Next-Generation Diagnostics for Acute Encephalitis

急性脑炎的下一代诊断

• 批准号: 10077591
• 负责人: Michael R Wilson
• 金额: $ 19.97万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10077591
• 关键词: 14 year old; Acute; Aftercare; Algorithms; Autoantibodies; Autoimmune encephalitis; Back; Bacteria; Bioinformatics; Biological Assay; Biological Sciences; Biopsy; Boston; Brain; California; Cerebrospinal Fluid; Cessation of life; Clinical; Clinical Research; Clustered Regularly Interspaced Short Palindromic Repeats; Communicable Diseases; Critical Illness; Custom; Data; Data Set; Databases; Diagnosis; Diagnostic; Disease; Early Diagnosis; Early treatment; Emerging Communicable Diseases; Encephalitis; Environment; Equipment; Etiology; Failure; Fellowship; Funding; General Hospitals; Genetic Materials; Genomics; Goals; Health Care Costs; Human; Hypercapnic respiratory failure; Impaired cognition; Individual; Infection; Infectious Agent; Infectious Diseases Research; Infectious Encephalitis; Inflammatory; Inpatients; Institutes; K-Series Research Career Programs; Knowledge; Libraries; Massachusetts; Mentored Clinical Scientist Development Award (K08); Mentors; Mentorship; Metagenomics; Methods; Microbe; Microbiology; Molecular; NCI Scholars Program; Neurologic; Neurologic Symptoms; Neurology; Neurosciences; Paralysed; Parasites; Participant; Pathogen detection; Patient-Focused Outcomes; Patients; Penicillins; Physicians; Pilot Projects; Population Surveillance; Positioning Attribute; Prospective cohort; Prospective cohort study; Publishing; RNA; Recovery; Research; Research Methodology; Research Personnel; Sampling; Scientist; Seizures; Speed; Statistical Models; Survivors; Syndrome; Techniques; Testing; Time; Tissues; Training; Transcript; United States; Universities; Virus; Work; base; boys; brain parenchyma; brain tissue; cohort; comorbidity; cost; design; detection limit; diagnostic platform; disability; experience; fungus; genomic tools; improved; improved outcome; innovation; mental state; microbial; microbial community; mortality; next generation sequencing; novel; novel diagnostics; nuclease; pathogen; professor; recruit; research clinical testing; statistics; success; targeted treatment; technological innovation; tool; translational research program; treatment trial

PROJECT SUMMARY/ABSTRACT Encephalitis is a heterogeneous syndrome defined by inflammation of the brain parenchyma leading to altered mental status and frequently, many other neurologic signs and symptoms including seizures, paralysis, hypoventilation and in some cases, death. Well over 100 viruses, autoantibodies, parasites, bacteria and fungi cause encephalitis, but in at least half of cases, no etiology is identified. Failure to identify an etiologic agent delays targeted therapies to patients and leads to empiric treatment trials that are sometimes ineffective and other times, actually exacerbate the patient's underlying condition. My goal in seeking a K08 Mentored Clinical Scientist Research Career Development Award is to acquire the necessary training, practical experience and knowledge to make major advances in our understanding of the causes of encephalitis. My long-term goal is to reduce the large number of idiopathic encephalitis cases by enhancing a novel diagnostic platform. I hypothesize that a novel molecular approach will improve the limits of detection for microbes in our next-generation sequencing (NGS) assay that aims to detect any class of microbe in cerebrospinal fluid and brain tissue (Subaim 1A). I hypothesize that a novel statistical approach will help to rigorously discriminate between microbial contamination vs. true infection in the metagenomic data collected from our NGS assay (Subaim 1B). I will harness these new molecular and analytic approaches to more frequently and accurately identify pathogens via metagenomic NGS in an ongoing, multicenter, prospective cohort study of patients with idiopathic encephalitis (Aim 2). During my self-designed fellowship in Neuro-Infectious Diseases at Massachusetts General Hospital and Boston University's National Emerging Infectious Diseases Laboratories, I acquired a unique skillset and was recruited back to UCSF as an Assistant Adjunct Professor in the Department of Neurology. I have put together a world-class team of mentors and advisors to guide me through this career development phase in order to launch myself successfully as an independent investigator. The research environment at UCSF is exceptional and includes cutting edge scientists and state-of-the-art equipment in the California Institute of Quantitative Biosciences (QB3) and the Sandler Neurosciences Building. My training plan is specifically designed to provide advanced training in clinical research methods, statistics, bioinformatics and microbiology that will be necessary to actualize these goals and position me to obtain R01 or equivalent funding as an independent investigator. I also intend to be an active participant in the K-Scholars program.

