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.

Public Health Relevance

More than half of the 20,000 people hospitalized for encephalitis each year in the United States fail to have the cause of their brain inflammation identified. The goal of this work is to employ a novel and innovative set of tools to identify more causes of encephalitis and to better differentiate between patients suffering from infectious encephalitis and those suffering from autoimmune encephalitis. This may allow physicians to start targeted therapies earlier in the disease course and thus improve outcomes for this rapidly progressive and frequently devastating condition.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS096117-05
Application #
10077591
Study Section
Neurological Sciences Training Initial Review Group (NST)
Program Officer
Wong, May
Project Start
2016-12-01
Project End
2021-11-30
Budget Start
2020-12-01
Budget End
2021-11-30
Support Year
5
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Neurology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Wilson, Michael R; O'Donovan, Brian D; Gelfand, Jeffrey M et al. (2018) Chronic Meningitis Investigated via Metagenomic Next-Generation Sequencing. JAMA Neurol 75:947-955
Gonzales, John; Doan, Thuy; Shantha, Jessica G et al. (2018) Metagenomic deep sequencing of aqueous fluid detects intraocular lymphomas. Br J Ophthalmol 102:6-8
Langelier, Charles; Zinter, Matt S; Kalantar, Katrina et al. (2018) Metagenomic Sequencing Detects Respiratory Pathogens in Hematopoietic Cellular Transplant Patients. Am J Respir Crit Care Med 197:524-528
Solomon, Isaac H; Spera, Kristyn M; Ryan, Sophia L et al. (2018) Fatal Powassan Encephalitis (Deer Tick Virus, Lineage II) in a Patient With Fever and Orchitis Receiving Rituximab. JAMA Neurol 75:746-750
Chiu, Charles Y; Coffey, Lark L; Murkey, Jamie et al. (2017) Diagnosis of Fatal Human Case of St. Louis Encephalitis Virus Infection by Metagenomic Sequencing, California, 2016. Emerg Infect Dis 23:1964-1968
Wilson, M R; Zimmermann, L L; Crawford, E D et al. (2017) Acute West Nile Virus Meningoencephalitis Diagnosed Via Metagenomic Deep Sequencing of Cerebrospinal Fluid in a Renal Transplant Patient. Am J Transplant 17:803-808
Murkey, Jamie A; Chew, Kara W; Carlson, Margrit et al. (2017) Hepatitis E Virus-Associated Meningoencephalitis in a Lung Transplant Recipient Diagnosed by Clinical Metagenomic Sequencing. Open Forum Infect Dis 4:ofx121
Wilson, Michael R; Suan, Dan; Duggins, Andrew et al. (2017) A novel cause of chronic viral meningoencephalitis: Cache Valley virus. Ann Neurol 82:105-114