IMPROVED ANTIGEN DETECTION TESTS FOR FILARIAL INFECTIONS

项目摘要 该项目将鉴定和表征人类丝虫感染的生物标志物， 针对循环丝虫抗原的抗体将比目前测试中使用的抗体更特异。的 此时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丝虫病的目标迈进。 到2020年消灭淋巴丝虫病。然而，诊断问题是一个重大挑战， 在中非，当前丝虫抗原检测的假阳性结果可能导致 不必要的和可能有害的过度治疗。 候选 我在生物医学、转化和公共卫生研究方面有10多年的经验和培训。 我在呼吸道合胞病毒方面的博士研究使我对呼吸道合胞病毒的原理有了广泛的了解。 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 认识到全球公共卫生计划的范围和潜在影响，以及 为公共卫生项目和研究提供准确的诊断工具。我是内科的董事会认证， 获得传染病临床医师的专科证书。这个项目支持我的长期职业目标， 成为全球传染病领域的独立研究者，专注于翻译 被忽视的热带疾病的研究;该项目计划也将使我能够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）的环境非常适合我的项目和职业 发展智力环境是杰出的，我打算利用这一点，完成 一个结构化的课程计划，重点是在资源匮乏的环境中进行实地研究。我 导师的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是全国仅有的几个具有强大专业知识的研究中心之一。 丝虫病我的导师是盘尾丝虫病死亡和LF项目（一个大型全球卫生项目）的PI。 该项目由比尔和梅林达盖茨基金会资助），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。这种良好的丝虫研究环境是 我于2014年加入WUSTL教师。 研究 LF是世界上导致残疾的主要原因之一，也是少数几种传染病之一， 有可能被根除世卫组织的全球环境法基金协调和支持企业、学术界、 政府和非政府合作伙伴，通过反复 大规模药物管理（MDA）周期使用行业捐赠的药物。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。世界上90%以上的LF负担（包括非洲的所有病例）是 引起的丝虫线虫班氏吴策线虫（Wb），以及全球消除计划的所有方面， 班氏丝虫病（定位、MDA、监测和验证）依赖于使用床旁诊断LF 采用单克隆抗体检测血液样本中的Wb循环丝虫抗原的试验。最近 研究表明，这些测试通常会产生假阳性结果， 感染了Loa loa，这是一种发生在中非11个国家的不同丝虫寄生虫。不准确 诊断测试结果可能具有严重甚至致命的影响，因为用于LF MDA的药物可能导致 严重的不良反应（包括脑病和死亡）时，采取的人与重L。Loa 感染.我们推测，在丝虫病患者中，假阳性的丝虫Wb抗原检测是由于 存在交叉反应性循环L。loa抗原。该项目旨在鉴定循环Loa抗原 并开发出可以区分这两种感染的检测方法。改进的诊断测试将大大提高 在11个中部非洲国家增加控制洛塞雷乌斯和消灭LF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.