项目摘要/摘要 脑炎是一种由脑实质的炎症定义的异质综合征，导致改变 精神状态，经常，许多其他神经系统症状和症状，包括癫痫发作，瘫痪， 不足驱动，在某些情况下是死亡。超过100多个病毒，自身抗体，寄生虫，细菌和真菌 引起脑炎，但在至少一半的情况下，未发现病因。无法识别病因 针对患者的延迟疗法的延迟，并导致有时无效的经验治疗试验 其他时候，实际上会加剧患者的潜在状况。 我寻求K08指导的临床科学家研究职业发展奖的目标是获得 我们对理解的重大进步的必要培训，实践经验和知识 脑炎的原因。我的长期目标是通过减少大量特发性脑炎病例 增强新颖的诊断平台。我假设一种新颖的分子方法将改善 我们的下一代测序（NGS）测定中的微生物检测，该测定旨在检测任何类别的微生物 在脑脊液和脑组织中（Subaim 1a）。我假设一种新颖的统计方法将有助于 严格区分微生物污染与收集的宏基因组数据中的真实感染 来自我们的NGS分析（Subaim 1b）。我将利用这些新的分子和分析方法 在正在进行的多中心中，经常，准确地通过元基因组NG识别病原体 对特发性脑炎患者的队列研究（AIM 2）。 在我在马萨诸塞州综合医院进行神经感染疾病的自我设计奖学金期间 波士顿大学的国家新兴传染病实验室，我获得了独特的技能，是 担任神经病学系的助理兼职教授，招募回到UCSF。我已经把 一个世界一流的导师和顾问团队，指导我进入这个职业发展阶段 作为独立调查员成功启动自己。 UCSF的研究环境非常出色 并包括加利福尼亚定量研究所的尖端科学家和最先进的设备 生物科学（QB3）和桑德勒神经科学大楼。我的培训计划是专门设计的 临床研究方法，统计，生物信息学和微生物学的高级培训将是 实现这些目标并定位我以获得R01或同等资金作为独立的必要 研究者。我还打算成为K-Scholars计划的积极参与者。

项目成果

Meningitis Caused by the Live Varicella Vaccine Virus: Metagenomic Next Generation Sequencing, Immunology Exome Sequencing and Cytokine Multiplex Profiling.

• DOI: 10.3390/v13112286
• 发表时间: 2021-11-16
• 期刊: Viruses
• 作者: Ramachandran PS;Wilson MR;Catho G;Blanchard-Rohner G;Schiess N;Cohrs RJ;Boutolleau D;Burrel S;Yoshikawa T;Wapniarski A;Heusel EH;Carpenter JE;Jackson W;Ford BA;Grose C
• 通讯作者: Grose C

Acute West Nile Virus Meningoencephalitis Diagnosed Via Metagenomic Deep Sequencing of Cerebrospinal Fluid in a Renal Transplant Patient.

• DOI: 10.1111/ajt.14058
• 发表时间: 2017-03
• 期刊: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
• 作者: Wilson MR;Zimmermann LL;Crawford ED;Sample HA;Soni PR;Baker AN;Khan LM;DeRisi JL
• 通讯作者: DeRisi JL

Hepatitis E Virus-Associated Meningoencephalitis in a Lung Transplant Recipient Diagnosed by Clinical Metagenomic Sequencing.

通过临床宏基因组测序诊断肺移植受者的戊型肝炎病毒相关脑膜脑炎。

• DOI: 10.1093/ofid/ofx121
• 发表时间: 2017
• 期刊: Open forum infectious diseases
• 影响因子: 4.2
• 作者: Murkey JA;Chew KW;Carlson M;Shannon CL;Sirohi D;Sample HA;Wilson MR;Vespa P;Humphries RM;Miller S;Klausner JD;Chiu CY
• 通讯作者: Chiu CY

A novel cause of chronic viral meningoencephalitis: Cache Valley virus.

• DOI: 10.1002/ana.24982
• 发表时间: 2017-07
• 期刊: Annals of neurology
• 影响因子: 11.2
• 作者: Wilson MR;Suan D;Duggins A;Schubert RD;Khan LM;Sample HA;Zorn KC;Rodrigues Hoffman A;Blick A;Shingde M;DeRisi JL
• 通讯作者: DeRisi JL

Detection of Cryptococcus DNA by Metagenomic Next-generation Sequencing in Symptomatic Cryptococcal Antigenemia.

通过宏基因组下一代测序检测有症状的隐球菌抗原血症中的隐球菌 DNA。

• DOI: 10.1093/cid/ciy1024
• 发表时间: 2019
• 期刊: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
• 作者: Ramachandran,PrashanthS;Cresswell,FionaV;Meya,DavidB;Langelier,Charles;Crawford,EmilyD;DeRisi,JosephL;Boulware,DavidR;Wilson,MichaelR
• 通讯作者: Wilson,MichaelR