Viral Zoonoses and Severe Febrile Illness in Northern Tanzania

摘要/摘要 这项提议目标是部署标准和创新的诊断工具，以便 调查坦桑尼亚北部多大比例的严重发热病(SFI)可归因于新出现 人畜共患病的病毒病原体。发烧是欠发达地区寻求医疗保健的最常见原因之一 然而，在撒哈拉以南非洲，多达一半的发烧住院患者可能没有实验室- 确诊--这是一个严重的知识鸿沟，阻碍了疾病预防工作。之前 坦桑尼亚北部的研究表明，动物传播的细菌感染是SFI的常见原因， 也许反映了亚热带许多地区人、牲畜和野生动物之间密切互动的影响 撒哈拉非洲。然而，动物传播的病毒感染的影响，如埃尼帕-，邦雅-，冠状病毒-和 呼肠孤病毒，目前尚不清楚。增强了对这些高后果是否以及哪些的理解 病毒病原体引起的SFI是预防和控制严重传染病的基础 非洲撒哈拉以南地区以及美国和其他七国集团国家的全球卫生安全议程。至 为了达到这些目的，这个职业发展奖建议使用具有良好特征的存档血液样本 从坦桑尼亚北部以前的发烧病因学研究中获得支持，以实现以下具体目标： 特定目标1-通过进行抗体检测来确定接触人畜共患病毒病原体的流行率 对来自SFI患者和以前登记的社区居民的血清进行评估。 特定目标2-确定部分人畜共患病中可检测到病毒血症的SFI病例的比例 通过对SFI患者血液样本进行实时聚合酶链式反应(PCR)分析来检测病原体。 特定目标3-通过以下方式实现增强的病毒病原体检测和发现新的病毒病原体 用杂交富集法下一代测序技术查询SFI血液样本。 实现这些具体目标所需的实验室工作将在杜克国家大学进行 新加坡大学医学院(Duke-NUS)在考生和 杜克国家大学新发传染病项目主任王林发博士(K23共同导师) 杜克大学/杜克国立大学教师，格雷格·格雷，医学博士，公共卫生硕士(K23共同导师)。未识别的血清、血浆和 全血将被用于这些目的。这些特征良好的血液样本代表了近1500份 参加由K23小学在坦桑尼亚北部进行的两个发烧疾病研究队列的患者 Mentor，John Crump，MB ChB，MD：艾滋病相关联合感染的国际共同研究(U01 AI062563)，一项全面的发烧病因学研究；以及细菌性人畜共患病的影响和社会生态 坦桑尼亚北部(R01TW009237)，人畜共患病原因的流行病学危险因素分析。这个 候选人马修·鲁巴赫，医学博士，是委员会认证的医学微生物学家和传染病内科医生。 2012-2014年间，鲁巴赫全职驻扎在坦桑尼亚的莫希。他已成功地从事临床工作。 温病与细菌性人畜共患传染病流行病学研究 在克伦普博士富有成效的人畜共患病研究计划的背景下，由20多个 来自多个学科的学者合作。这种制度环境在坦桑尼亚是非常好的 指导团队以及伦敦卫生与热带医学院的指导课程 MSC流行病学远程学习计划将共同使考生实现以下目标 培训目标： 培训目标1-在流行病学研究、临床研究研究方面发展更多的专业知识 设计和定量分析(Crump&Gray博士；课程作业)。 培训目标2--进一步发展人畜共患传染病流行病学方面的专门知识。 Crump&Gray；课程作业)。 培训目标3--进一步发展创新诊断微生物学方面的技术专长 通过指导临床研究，利用新的病原体检测和病原体发现实验室 技术(王博士)。 归根结底，鲁巴赫博士渴望在资源有限的情况下提高传染病诊断能力 作为杜克大学教职员工全职派驻KCMC进行相关临床研究的环境- 杜克大学在坦桑尼亚摩西的健康研究合作。这一早期职业奖项将为Dr。 鲁巴赫拥有创新诊断方面的技术专长，这将使他有别于他的主要导师和 将使鲁巴赫博士能够开发一种独立的研究轨道，用新的方法治疗传染病 临床和流行病学研究的诊断学。通过这方面的指导和培训目标 提议，鲁巴赫博士将以一种高度独特的技能在世界级传染病之间架起桥梁 在诊断微生物学领域拥有最先进的技术专长的流行病学研究。因此， 他将处于有利地位，为进一步的诊断、管理和研究寻求R01资金支持 人畜共患病和非人畜共患病原因的流行病学。

SUMMARY/ABSTRACT The objective of this proposal is to deploy standard as well as innovative diagnostic tools in order to investigate what proportion of severe febrile illness (SFI) in northern Tanzania is attributable to emerging zoonotic viral pathogens. Fever is among the most common reasons for seeking health care in less developed countries, yet up to half of patients hospitalized with fever in sub-Saharan Africa may go without a laboratory- confirmed diagnosis—this represents a serious knowledge gap that hinders disease prevention efforts. Prior research in northern Tanzania has revealed that animal-borne bacterial infections are a common cause of SFI, perhaps reflecting the effects of close interaction between humans, livestock and wildlife in many parts of sub- Saharan Africa. Yet the impact of animal-borne viral infections, such as henipa-, bunya-, corona- and reoviruses, remains unknown. An enhanced understanding of whether and which of these high-consequence viral pathogens are causing SFI is fundamental to the prevention and control of severe infectious diseases in sub-Saharan Africa and to the global health security agenda of the United States and other G7 countries. To these ends, this career development award proposes to utilize well-characterized archived blood specimens from prior fever etiology research in northern Tanzania in order to undertake the following SPECIFIC AIMS: SPECIFIC AIM 1—Establish the prevalence of exposure to zoonotic viral pathogens by performing antibody evaluations of serum from patients with SFI and from previously enrolled community-dwellers. SPECIFIC AIM 2— Establish the proportion of SFI cases with detectable viremia from select zoonotic pathogens by performing real-time polymerase chain reaction (PCR) assays on SFI patient blood samples. SPECIFIC AIM 3—Achieve enhanced viral pathogen detection and discover new viral pathogens by interrogating SFI blood samples with hybridization enrichment next-generation sequencing technology. The requisite laboratory work to achieve these SPECIFIC AIMS will be conducted at Duke-National University of Singapore Graduate Medical School (Duke-NUS) under the direction of the Candidate and the Director of the Duke-NUS Program in Emerging Infectious Disease, Lin-Fa Wang, PhD (K23 Co-Mentor), and Duke University/Duke-NUS faculty, Greg Gray, MD, MPH (K23 Co-Mentor). De-identified serum, plasma and whole blood will be utilized for these aims. These well-characterized blood specimens represent nearly 1500 patients enrolled in two febrile illness research cohorts conducted in northern Tanzania by K23 Primary Mentor, John Crump, MB ChB, MD: International Co-Studies of AIDS-Associated Co-Infections (U01 AI062563), a comprehensive fever etiology study; and The Impact and Social Ecology of Bacterial Zoonoses in Northern Tanzania (R01TW009237), an epidemiologic risk factor analysis on zoonotic causes of SFI. The Candidate, Matthew Rubach, MD, is a board-certified medical microbiologist and infectious disease physician. Dr. Rubach was stationed full-time in Moshi, Tanzania 2012-2014. He has engaged successfully in clinical research on febrile illness and the epidemiology of bacterial zoonotic infections under the mentorship of Dr. Crump and in the context of Dr. Crump's productive zoonoses research program, comprised of over 20 collaborating scholars from multiple disciplines. This institutional environment in Tanzania, the excellent mentorship team as well as directed coursework through the London School of Hygiene & Tropical Medicine MSc Epidemiology distance learning program will collectively enable the Candidate to achieve the following TRAINING OBJECTIVES: TRAINING OBJECTIVE 1—To develop further expertise in epidemiologic research, clinical research study design, and quantitative analysis (Drs. Crump & Gray; coursework). TRAINING OBJECTIVE 2 – To develop further expertise in the epidemiology of zoonotic infections (Drs. Crump & Gray; coursework). TRAINING OBJECTIVE 3—To develop further technical expertise in innovative diagnostic microbiology through mentored clinical research that utilizes novel pathogen detection and pathogen discovery laboratory techniques (Dr. Wang). Ultimately, Dr. Rubach aspires to improve infectious disease diagnostic capacity in resource-limited settings by conducting relevant clinical research as Duke University faculty stationed full-time at the KCMC- Duke University Health Research Collaboration in Moshi, Tanzania. This early career award will equip Dr. Rubach with technical expertise in innovative diagnostics that will differentiate him from his Primary Mentor and will enable Dr. Rubach to develop an independent research track with novel approaches to infectious disease diagnostics for clinical and epidemiologic research. Through the mentorship and training objectives in this proposal, Dr. Rubach will emerge with a highly unique skillset that bridges world-class infectious disease epidemiology research in the field with state-of-the-art technical expertise in diagnostic microbiology. As such, he will be well positioned to seek R01 funding support for further studies on the diagnosis, management and epidemiology of zoonotic and non-zoonotic causes of SFI.