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Principal Investigator: Chris G Dulla
Organization: TUFTS UNIVERSITY BOSTON
Fiscal Year: 2024
Award: $467,875
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY
Tuberculosis is a global disease affecting millions of people in primarily developing regions of the world. Central
nervous system tuberculosis (CNS-TB) is the most severe extra pulmonary form of the disease, which, despite
aggressive therapeutic intervention, can have a fatality rate of up to 80%. Significant barriers to understanding
disease pathogenesis exist, which translates to poor diagnosis and treatment outcomes. Thus, improved insight
into neuro-glial-immune cell interactions in CNS TB, and the factors that regulate brain pathology require a global
molecular and cellular perspective. Our long-term goal is to understand the mechanisms associated with
the development of CNS-TB, and different CNS-TB outcomes, in order to develop novel, effective, and
broadly accessible therapeutics. Single cell/nucleus RNA sequencing (sc/snRNA-seq) gene expression
analysis allows for a large-scale view of the cells and molecular pathways involved in neuropathogenesis, with
the potential to identify novel differences between TB diseased states. In this study, we will investigate
transcriptional changes induced by M. tuberculosis infection of the brain under clinical and experimental
conditions to determine how CNS-TB starts and progresses to different outcomes. This is made possible by
preliminary snRNA-seq data generated during our Global Brain R21 that we recently completed. We hypothesize
that M. tuberculosis invades the CNS due to the failed generation of an appropriate neuroimmune response in
CNS resident and peripherally recruited immune cells. This is strongly supported by our preliminary data from
human and rodent snRNA-seq studies. By exploring the transcriptional differences in cells from normal and
diseased states we will be able to identify the cell type-specific molecular and cellular processes that underpin
the pathogenesis of CNS-TB, including neuroinflammation and immune system engagement. Understanding
cell type-specific CNS and immune signaling in CNS-TB will enable us to develop novel therapies and
improve clinical outcomes. To test our central hypothesis, we will determine the molecular pathways across
CNS and immune cells that define clinical phenotypes in patients with CNS-TB and create a full disease spectrum
signaling framework of CNS-TB using multiple mouse models. In addition to our scientific aims, we will expand
the single cell gene expression analysis platform, established at the University of Cape Town (UCT) during our
Global Brain R21 support, to the broader African scientific community. We aim to provide training in project
planning, library preparation, and data analysis. When complete, we will have a novel understanding of the
cell type-specific inflammatory signaling events that drive CNS-TB and will be poised to engage novel
molecular targets to improve CNS-TB outcomes. Furthermore, UCT will be established as a hub of single
cell biology, to launch scientific careers of the next generation of African scientists, and to improve
health care across Africa.
Terms: <(TNF)-α><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Affect><Africa><African><Biochemistry><Biological><Biological Chemistry><Brain><Brain Diseases><Brain Disorders><Brain Nervous System><Brain Pathology><C3HeB/FeJ Mouse><COVID-19 virus><COVID19 virus><Cachectin><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Death><Cell Function><Cell Interaction><Cell Nucleus><Cell Physiology><Cell Process><Cell Signaling><Cell-to-Cell Interaction><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular biology><Central Nervous System Tuberculosis><Cessation of life><Clinical><CoV-2><CoV2><Communities><Computational Biology><Data><Data Analyses><Data Analysis><Death><Development><Diagnosis><Disease><Disorder><Education><Educational aspects><Encephalon><Encephalon Diseases><Event><Expression Signature><Fatality rate><Future Generations><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profile><Gene Expression Profiling><Gene Transcription><Generalized Growth><Generations><Genetic Transcription><Goals><Granulomatous><Growth><Healthcare><Human><Human Pathology><Immune><Immune signaling><Immune system><Immunes><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Immunosuppressed Host><Infection><Inflammatory><Infrastructure><Intracellular Communication and Signaling><Intracranial CNS Disorders><Intracranial Central Nervous System Disorders><Invaded><Libraries><M tb><M tuberculosis><M tuberculosis infection><M. tb><M. tb infection><M. tuberculosis><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MTB infection><Macrophage-Derived TNF><Meningeal TB><Meningeal Tuberculosis><Meningitis><Mice><Mice Mammals><Modern Man><Molecular><Molecular Target><Monocyte-Derived TNF><Mouse Strains><Murine><Mus><Mycobacterium tuberculosis><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><Neuroimmune><Neurologic><Neurologic Dysfunctions><Neurological><Neuropathogenesis><Nucleus><Outcome><Pathogenesis><Pathway interactions><Patients><Peripheral><Persons><Phenotype><Preparation><Program Development><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Reagent><Research><Research Infrastructure><Resected><Rodent><Rodent Model><Rodentia><Rodents Mammals><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Scientist><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Severities><Signal Transduction><Signal Transduction Systems><Signaling><Single-Nucleus Sequencing><South Africa><Specificity><Structure><Subcellular Process><TB infection><TB meningitis><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Testing><Therapeutic><Therapeutic Intervention><Tissue Growth><Training><Transcript Expression Analyses><Transcript Expression Analysis><Transcription><Translating><Treatment outcome><Tuberculoma><Tuberculosis><Tuberculosis Meningitis><Tuberculous Meningitis><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Universities><Work><Wuhan coronavirus><analyze gene expression><biologic><biological signal transduction><brain tissue><career><cell biology><cell type><clinical phenotype><computer biology><coronavirus disease 2019 virus><coronavirus disease-19 virus><data interpretation><developmental><differential expression><differentially expressed><disseminated TB><disseminated tuberculosis><gene expression analysis><gene expression assay><gene expression pattern><gene expression signature><hCoV19><health care><human RNA sequencing><human RNA-seq><human data><human disease><immunosuppressed patient><improved><infection due to Mycobacterium tuberculosis><innovate><innovation><innovative><insight><intervention therapy><mouse model><mtb><murine model><nCoV2><necrocytosis><neural inflammation><neuroinflammation><neuroinflammatory><neurological dysfunction><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><ontogeny><pathogen><pathway><preparations><recruit><response><sNuc-Seq><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single nucleus RNA-sequencing><single nucleus seq><single-cell RNA sequencing><single-nucleus RNA-seq><skill acquisition><skill development><skills><snRNA sequencing><snRNA-seq><synergism><transcriptional differences><transcriptional profile><transcriptional profiling><transcriptional signature><transcriptome sequencing><transcriptomic sequencing><transcriptomics><tuberculosis infection><tuberculous spondyloarthropathy>