IMPROVED ANTIGEN DETECTION TESTS FOR FILARIAL INFECTIONS

项目总结 该项目将识别和表征人类丝虫感染的生物标记物，并产生单克隆 针对循环丝虫抗原的抗体将比目前检测中使用的抗体更具特异性。这个 目前迫切需要改进诊断测试。世界卫生组织(WHO)全球 消除淋巴丝虫病计划(GPELF)正在迅速朝着全球消除淋巴丝虫病的目标迈进 到2020年，淋巴丝虫病(LF)。然而，诊断问题是对 在中部非洲，目前丝虫抗原检测的假阳性结果可能导致 对人口进行不必要且可能有害的过度治疗。 侯选人 我在生物医学、翻译和公共卫生研究方面有10多年的经验和培训。 我对呼吸道合胞病毒的博士研究让我对病毒的原理有了广泛的理解 免疫学、病毒学和宿主-病原体相互作用。我最近在流行病学方面的工作给了我一个 认识到全球公共卫生方案的范围和潜在影响以及 为公共卫生项目和研究提供准确的诊断工具。我是内科委员会认证的医生 传染病临床医生的专科认证。这个项目支持我长期的职业目标 成为全球传染病领域的独立调查者，专注于翻译 研究被忽视的热带病；该项目计划还将使我进一步发展我的临床 传染病的研究技能和知识。 环境 我在圣路易斯华盛顿大学(WUSTL)的环境非常适合我提议的项目和职业 发展。智力环境非常出色，我打算利用这一点，完成 一个有组织的课程计划，重点是在资源匮乏的环境下进行实地研究。我的 门拓实验室团队在基础和应用研究方面拥有丰富的经验 寄生虫学，WUSTL是全国为数不多的几个拥有丰富专业知识的研究中心之一 丝虫病。我的导师是死亡到盘尾丝虫病和LF项目(一个大规模的全球卫生项目)的PI 由比尔和梅林达·盖茨基金会资助的项目)，并在寄生虫学方面拥有广泛的专业知识， 免疫学和国际实地研究。这种出色的丝虫病研究环境是 我于2014年加入WUSTL教职员工。 研究 LF是世界上导致残疾的主要原因之一，也是为数不多的几种传染性疾病之一 可能是可以根除的。世卫组织的GPELF协调和支持企业、学术界、 政府、政府和非政府伙伴在73个地方性国家通过反复 使用行业捐赠药物的大规模药物管理(MDA)周期。GPELF是最大的基于MDA的 公共卫生干预迄今已分发了超过53亿剂抗寄生虫药物 2000年至2014年，在60个国家和地区。世界90%以上的低频电磁场负担(包括非洲的所有病例)是 由丝状线虫Wuchereria bancrofti(WB)引起，以及全球消除计划的各个方面 班克罗夫斯坦丝虫病(测绘、丙二醛、监测和验证)依赖于使用护理点诊断LF 使用单抗检测血液样本中的WB循环丝虫抗原的试验。近期 研究表明，这些测试经常产生假阳性结果，样本来自于 感染Loa Loa是一种不同的丝虫寄生虫，发生在中部非洲的11个国家。不准确 诊断测试结果可能会有严重甚至致命的影响，因为用于治疗LF的丙二醛药物可能会导致 严重的不良反应(包括脑病和死亡) 感染。我们假设血吸虫病患者的丝虫Wb抗原检测假阳性是由于 存在交叉反应的循环L.LoA抗原。该项目旨在识别循环中的LOA抗原 并开发出能够区分这两种感染的检测方法。改进的诊断测试将显著 提高在同时拥有这两种疾病的11个中非国家控制血吸虫病和消除低频疾病的机会 这些疾病。

PROJECT SUMMARY This project will identify and characterize biomarkers for human filarial infections and generate monoclonal antibodies against circulating filarial antigens that will be more specific than those used in current tests. The need for improved diagnostic tests is pressing at this time. The World Health Organization’s (WHO) Global Program to Eliminate Lymphatic Filariasis (GPELF) is rapidly moving towards its goal of global elimination of lymphatic filariasis (LF) by 2020. However, problems with diagnosis represent a major challenge to the program in Central Africa, where false positive results with the current filarial antigen tests may result in unnecessary and potentially harmful overtreatment of populations. Candidate I have more than 10 years of experience and training in biomedical, translational, and public health research. My doctoral studies on Respiratory Syncytial Virus gave me a broad understanding of principles of immunology, virology, and host-pathogen interactions. My more recent work in epidemiology has given me an appreciation of the scope and potential impact of global public health programs and of the critical importance of accurate diagnostic tools for public health programs and research. I am board certified in Internal Medicine with subspecialty certification as an Infectious Diseases clinician. This project supports my long-term career goal of becoming an independent investigator in the area of global infectious diseases with a focus on translational research of neglected tropical diseases; the project plan will also allow me to further develop my clinical research skills and knowledge of infectious diseases. Environment My surroundings at Washington University in St. Louis (WUSTL) are ideal for my proposed project and career development. The intellectual environment is outstanding and I intend to take advantage of this by completing a structured program of coursework focused on conducting field research in resource-poor settings. My mentor’s laboratory group has a tremendous amount of experience in basic and applied research in parasitology, and WUSTL is one of only a handful of research centers in the nation with strong expertise in filarial diseases. My mentor is the PI of the Death to Onchocerciasis and LF project (a large-scale global health project funded by the Bill and Melinda Gates Foundation), and has extensive expertise in parasitology, immunology, and international field research. This outstanding environment for filarial research was the reason I joined the WUSTL faculty in 2014. Research LF is one of the world’s leading causes of disability, and is one of a small number of infectious diseases that are potentially eradicable. WHO’s GPELF coordinates and supports the efforts of corporate, academic, governmental, and non-governmental partners to eliminate LF in 73 endemic countries through repeated cycles of mass drug administration (MDA) using industry-donated drugs. GPELF is the largest MDA-based public health intervention to date with more than 5.3 billion doses of antiparasitic medications distributed between 2000 and 2014 in 60 countries. Over 90% of the world’s LF burden (including all cases in Africa) is caused by the filarial nematode Wuchereria bancrofti (Wb), and all aspects of global elimination programs for bancroftian filariasis (mapping, MDA, surveillance, and verification) rely on diagnosis of LF using point-of-care tests that employ monoclonal antibodies to detect Wb circulating filarial antigen in blood samples. Recent studies have shown that these tests often produce falsely positive results with samples from people that are infected with Loa loa, a different filarial parasite that occurs in 11 countries in Central Africa. Inaccurate diagnostic test results can have serious or even fatal implications since drugs used in MDA for LF can cause serious adverse reactions (including encephalopathy and death) when taken by people with heavy L. loa infections. We hypothesize that falsely-positive filarial Wb antigen tests in patients with loiasis are due to the presence of a cross-reactive circulating L. loa antigen. This project aims to identify the circulating Loa antigen and develop assays that can distinguish the two infections. Improved diagnostic tests would significantly improve chances for control of loiasis and elimination of LF in the 11 Central African nations that have both of these diseases.