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了巨大的经济损失，加剧了受影响地区的贫困。三种致病性物种共同循环，布氏锥虫，刚果锥虫和间日锥虫，感染通过化学预防和药物治疗进行管理。然而，物种之间的共感染是常见的，一些文献报道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疾病病理学与单一物种或菌株的单感染。这在暴露于次优剂量的共感染锥虫之间存在差异药物敏感性或在某些循环寄生虫群体中存在耐药性的环境中产生风险。具体而言，通过将合并感染恢复为仅包含更具抗性的菌株或物种的单一感染，药物干预可能导致病理学增强。因此，药物的应用可能会产生一个反常的结果，增加diseases.In本提案中，我们将探讨共同感染，药物敏感性和病理学在小鼠模型和疾病相关的牲畜宿主之间的相互作用。具体来说，我们将：1。使用已知的对亚胺氮（家畜锥虫最常用的治疗方法）的分子耐药性/敏感性机制，分别对耐药性和敏感性布氏锥虫和刚果锥虫进行工程改造。具体而言，在T.布氏杆菌产生抗性寄生虫和T.将工程改造成异源表达T.布氏杆菌AT 1基因，产生一个对二氮烯超敏感株系。这将允许精确去除T。实验性混合感染T.布氏杆菌为我们的研究，避免了复杂的可变diminazene敏感性不同的野生型实验室和现场菌株可能会出现.工程化细胞系将用于评价合并感染或合并感染后再进行亚胺氮诱导的单一感染对小鼠中锥虫种群比例和分布及其病理学的影响。这将通过对每个种属和T.通过IVIS成像检测布氏杆菌。小鼠病理学将根据既定标准进行评分。工程系将用于测试如何共同感染，或共同感染后，二氮亚胺诱导的单一感染，影响寄生虫的流行和病理学在疾病相关的牛宿主使用独特的和专用的大型动物遏制设施在Roslin Institute.这些研究将确定寄生虫流行和宿主病理学的后果时，通过治疗干预将共同感染重定向为单一感染。这可能对牲畜健康造成意想不到的危害，因为在混合感染情况下存在不同的耐药性。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，并促进优化剂量的策略，或治疗患病动物并维持治疗效果。这也将加快替代锥虫剂的有针对性的采用，因为它们是可用的，撒哈拉以南非洲的农民和政策制定者没有预料到在合并感染环境中治疗干预的潜在不利影响，可能被忽视或作为轶事而被忽视。我们将确保我们的研究结果通过我们计划的推广活动和重点关注牲畜锥虫的合作传播给科学界，政策制定者和农民。其中包括计划中的会议，例如莫里森将于2023年在坦桑尼亚组织的会议，与比尔和梅林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非洲进行的实地工作。