Host and Pathogen Evolution in Lassa Fever

描述（由申请人提供） 摘要：致病病原体是塑造人类进化的最有趣的力量之一，因为它们对我们的基因组产生了巨大的影响，而且它们本身也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，两个与拉沙热有生物学联系的基因是西非自然选择的最强信号之一。拉沙热是西非的一种严重的出血性疾病，我们的研究结果表明，它是一种古老的选择性力量，推动了遗传抗性的出现。虽然人们对拉沙热知之甚少，但它可以说是所有人类传染病中最大的潜在影响，因为它既是一种直接的公共卫生危机，也是一种A类潜在的生物恐怖分子。为了追求与拉沙热有关的自然选择的有趣信号，我们首先着手解决知识，能力和诊断方面的关键差距。我们在尼日利亚的伊鲁阿建立了一个基础诊断和研究实验室，那里每年都会爆发拉沙热，人群暴露率约为30%。初步数据表明，我们的初步措施已将拉沙热病例的死亡率从估计的65%显著降低至20%。我们现在的目标是设计一个强大的，现场部署的诊断，基于不同菌株的基因组测序，以快速检测和区分拉沙病毒株。这项工作解决了当前的公共卫生需求，并为研究病毒和人类中的遗传因素奠定了基础，这些遗传因素是许多西非人对拉沙热产生耐药性的基础。我们工作的最终目标是确定自然的防御机制，并阐明进化适应，使人类能够承受我们最复杂和最具挑战性的选择性代理。此外，这些努力将为拉沙病毒研究创造新的机会，包括调查病毒的致病性以及新疫苗的进化和开发。 公共卫生相关性：拉沙出血热是西非的一种严重流行病，估计每年感染30多万人，住院10万人，并造成2万人或更多人死亡。这些数字很可能被低估;在过去的20年里，很少进行血清学调查，大多数患者由于医疗设施的条件差而从未在医院就诊，最初的症状与其他发热性疾病相似，通常被误诊。拉沙病可以说是最被忽视的热带疾病之一，因为它影响的人数，它的病例死亡率，它作为生物恐怖分子的潜力，以及对更好的诊断，实地研究和治疗的未解决需求。我在尼日利亚伊鲁阿的专科教学医院建立了一个基础诊断和研究实验室，这是一个农村地区，每年都会爆发拉沙热，估计人口暴露率为30%。我们在那里采取的初步措施已经开始将拉沙热医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方法仍然遗漏了许多疾病病例，并且在临床环境中不容易获得。RT-PCR检测基于20年前在塞拉利昂分离的单一拉沙菌株，估计灵敏度为50%。拉沙病毒株之间的遗传差异可能是这种表现不佳的原因，尼日利亚的病毒株多样性最大。我们的目标是设计一个强大的，现场部署的诊断测试，将快速诊断拉沙病毒，通过测序100分离的拉沙病毒。这项工作将解决这一广泛和毁灭性疾病的紧迫公共卫生需求。此外，我们将利用这些基础来研究许多西非人对拉沙热产生抵抗力的宿主遗传因素，并有可能揭示抗病性的自然机制。最后，这些努力将为拉沙病毒研究创造新的机会，包括调查病毒的致病性和新疫苗的进化和开发。

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.