Novel CSF Diagnostics and Genotype Markers of Tuberculous Meningitis in Zambia

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DESCRIPTION (provided by applicant): I am a board-certified neurologist with fellowship training in epilepsy at Beth Israel Deaconess Medical Center (BIDMC). I am now based full-time in Lusaka, Zambia at the University Of Zambia School Of Medicine (UNZA-SOM). I am interested in maximizing cerebrospinal fluid (CSF) diagnostics of HIV- associated neurological diseases and leveraging this information to improve patient outcomes in sub-Saharan Africa. My proposed research training will include coursework and tutorials with a focus on developing research skills in (1) neuroepidemiology, (2) laboratory diagnostics in resource limited settings, (3) genetics, (4) neuroimaging. Through the K23, I will obtain the mentored research training needed to establish myself as an independent researcher in the field of neuroinfectious diseases. The Environment: I have assembled a mentoring committee composed of three neurologists with expertise in global health, neuroepidemiology, neuroimaging, genetics, and Neuro-HIV. My primary mentor, Dr. Igor Koralnik, is a neurologist with expertise in Neuro-HIV and molecular diagnostics. I have two talented co- mentors with more than 30 years of combined experience in neurological research in Zambia: (1) Dr. Gretchen Birbeck is a preeminent neurological researcher in the field of global health in sub-Saharan Africa; (2) Dr. Masharip Atadzhanov has clinical expertise in Neuro-HIV care with active research projects in neurogenetics and neuroinfectious diseases. I have access to unprecedented laboratory and neuroimaging facilities in sub- Saharan Africa to carry out the proposed study. I have my own molecular diagnostic laboratory developed over the last three years at UNZA-SOM. The University Teaching Hospital has modern computed tomography and magnetic resonance imaging units that are already employed in active research. I have also secured research collaboration with the Zambian AIDS Related Tuberculosis (ZAMBART) Project, internationally recognized as one of the most well-established HIV/TB research programs in the world. Research Plan: Tuberculosis meningitis (TBM) is a major cause of morbidity and mortality in Zambia. There is a lack of ability to properly diagnose TBM worldwide. As a result, patients are often treated empirically with minimal objective measures to help guide treatment. We will focus on three important areas to help guide TBM diagnosis, treatment, and prognosis. First, we will attempt to improve the diagnosis of tuberculosis meningitis (TBM) through the use of two novel technologies established for the diagnosis of pulmonary tuberculosis. Second, we will examine host genetic factors as they relate to survival. Third, we will correlate host genetic factors with neuroinflammatory changes seen on neuroimaging. Aim 1: To determine the sensitivity and specificity of Expert MTB/RIF and LAM lateral flow dipstick to diagnose TBM in fresh CSF samples. We will use existing technologies developed for sputum and urine studies to examine the CSF of 550 HIV+ Zambians presenting to the University Teaching Hospital with clinical symptoms concerning for TBM and compare the results to the reference standard of CSF culture. Aim 2: To characterize the impact of LTA4H polymorphisms on survival of Zambian patients with TBM. We will determine if a single nucleotide polymorphism for a gene involved in the neuroinflammatory response to TBM affects survival in 157 patients. Aim 3: To decipher the role of LTA4H genotypes in neuroinflammation in Zambian patients with TBM. We will correlate host genotype for the LTA4H polymorphism with MRI neuroinflammatory findings in 100 TBM patients. These studies will provide objective measures to aid the diagnosis and appropriate treatment of TBM while having a global impact. The findings from this research will build towards future treatment studies that will improve neurological outcomes in TBM patients throughout the world and help me transition into an independent physician scientist.