Ancient American tuberculosis: origin(s), spread, and replacement

古代美国结核病：起源、传播和替代

• 批准号: 1515163
• 负责人: Anne Stone
• 金额: $ 33.35万
• 依托单位: Arizona State University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1515163&HistoricalAwards=false
• 关键词: Ancient; American; tuberculosis; origin; spread

The exchange of pathogens between humans and other animals has been longstanding, and recent examples include HIV, SARS, flu viruses, and Yersinia pestis (which causes the plague). Today, especially in the developing world, humans and their domesticated animals continue to encroach upon wild animal habitats, with opportunities for cross-species transmission (or "spillover") expanding as exposure increases. This project will provide insight into the process by which pathogens adapt to new hosts and the impact of human migration and interaction on the spread of pathogens in the past. In particular, the project will use ancient DNA and skeletal analyses to investigate how human migration events and possible changes in virulence of M. tuberculosis strains have facilitated the spread of tuberculosis (TB) during human evolutionary history, with specific hypotheses about how tuberculosis may have been transmitted from animals to humans, and from the Old World to the Americas. A better understanding of the evolutionary history of mycobacteria such as those causing TB and leprosy can provide insights for other researchers interested in developing clinical treatments. Because human TB (and its descendants) has had a profound impact on other species, it is thus also a conservation concern. During this project, both undergraduate and graduate students will be trained in molecular techniques and data analysis. The data generated will be deposited in public databases such as GenBank, and the results of data analyses will be published in scholarly articles as well as in formats accessible to the general public.This project will identify, document, and sample 285 remains with skeletal lesions characteristic of TB that date to before and after European contact in the Americas. Newly developed methods will then be used to extract DNA from these samples, as well as to target and sequence the ancient pathogen genomes. We have assembled a team of experts in ancient DNA, bioarchaeology, bioinformatics, and population genetics to address two specific aims. The first is to examine the geographic patterning of pathogenic mycobacteria, particularly M. tuberculosis complex (MTBC), in the Americas through time. Specifically, we will test whether prehistoric TB in Peru and South America were the result of a single jump of M. pinnipedii into humans, if prehistoric TB in North America was caused by MTBC strains that are most closely related to M. pinnipedii strains found in ancient South Americans, and whether strains found in specimens with atypical skeletal pathologies from pre-contact Mexico are M. lepromatosis (a newly discovered strain of mycobacteria that causes atypical leprosy). The second aim is to discern signatures of adaptation to humans by mycobacteria through time. For this aim, we will test the hypotheses that 1) the zoonotic M. pinnipedii strain(s) that "jumped" into humans in South America shows signs of selection that indicate adaptation to this new host and 2) local mycobacterial strains in the Americas were replaced by more virulent strains at contact over a relatively short time period (ex: following contact/increased trade in the New World). The genome data obtained from the ancient samples along with comparative data from modern strains will be used to construct phylogenies of these pathogens, to assess patterns of diversity across the Americas (and through time), and to test for signals of selection. The pattern of adaptation of the MTBC and other mycobacteria in humans over time is of interest since it helps understand the success of these organisms and their possible future trajectories.

长期以来，人类与其他动物之间病原体的交换已经存在，最近的例子包括HIV，SARS，流感病毒和Pestis Yersinia Pestis（导致鼠疫）。如今，尤其是在发展中国家，人类及其驯养的动物继续侵占野生动物栖息地，随着暴露量的增加，跨物种传播（或“溢出”）的机会不断扩大。该项目将洞悉病原体适应新宿主的过程以及人类迁移和互动对过去病原体传播的影响。特别是，该项目将使用古老的DNA和骨骼分析来研究人类移民事件以及结核分枝杆菌菌株的毒力的可能变化，促进了人类进化史期间结核病（TB）的传播，并有关于肺结核可能如何从动物传播到人类和美国旧世界的特定假设。更好地了解分枝杆菌的进化史，例如引起结核病和麻风病的史，可以为有兴趣开发临床治疗的其他研究人员提供见解。由于人类结核病（及其后代）对其他物种产生了深远的影响，因此这也是一个保护的问题。在此项目中，本科生和研究生都将接受分子技术和数据分析的培训。生成的数据将存放在GenBank等公共数据库中，数据分析的结果将在学术文章以及公众可访问的格式中发表。此项目将识别，文档和样本285保留的骨骼病变特征，与TB的骨骼病变特征与欧洲的欧洲接触之前和之后的美洲接触。然后，新开发的方法将用于从这些样品中提取DNA，并靶向和序列古代病原体基因组。我们已经组建了一支在古代DNA，生物考古学，生物信息学和人群遗传学方面的专家团队，以解决两个具体目标。首先是检查美洲的致病性分枝杆菌的地理图案，尤其是结核分枝杆菌（MTBC）。具体而言，我们将测试在秘鲁和南美的史前结核病是否是pinipedii大麻菌进入人类的结果，如果北美的史前结核病是由MTBC菌株造成的，MTBC菌株与pinnipedii菌株最紧密相关，与北美菌株相关，以及在古代菌株中发现的菌株，以及在脑海中发现了新的骨骼骨架，是否是在脑海中发现的，是骨骼的骨骼疾病。会导致非典型麻风病的分枝杆菌菌株）。第二个目的是辨别分枝杆菌对人类适应人类的签名。为此，我们将测试以下假设：1）“跳入”南美人类的人畜共动性M. pinnipedii菌株显示出选择的迹象，表明适应了这个新宿主和2）美洲当地的分枝杆菌菌株被相对较短的时间越短时间以外的时间替代了更短的时间（随着新的接触：新的接触/贸易，都会在新的世界中贸易。从古代样品获得的基因组数据以及现代菌株的比较数据将用于构建这些病原体的系统发育，以评估美洲多样性的模式，并测试选择信号。随着时间的流逝，MTBC和其他分枝杆菌适应的模式令人兴奋，因为它有助于了解这些生物的成功及其可能的未来轨迹。