Hsp90 as a modulator of pathogenicity, virulence and transmission in veterinary infections caused by Theileria and Babesia species

就广泛的人类贫困而言，南亚的农村地区是地球上最贫困的地区之一。仅在印度，就有4亿人可能被认为生活在极端贫困中。这些人中的许多人依靠奶牛获得食物和收入。增加畜牧业产量是促进减贫的重要途径。然而，轮状泰勒氏菌等病原体的存在阻碍了畜牧业的生产力。仅在印度，环毛虫感染造成的损失估计每年约为4亿美元。在印度，由于对这种寄生虫的研究较少，因此很难给出感染巴贝斯虫造成的潜在损失的数字，但感染人数正在上升，可能是由于气候变化和扁虱媒介传播的增加。最近的一项血清流行率研究表明，北方邦和旁遮普邦流行区的牛感染水平为56%。这两种寄生虫都是通过壁虱传播的，它们会在壁虱吃血的时候感染牛。感染可能导致死亡，这对拥有少量动物的贫穷农民来说是毁灭性的。那些在感染中幸存下来的动物表现出生产力的显著下降。因此，迫切需要新的控制措施来打破感染循环。对于热带泰勒虫病和巴贝斯虫病，目前的控制要么依靠使用活疫苗，要么依靠药物治疗，要么依靠应用杀螨剂，所有这些都受到各种限制。质量控制和冷链维护方面的困难，限制了向印度农村地区的大量动物运送活疫苗。有可能恢复毒力，并且已经发生了通过巴贝西亚疫苗传播病毒病原体的情况。现有的活疫苗不能诱导无菌免疫，接种疫苗的动物很可能受到感染，从而显著降低它们的生产力。虽然杂交牛对感染的抵抗力更强，但这是有回报的，因为相对于欧洲牛来说，产量减少了，而且杂交小牛仍然容易感染疾病。扑热息痛等药物可以杀死泰勒氏菌，但价格昂贵；此外，世界各地都有抗药性的报道，而且抗药性是一个日益严重的威胁。治疗巴贝斯虫感染的药物也同样有限：咪唑是英国唯一获得许可的药物，需要很长的停药时间。在世界上的一些地区，杀螨剂被广泛用于控制虱子，但抗药性的发展和与这些化学品相关的环境破坏限制了它们的长期用途。对其他顶端复合体寄生虫的研究表明，Hsp90在分化、感染和毒力方面发挥着重要作用。HSP90在许多其他系统中是一种具有良好特性的分子，重要的是，许多特定的小分子抑制剂都是可用的。环状泰勒虫感染细胞具有肿瘤细胞的一些特性(无控制的增殖和转移能力)，由于Hsp90在许多癌细胞中发挥着维持转化表型的重要作用，我们认为它可能是理解泰勒氏菌感染致病性的关键。此外，专为治疗肿瘤而设计的Hsp90小分子抑制剂的问世，为将这些化合物用于重要的家畜感染提供了潜力。

In terms of wide-scale human poverty, rural regions of South Asia are some of the most afflicted places on earth. In India alone, 400 million people may be considered to live in extreme poverty. Many of these people are dependent on dairy cattle for food and income. Increased production from livestock represents an important way to contribute to poverty reduction. However livestock productivity is impeded by the presence of pathogens such as Theileria annulata. In India alone, losses due to T. annulata infection are estimated to be in the region of $400 million per annum. It is more difficult to put a figure on potential losses due to Babesia infection in India as this parasite is less well studied, but infections are on the rise, possibly due to climate change and the increased spread of the tick vector. A recent sero-prevalence study indicated infection levels of 56% in cattle from endemic zones of Uttar Pradesh and Punjab. Both parasites are transmitted by ticks and infect cattle when the tick takes a blood meal. Infection can result in death, which is devastating for poor farmers with a small number of animals. Those animals that survive infection show significant reductions in productivity. Thus new control measures are desperately needed to break the cycle of infection. For both tropical theileriosis and babesiosis, current control relies either on the use of a live vaccine, drug treatment, or the application of acaricides, all of which suffer from various limitations. Difficulties with quality control and the maintenance of a cold-chain, restricts delivery of the live vaccines to large numbers of animals across rural India. Reversion to virulence is possible and transmission of viral pathogens via the Babesia vaccine has occurred. The available live vaccines do not induce a sterile immunity, and vaccinated animals are likely to become infected, significantly reducing their productivity. While crossbred cattle are more resistant to infection, there is a pay-off because production relative to European cattle is reduced, and crossbred calves are still susceptible to disease. Drugs, such as buparvaquone, kill Theileria but are expensive; additionally drug resistance has been reported from different parts of the world and is a growing threat. Drugs for the treatment of Babesia infections are similarly limited: Imizol, the only licensed drug in the UK requires a long withdrawal period. In some parts of the world acarcidides are extensively used to control ticks, but the development of resistance and the environmental damage associated with these chemicals limits their long-term usefulness. Studies in other apicomplexan parasites have demonstrated an essential role for Hsp90 in differentiation, infection and virulence. Hsp90 is a well-characterised molecule in many other systems and importantly many specific small molecule inhibitors are available. T. annulata infected cells adopt several characteristics of tumour cells (uncontrolled proliferation, ability to metastasize) and, as Hsp90 plays an important role in many cancer cells in maintaining the transformed phenotype, we believe that it may hold the key to understanding the pathogenicity of Theileria infection. In addition, the availability of small molecule inhibitors of Hsp90, designed for use in tumours, offers the potential for repurposing of these compounds to important infections of livestock.