Are coinfections a threat to drug control programmes for livestock trypanosomes?

混合感染是否对家畜锥虫药物控制计划构成威胁？

• 批准号: BB/X013650/1
• 负责人: Keith Matthews
• 金额: $ 85.57万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX013650%2F1
• 关键词: coinfections; threat; drug; control; programmes

African trypanosomes cause substantial economic cost to livestock production in sub-Saharan Africa exacerbating poverty in afflicted regions. Three pathogenic species co-circulate, Trypanosoma brucei, Trypanosoma congolense and Trypanosoma vivax, with infections being managed by chemoprophylaxis and drug therapy. However, coinfections between the species are common and several literature reports and our own data indicate that coinfection between trypanosome species and strains can ameliorate disease pathology with respect to monoinfections with a single species or strain. This generates a risk in settings where there is differential drug sensitivity among coinfecting trypanosomes exposed to suboptimal dosing, or where drug resistance is present in some circulating parasite populations. Specifically, by reverting coinfections to monoinfections comprising only the more resistant strain or species, drug intervention may lead to enhanced pathology. Consequently, drug application may generate a perverse outcome of increased disease.In this proposal we will explore the interaction between coinfection, drug sensitivity and pathology in both a mouse model and disease-relevant livestock host. Specifically, we will:1. Engineer drug resistant and sensitive Trypanosoma brucei and Trypanosoma congolense, respectively, using a known molecular resistance/sensitivity mechanism for diminazene, the most commonly used therapy for livestock trypanosomes. Specifically, the diminazene resistance determinant TbAT1, a nucleoside transporter, will be deleted in T. brucei to generate resistant parasites and T. congolense will be engineered to heterologously express the T. brucei AT1 gene, generating a diminazene super-sensitive line. This will allow the precision removal of T. congolense in experimental coinfections with T. brucei for our studies, avoiding the complexity of variable diminazene sensitivities different wild type laboratory and field strains may exhibit.2. The engineered lines will be used to evaluate the impact of coinfection, or coinfection followed by diminazene induced monoinfections, on the proportion and distribution of the trypanosome populations and their pathology in mice. This will be achieved by quantitating parasite numbers for each species and reservoirs of T. brucei by IVIS imaging. Murine pathology will be scored by established criteria.3. The engineered lines will be used to test how coinfection, or coinfection followed by diminazene-induced monoinfections, affects parasite prevalence and pathology in the disease-relevant bovine host using unique and dedicated large animal containment facilities at Roslin Institute.The studies will determine the consequences for parasite prevalence and host pathology when a coinfection is redirected to a monoinfection through therapeutic intervention. This could be unexpectedly harmful for livestock health where differential resistance exists in mixed infection scenarios. Our experiments could prioritise epidemiological studies of this previously overlooked threat, and promote strategies to optimise dosing, or to treat diseased animals and sustain therapeutic efficacy. This would also accelerate the targeted adoption of alternative trypanocides as they become available.The potential for adverse impact of therapeutic intervention in coinfection settings is unanticipated among farmers and policymakers in sub-Saharan Africa and may have been overlooked or dismissed as anecdote. We will ensure our findings are disseminated to the scientific community, policymakers and famers through our planned outreach activities and collaborations focused on livestock trypanosomes. These include planned meetings, for example a meeting Morrison is organising in Tanzania in 2023, and collaborative work with the Bill and Melinda Gates Foundation, links with the International livestock research Institute in Kenya and ongoing field work in Africa.

非洲锥虫给撒哈拉以南非洲的畜牧业生产造成巨大的经济损失，加剧了受影响地区的贫困。布氏锥虫、刚果锥虫和间日锥虫这三种致病菌同时传播，感染可通过化学预防和药物治疗来控制。然而，物种之间的共感染很常见，一些文献报告和我们自己的数据表明，锥虫物种和菌株之间的共感染可以改善与单一物种或菌株的单一感染有关的疾病病理学。如果暴露于次优剂量的共感染锥虫之间存在不同的药物敏感性，或者某些循环寄生虫种群存在耐药性，这会产生风险。具体而言，通过将合并感染恢复为仅包含更具耐药性的菌株或物种的单一感染，药物干预可能会导致病理学增强。因此，药物应用可能会产生疾病增加的不良结果。在本提案中，我们将探讨小鼠模型和疾病相关牲畜宿主中的共感染、药物敏感性和病理学之间的相互作用。具体来说，我们将： 1．使用已知的二胺脒（家畜锥虫最常用的疗法）的分子抗性/敏感性机制，分别设计耐药和敏感的布氏锥虫和刚果锥虫。具体来说，二胺氮烯抗性决定子TbAT1（一种核苷转运蛋白）将在布氏锥虫中被删除，以产生抗性寄生虫，刚果锥虫将被工程改造以异源表达布氏锥虫AT1基因，产生二胺氮超敏感品系。这将允许在我们的研究中精确去除与布氏锥虫混合感染的刚果锥虫，避免不同野生型实验室和现场菌株可能表现出的可变二氨基氮烯敏感性的复杂性。2．这些工程系将用于评估双重感染或双重感染后二氨基氮烯诱导的单一感染对小鼠锥虫群体的比例和分布及其病理学的影响。这将通过 IVIS 成像对布氏锥虫每个物种和宿主的寄生虫数量进行定量来实现。小鼠病理学将按照既定标准进行评分。3．这些工程系将用于使用罗斯林研究所独特且专用的大型动物收容设施来测试双重感染或双重感染随后由二氨基氮烯诱导的单一感染如何影响疾病相关牛宿主中的寄生虫流行和病理学。这些研究将确定后果当通过治疗干预将合并感染重定向为单一感染时，了解寄生虫流行率和宿主病理学。这可能会对牲畜健康造成意想不到的损害，因为在混合感染情况下存在不同的抵抗力。我们的实验可以优先考虑这种以前被忽视的威胁的流行病学研究，并促进优化剂量或治疗患病动物和维持治疗效果的策略。这也将加速替代锥虫杀剂的有针对性采用。撒哈拉以南非洲的农民和政策制定者没有预料到，在混合感染环境中进行治疗干预可能会产生不利影响，并且可能被忽视或当作轶事而被忽视。我们将确保通过我们计划的针对牲畜锥虫的外展活动和合作，将我们的研究结果传播给科学界、政策制定者和农民。其中包括计划的会议，例如莫里森将于 2023 年在坦桑尼亚组织的会议，以及与比尔和梅琳达·盖茨基金会的合作，与肯尼亚国际畜牧研究所的联系以及正在进行的非洲实地工作。