Host and Pathogen Evolution in Lassa Fever

描述(由申请人提供) 摘要：致病病原体是影响人类进化的最耐人寻味的力量之一，因为它们对我们的基因组有巨大的影响，而且它们自己会随着时间的推移而进化。一项对人类变异的全基因组调查发现，在生物学上与拉沙热有关的两个基因是西非自然选择的最强信号之一。拉沙热是西非流行的一种严重出血性疾病，我们的发现表明，它是一种古老的选择性力量，推动了遗传抗性的出现。尽管人们对拉沙热知之甚少，但可以说它是人类所有传染病中潜在影响最大的，因为它既是直接的公共卫生危机，也是A类潜在的生物恐怖分子。为了追寻与拉沙热有关的耐人寻味的自然选择信号，我们首先着手解决知识、能力和诊断方面的关键差距。我们在尼日利亚伊鲁阿建立了一个基本的诊断和研究实验室，那里每年都会发生拉沙热暴发，人口暴露率约为30%。初步数据表明，我们的初步措施大大降低了拉沙热病例的死亡率，从估计的65%降至20%。我们现在的目标是设计一种强大的、可现场部署的诊断方法，基于不同毒株的基因组测序，以快速检测和区分拉萨病毒株。这项工作解决了迫在眉睫的公共卫生需求，并为研究病毒和人类的遗传因素奠定了基础，这些因素是许多西非人对拉沙热产生抵抗力的基础。我们工作的最终目标是识别自然的防御机制，并阐明使人类能够抵御一些最复杂和最具挑战性的选择性代理人的进化适应。此外，这些努力将为拉萨病毒研究创造新的机会，包括调查病毒的致病性以及新型疫苗的进化和开发。 公共卫生相关性：拉萨出血热是西非流行的一种严重疾病，据估计每年感染30多万人，使100,000人住院，并造成20,000人或更多人死亡。这些数字可能被低估了；在过去的20年里，很少进行血清学调查，大多数患者由于缺乏医疗设施而从未在医院见过面，最初的症状类似于其他发热性疾病，经常被误诊。拉萨可以说是最被忽视的热带疾病之一，因为它影响的人数、病例致死率、作为生物恐怖分子的潜力以及对更好的诊断、实地研究和治疗的需求尚未得到解决。我已经在尼日利亚伊鲁阿的专科教学医院建立了一个基本诊断和研究实验室，这是一个农村地区，每年都会发生拉沙热疫情，那里的人口估计暴露在那里的比例为30%。我们在那里采取的初步措施已经开始降低拉沙热住院病例的死亡率，从估计的65%降至20%。然而，我们正在使用的诊断仍然遗漏了许多疾病病例，并且在临床环境中并不容易获得。RT-PCR检测是基于20年前在塞拉利昂分离的单一Lassa毒株，估计灵敏度为50%。拉萨病毒株之间的遗传差异可能是这种糟糕表现的原因，尼日利亚的病毒株多样性最大。我们的目标是设计一种强大的、可现场部署的诊断测试，通过对100株拉萨病毒分离物进行测序，快速诊断拉萨病毒。这项工作将解决这种广泛和破坏性疾病对公共卫生的迫切需求。此外，我们将利用这些基金会调查在许多西非人中发现的拉沙热抵抗的宿主遗传因素，并可能揭示疾病抵抗的自然机制。最后，这些努力将为拉萨病毒研究创造新的机会，包括调查病毒的致病性以及新型疫苗的进化和开发。

DESCRIPTION (Provided by the applicant) Abstract: Disease-causing pathogens are among the most intriguing forces shaping human evolution, as they have a tremendous impact on our genome and themselves evolve over time. A genome-wide survey of human variation identified two genes biologically linked to Lassa fever as among the strongest signals of natural selection in West Africans1. Lassa fever is a severe hemorrhagic disease endemic in West Africa, and our findings suggest it is an ancient selective force driving the emergence of genetic resistance. While poorly understood, Lassa fever has arguably the greatest potential impact of all infectious diseases of humans, because of its unique status as both an immediate public health crisis and a category A potential bioterrorist agent. With the aim to pursue the intriguing signal of natural selection linked to Lassa fever, we first set out to address critical gaps in knowledge, capacity, and diagnostics. We established a basic diagnostic and research lab in Irrua, Nigeria, where yearly outbreaks of Lassa fever occur with population exposure of ~30%. Preliminary data suggests our initial measures have significantly reduced fatality from an estimated 65% to 20% among Lassa fever cases. We now aim to design a robust, field-deployable diagnostic, based on genomesequencing of diverse strains, to rapidly detect and distinguish Lassa virus strains. This work addresses immediate public health needs and sets the foundations for research into the genetic factors in both virus and human that underlie resistance to Lassa fever found among many West Africans. The ultimate goal of our work is to identify natural mechanisms of defense and illuminate the evolutionary adaptations that have allowed humans to withstand some of our most complex and challenging selective agents. Moreover, these efforts will create new opportunities in Lassa virus research, including investigations of viral pathogenicity and evolution and development of novel vaccines. Public Health Relevance: Lassa hemorrhagic fever, a severe illness endemic in West Africa, is estimated to infect more than 300,000 individuals, hospitalize 100,000, and cause 20,000 or more deaths each year. These numbers are likely to be underestimates; few serological surveys have been conducted in the last 2 decades, most patients are never seen in the hospital due to poor access to medical facilities, and the initial symptoms are similar to other febrile illnesses and commonly misdiagnosed. Lassa is arguably one of the most neglected of the tropical diseases, given the number of people that it affects, its case fatality, its potential as a bioterrorist agent, and the unaddressed need for better diagnostics, field studies, and therapies. I have established a basic diagnostic and research lab at the Specialist Teaching Hospital in Irrua, Nigeria, a rural area where yearly outbreaks of Lassa fever occur and where estimated population exposure is 30%. Our initial measures there have already begun to reduce fatality among hospital cases of Lassa fever, from an estimated 65% to 20%. The diagnostic we are using, however, still misses many cases of the disease and is not readily available in the clinical setting. The RT-PCR assay is based on a single Lassa strain isolated 2 decades ago in Sierra Leone, and has an estimated sensitivity of 50%. Genetic divergence between Lassa virus strains likely underlies this poor performance, with the greatest diversity of virus strains in Nigeria. We aim to design a robust, field-deployable diagnostic test that will rapidly diagnose Lassa virus, by sequencing 100 isolates of Lassa virus. This work will address urgent public health needs in this widespread and devastating disease. Moreover we will use these foundations to investigate host genetic factors underlying resistance to Lassa fever seen among many West Africans, and potentially uncover natural mechanisms of disease resistance. Finally these efforts will create new opportunities in Lassa virus research, including investigations of viral pathogenicity and evolution and development of novel vaccines.