Doctoral Dissertation Improvement: The Origin of Syphilis and the Evolution of the Treponema Pallidum Subspecies: A Phylogenetic Approach

自15世纪以来，关于梅毒的起源一直存在争议。一些人推测梅毒是由哥伦布和他的船员在新大陆获得的一种病原体引起的。另一种假设是：1)梅毒在欧洲一直存在，但以前被与麻风病等其他疾病混淆；2)梅毒在文艺复兴时期传入欧洲，但起源于非洲，而不是新大陆。古病理记录显示，对梅毒螺旋体病随时间分布的地理范围的回顾表明，在哥伦布发现新大陆之前，梅毒螺旋体病的证据很丰富，而在欧洲和北非地区似乎没有。然而，在14世纪90年代之前，这些地区关于密螺旋体疾病的孤立报道使争论继续下去。此外，梅毒螺旋体亚种与梅毒螺旋体的关系。引起梅毒的梅毒分枝杆菌和引起类似但非性病的雅司病、地方性梅毒和平塔病的其他梅毒分枝杆菌亚种继续困扰着生物学家。虽然这些疾病的特点是症状明显不同，但形态学和遗传上的差异仍然难以用于区分病原体。本项目旨在利用系统地理学阐明亚种的进化轨迹。从世界各地的梅毒、雅司病和地方性梅毒病例中收集了样本。它们代表了目前实验室收集的最多的非性传播T. pallidum DNA。利用有针对性的遗传分析，亚种内部和亚种之间的可变位点将被确定。然后将对这些差异进行系统发育分析，以检验关于梅毒起源和梅毒T. pallidum亚种之间关系的各种假设。该项目解决了疾病历史上两个长期存在的问题，同时研究了病原体在人类施加的选择压力下的进化机制。由于来自系统发育方法的信息将与过去种群中丰富的苍白球绦虫感染的古病理学数据相结合，因此拟议的研究提供了一个独特的机会，将病原体的适应性事件与流行病学和疾病表现以及宿主社会和性行为的变化联系起来。这种类型的知识将适用于其他人类病原体，如艾滋病毒。传播方式的进化变化导致新的感染方式或现有方式的效率提高，在过去的流行病中发挥了重要作用，是一个重大的公共卫生问题。这项研究可能阐明这些变化的周围条件和机制，从而有助于为干预措施提供信息。此外，比较遗传分析产生的数据可能有助于解释令人困惑的古病理学发现，并通过提供新的客观数据来消除围绕梅毒起源的谜团。最后，本研究将培养一名博士研究生。

Controversy has surrounded the origin of syphilis since the 15th century. Some have speculated that syphilis arose from a pathogen acquired in the New World by Columbus and his men. Alternative hypotheses are that 1) syphilis was always present in Europe but was previously confused with other diseases such as leprosy; and 2) syphilis arrived in Europe during the Renaissance but originated in Africa and not the New World. A review of the geographical span of the treponematoses over time, as revealed in the paleopathological record, has demonstrated that evidence of treponemal disease is abundant in the Pre-Columbian New World and seemingly absent from European and North African sites. However, isolated reports of treponemal disease in these areas before the 1490s have kept the debate alive. In addition, the relationship between Treponema pallidum subsp. pallidum, the bacterium that causes syphilis, and the other T. pallidum subspecies that cause the similar but non-venereal diseases yaws, endemic syphilis, and pinta continues to puzzle biologists. Although the diseases are characterized by strikingly different symptoms, morphological and genetic differences which can be used to distinguish the pathogens have remained elusive. This project seeks to elucidate the evolutionary trajectory of the subspecies using phylogeography.Samples have been gathered from cases of syphilis, yaws, and endemic syphilis all over the world. They represent the largest collection of non-venereally transmitted T. pallidum DNA available in a lab collection today. Using targeted genetic analysis, variable sites within and between the subspecies will be identified. Phylogenetic analyses will then be performed upon these differences in order to test various hypotheses regarding the origin of syphilis and the relationship of the T. pallidum subspecies to one another.This project addresses two long-standing problems in the history of disease while simultaneously studying mechanisms of pathogen evolution in response to human-imposed selective pressures. Because information from phylogenetic methods will join copious paleopathological data on T. pallidum infection in past populations, the proposed research provides a unique opportunity to link adaptive events in a pathogen to changes in epidemiology and disease manifestations as well as host social and sexual practices. This type of knowledge will be applicable to other human pathogens, such as HIV. Evolutionary changes in transmission, resulting in either a novel mode of infection or greater efficiency in an existing mode, have played important roles in past epidemics and are a major public health concern. This study may elucidate the conditions surrounding and mechanisms underlying such changes and could thus help to inform interventions. In addition, the data produced from comparative genetic analysis may help make sense of puzzling paleopathological findings and dispel the mystery surrounding the origin of syphilis by providing novel objective data. Finally, this study will result in the training of a PhD student.