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.

非洲锥虫会导致撒哈拉以南非洲以下非洲牲畜生产的大量经济成本加剧了受苦地区的贫困。三种致病物种共同循环，brucei锥虫，粘粉刺粘膜素和锥虫瘤，并通过化学预防和药物治疗来控制感染。但是，该物种之间的共感染是常见的，几项文献报道，我们自己的数据表明，锥虫物种和菌株之间的共感染可以减轻与单个物种或菌株的单感染有关的疾病病理学。这会在与暴露于次优剂量的锥虫中具有差异药物敏感性的环境中产生风险，或者在某些循环寄生虫种群中存在耐药性。具体而言，通过将共同感染恢复为仅包含更具抗性菌株或物种的单感染，药物干预可能会导致病理增强。因此，药物施用可能会产生疾病增加的不良结果。在这项提案中，我们将探讨小鼠模型和与疾病相关的牲畜宿主的共同感染，药物敏感性和病理之间的相互作用。具体来说，我们将：1。工程师耐药性和敏感的锥虫瘤Brucei和锥虫分别使用已知的分子耐药性/敏感性机制，用于Diminazene，这是最常用的牲畜锥虫疗法。具体而言，将在T. brucei中删除核苷抗性TBAT1（一种核苷转运蛋白），以产生耐药性寄生虫，而T. concolense将被设计为异源表达Brucei AT1基因，从而产生降低的超敏感线。这将允许在与Brucei的实验共同感染中精确去除粘霉素的研究，以避免可变降低敏感性的复杂性不同的野生型实验室和野外菌株可能表现出来。2。该工程线将用于评估共同感染的影响，或共同感染的影响，然后是减少诱导的单感染对锥虫种群的比例和分布及其在小鼠中的病理学的比例和分布。这将通过通过IVIS Imaging定量针对每种物种的寄生虫数量和T. Brucei的储层来实现。鼠病理学将通过既定标准进行评分。3。该工程线将用于测试与疾病与疾病相关的牛宿主中寄生虫的流行和病理的结合感染或共同感染，然后如何使用Roslin Institute的独特和专用的大型动物遏制设施来影响寄生虫的患病率和病理学。 干涉。这可能对牲畜健康有害，在混合感染情况下存在差异性抗性。我们的实验可以优先考虑这种先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者并维持治疗功效的策略。这也将加速有针对性地采用替代锥虫的可用性。在撒哈拉以南非洲地区的农民和政策制定者中，意想不到治疗性干预对共同感染环境的不利影响，并可能被忽视或被视为轶事。我们将通过我们计划的外展活动和关注牲畜锥虫的计划来确保我们的发现将科学界，政策制定者和名人传播到科学界，决策者和名人。其中包括计划的会议，例如，莫里森（Morrison）的会议于2023年在坦桑尼亚组织，以及与比尔（Bill）和梅琳达·盖茨基金会（Melinda Gates Foundation）的合作合作，与肯尼亚国际牲畜研究所的联系以及非洲正在进行的现场工作。