Novel weapon evolution in mycobacterial pathogenesis, dispersal and ecological persistence

了解和控制新出现的传染病，在它们达到流行病的程度之前，对于防止对人类健康的破坏性影响、促进动物福利和加强物种保护是重要的。布鲁里溃疡病是一种慢性、使人衰弱的感染，可破坏皮肤、软组织和骨骼，全世界有30多个国家报告了该病。这种疾病是由溃疡分枝杆菌引起的，这种病原体与引起肺结核和麻风病的病原体密切相关。目前尚不清楚人类是如何感染溃疡分枝杆菌的，因为在确定人们可能被感染的生态宿主以及允许病原体在环境中生存和移动的机制方面存在不确定性。这个项目测试了溃疡分枝杆菌是如何进化产生一种新的分子武器的，它利用这种武器成功地在人类接触它的风险最高的环境中生存。这种分子武器是导致布鲁里溃疡的毒素。此外，由于像引起布鲁里溃疡的病原体这样的病原体不断与其他微生物群落（微生物组）相互作用，因此本项目研究了它如何在环境和宿主微生物组中持续存在和复制。发现致病生物、它们生活的地方以及与它们一起生活的其他微生物之间的新相互作用，有助于深入了解疾病是如何出现和传播的。这个跨学科项目将培养本科生、研究生和研究专业人员，重点包括来自代表性不足的群体、退伍军人和土著文化的不同个人。此外，这项工作将提供可供其他研究人员和公共卫生专业人员使用的公开数据，以提供必要的教育工具，以改善更广泛的健康结果。这项研究将测试“新武器假说”，该假说认为，一些分类群可以由于毒素的产生而成为主导，然后在入侵者的成功中，这些毒素会被选择为这个角色。这将通过一种分枝杆菌分支来实现，该分支显示出产生菌内酯（布鲁里溃疡的毒素）的基因多样性。据推测，菌内酯最初的进化是为了促进分枝杆菌在环境宿主和宿主的复杂微生物群落中的定植和持久性，但在脊椎动物的发病机制中也有功能作用：这一属性与毒力巧合假说相一致。该项目将确定霉菌内酯在法属圭亚那流域生态系统中的生态和进化作用。法属圭亚那是巴西东北部的一个法国领土，疾病在那里流行。先前对全球溃疡分枝杆菌遗传多样性的评估表明，圭亚那盾是分子进化的热点。该研究将通过考察收集水生群落来完成，以量化三个流域产生霉菌内酯的分枝杆菌的多样性。该小组将对环境分枝杆菌进行比较基因组研究，包括一项涉及候选鱼类宿主水库（孔雀鱼）的共系统发育分析，由于人类活动的分散，该水库现在已分布在全球。几种综合数学建模方法将用于综合项目结果，以确定病原体毒素的分子进化如何通过复杂的跨尺度生态相互作用导致人类疾病。这些结果将有助于深入了解致病因子在初始宿主和环境社区中建立、持续和传播的机制。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Understanding and controlling emerging infectious diseases before they reach epidemic proportions is important for preventing devastating effects on human health, for promoting animal welfare, and for improving species conservation. Buruli ulcer disease is a chronic, debilitating infection that destroys skin, soft tissues, and bone, and has been reported from over 30 countries worldwide. Disease is caused by Mycobacterium ulcerans, a pathogen closely related to those that cause tuberculosis and leprosy. It is not clear how humans get M. ulcerans because there is uncertainty in identifying ecological reservoirs from which people can become infected, and mechanisms that allow the pathogen to live in and move around in the environment. This project tests how M. ulcerans has evolved to produce a novel molecular weapon that it uses to successfully live in environments where risk of humans contacting it is highest. This molecular weapon is the toxin responsible for Buruli ulcer. Furthermore, because pathogens like the one that causes Buruli ulcer constantly interact with communities of other microbes (microbiomes), this project examines how it persists and replicates in environmental and host microbiomes. Discovering new interactions between disease-causing organisms, where they live, and the other microbes living with them provides insight into the basic understanding of how diseases emerge and spread. This interdisciplinary project will train undergraduates, graduate students, and research professionals with focused inclusion of diverse individuals from underrepresented groups, military veterans, and indigenous cultures. In addition, this work will contribute publicly available data that can be used by other researchers and public health professionals to deliver educational tools necessary to improve broader health outcomes.The research will test the Novel Weapons Hypothesis, which posits that some taxa can become dominant due to toxin production that is then subject to selection for this role in the invader's success. This will be achieved using a mycobacterial clade that demonstrates diversity of genes that produce mycolactone, the toxin responsible for Buruli ulcer. Mycolactone is hypothesized to have initially evolved to facilitate mycobacterial colonization and persistence in complex microbial consortia of environmental hosts and reservoirs, but also has a functional role in vertebrate pathogenesis: an attribute that aligns with the Coincidence of Virulence Hypothesis. This project will identify the ecological and evolutionary roles of mycolactone in watershed ecosystems of French Guiana, a French territory northeast of Brazil, where disease is endemic. Previous assessments of global M. ulcerans genetic diversity reveal the Guiana Shield to be a hotspot of molecular evolution. The research will be accomplished through expeditions to collect aquatic communities for quantifying the diversity of mycolactone producing mycobacteria along three watersheds. The team will conduct comparative genomic research on environmental mycobacteria, including a co-phylogenetic analysis involving a candidate fish host reservoir (guppies), which is now globally distributed due to anthropogenic dispersal. Several integrated mathematical modeling approaches will be used to synthesize project results to determine how molecular evolution of a pathogen toxin leads to human disease through complex ecological interactions across scales. The results will contribute insights into the mechanisms behind establishment, persistence and spread of disease-causing agents in naive host and environmental communities.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.