The impact of gastrointestinal helminths on susceptibility to African trypanosome infections

非洲锥虫是细胞外原生动物寄生虫，通过采采蝇在哺乳动物之间传播。这些寄生虫在哺乳动物血液中引起慢性感染（非洲锥虫病），给非洲畜牧业造成经济压力。我们对非洲锥虫病的了解大多来自于单个寄生虫菌株对小鼠或牛的实验性传播。然而，在自然环境中，与同一宿主物种内的其他病原体共同感染是常见的。例如，在一些发展中国家，包括疟疾寄生虫、胃肠道蠕虫寄生虫、结核分枝杆菌和艾滋病毒在内的病原体可能影响多达三分之一的人口。越来越多的证据表明，与这些病原体合并感染可改变对其他重要病原体的易感性，并通过影响宿主免疫功能来影响疫苗效力。在英国，随着人口开始摆脱COVID-19限制，流感病毒合并感染对SARS-CoV-2冠状病毒易感性的影响尚不确定。与某些病原体合并感染也可能妨碍针对其他病原体的诊断测试的准确性。对小鼠的研究表明，对胃肠道蠕虫感染的免疫反应可以改变对许多其他细菌和病毒病原体的易感性，包括肠沙门氏菌血清型鼠伤寒沙门氏菌、啮齿柠檬酸杆菌和诺如病毒。虽然牛和水牛等牲畜经常接触胃肠道寄生虫，但对这些寄生虫的共同感染如何影响对非洲锥虫的易感性尚不清楚。因此，本项目的第一个主要目的是验证与胃肠道蠕虫共同感染显著影响非洲锥虫感染易感性的假设。在非洲锥虫感染期间，人体的巨噬细胞被激活以清除寄生虫。然而，这些促炎巨噬细胞对锥虫感染的过度反应可引起免疫病理并抑制抗原特异性免疫。相反，在蠕虫感染期间，巨噬细胞采用替代激活表型，在免疫调节和修复组织损伤中发挥重要作用。非洲锥虫感染是否能调节巨噬细胞极性和功能以应对蠕虫尚不清楚。因此，本项目的第二个主要目的是验证在非洲锥虫感染中诱导的强效促炎巨噬细胞反应对巨噬细胞修复肠道蠕虫造成的损伤的能力产生负面影响的假设。目前还没有针对非洲锥虫感染的疫苗，对常用的锥虫药物产生耐药性是一个持续存在的问题。彻底了解病原体合并感染等因素如何影响对非洲锥虫病的易感性，将有助于揭示有效干预和预防的新目标。本项目将利用导师实验室现有的小鼠胃肠道蠕虫和非洲锥虫感染模型。该项目汇集了几个重要的生物学学科，包括寄生虫学，粘膜免疫学和生物成像。这将为学生提供以下重要可转移技能的良好培训机会：体内生物学；最先进的能;细胞培养;转录组。

African trypanosomes are extracellular protozoan parasites that are transmitted between mammals by tsetse flies. These parasites cause chronic infections in the mammalian bloodstream (African trypanosomiasis), inflicting economic strain on African livestock industries. Much of our understanding of African trypanosomiasis is derived from experimental transmissions of individual parasite strains to mice or cattle. However, in natural settings co-infections with other pathogens within the same host species are common. For example, pathogens including malarial parasites, gastrointestinal helminth parasites, Mycobacterium tuberculosis and viruses such as HIV may affect up to a third of the human population in some developing countries. Increasing evidence shows that co-infection with these pathogens can alter susceptibility to other important pathogens, and influence vaccine efficacy by affecting host immune function. In the UK as the population begins to emerge from the COVID-19 restrictions, the impacts of influenza virus co-infection on susceptibility to the SARS-CoV-2 coronavirus are uncertain. Co-infection with some pathogens may also hinder the accuracy of diagnostic tests against other pathogens. Studies in mice show that the immune response to a gastrointestinal helminth infection can alter susceptibility to co-infection to many other bacterial and viral pathogens including Salmonella enterica serovar Typhimurium, Citrobacter rodentium and norovirus. Although livestock species such cattle and buffalo are regularly exposed to gastrointestinal helminth parasites, nothing is known of how co-infection with these parasites may affect susceptibility to African trypanosomes. Therefore, the first major aim of this project is to test the hypothesis that co-infection with gastrointestinal helminths significantly influences susceptibility to African trypanosome infections. During African trypanosome infections the body's macrophages are activated to clear the parasites. However, the over-reaction of these pro-inflammatory macrophages to the trypanosome infection can cause immunopathology and suppress antigen-specific immunity. Conversely, during helminth infections the macrophages adopt an alternatively-activated phenotype that plays an important role in immune regulation and repairing tissue damage. Whether African trypanosome infections can modulate macrophage polarity and function in response to helminths is unknown. Therefore, the second major aim of this project is to test the hypothesis that the potent pro-inflammatory macrophage response that is induced in African trypanosome infections negatively impacts on the ability of macrophages to repair the damage caused by helminths in the intestine. No vaccines are available against African trypanosome infections, and the development of resistance to commonly used trypanocidal drugs is a constant issue. A thorough understanding how factors such as pathogen co-infection can affect susceptibility to African trypanosomiasis will help reveal novel targets for effective intervention and prevention.This project will utilize mouse gastrointestinal helminth and African trypanosome infection models that are available in the supervisors' laboratories. The project brings together several important biological disciplines, including parasitology, mucosal immunology and bio-imaging. This will provide the student with excellent training opportunities in the following important transferable skills: in vivo biology; state-of-the-art bio-imaging; cell culture; transcriptomics.