得注意的应用中，我们建议该系统可以允许表达牛血清锥虫溶解因子，通过杀死牲畜中的致病性锥虫，有可能减轻非洲的贫困。
Trypanosomatid parasites are notorious for the human diseases they cause throughout Africa and South America. However, non-pathogenic trypanosomatids are also found worldwide, infecting a wide range of hosts. One example is Trypanosoma (Megatrypanum) theileri, a ubiquitous protozoan commensal of bovids, which is distributed globally. Exploiting knowledge of pathogenic trypanosomatids, we have developed Trypanosoma theileri as a novel vehicle to deliver vaccine antigens and other proteins to cattle. Conditions for the growth and transfection of T. theileri have been optimised and expressed heterologous proteins targeted for secretion or specific localisation at the cell interior or surface using trafficking signals from Trypanosoma brucei. In cattle, the engineered vehicle could establish in the context of a pre-existing natural T. theileri population, was maintained long-term and generated specific immune responses to an expressed Babesia antigen at protective levels. Building on several decades of basic research into trypanosomatid pathogens, Trypanosoma theileri offers significant potential to target multiple infections, including major cattle-borne zoonoses such as Escherichia coli, Salmonella spp., Brucella abortus and Mycobacterium spp. It also has the potential to deliver therapeutics to cattle, including the lytic factor that protects humans from cattle trypanosomiasis. This could alleviate poverty by protecting indigenous African cattle from African trypanosomiasis. Single-celled parasites of the order Kinetoplastida are responsible for devastating diseases of humans and animals, including African trypanosomiasis, Chagas' disease and leishmaniasis. However, there are also many species of trypanosomatids that do not cause disease and are distributed globally. One example is Trypanosoma (Megatrypanum) theileri, which is restricted to bovids and ubiquitous in cattle herds worldwide. This organism is maintained extracellularly in the blood and tissues long-term without any observed ill effects on host health or productivity. Using knowledge of gene expression and protein trafficking in pathogenic trypanosomatids, we have successfully developed, from first principles, Trypanosoma theileri as a delivery system for vaccine antigens and therapeutics. Procedures for the growth, transfection and heterologous gene expression of T. theileri have been developed, and the delivery of a vaccine antigen derived from Babesia divergens evaluated in vivo. Our results demonstrate the ability of T. theileri to be used as a flexible and easily manipulated protein delivery system suitable for the control of cattle pathogens and cattle-borne zoonoses. In one notable application, we propose that the system could allow the expression of serum trypanolytic factors in cattle, with the potential to alleviate poverty in Africa through the killing of pathogenic trypanosomatids in livestock.
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