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Principal Investigator: Andrew Olive
Organization: MICHIGAN STATE UNIVERSITY
Fiscal Year: 2024
Award: $523,984
Funding agency: National Institute of Allergy and Infectious Diseases
Summary
Tuberculosis (TB) is a leading cause of death by infectious disease worldwide. Current therapy requires at least six
months of treatment and there is no effective vaccine that prevents pulmonary disease. There is a critical need to
develop new therapies that will shorten treatment time and activate protective responses to prevent TB progression.
Unfortunately, we continue to lack a fundamental understanding of the host immune pathways that protect against
TB. While the cytokine interferon γ (IFNγ) is absolutely required, the precise mechanisms that drive IFNγ-mediated
protection remain unclear. This is because IFNγ is a pleotropic mediator that controls both bacterial growth and the
inflammatory response in the lungs, while bridging the innate and adaptive immune responses. To dissect the
complex regulation of IFNγ responses, we conducted a genome-wide CRISPR Cas9 screens in macrophages to
define the networks required for the IFNγ-mediated surface expression of MHCII. This screen uncovered an important
role for the glycerol 3 kinase beta (GSK3b) in controlling IFNγ-dependent MHCII expression. Using chemical and
genetic approaches coupled with transcriptome analysis we found that GSK3b and the paralog GSK3a contribute to
the expression of a subset of IFNγ-inducible genes. Further mechanistic studies found that the loss of
GSK3a/b blocks the ability of macrophages to serve as antigen presenting cells to CD4+ T cells ex vivo and results
in dysregulated cytokine production by macrophages during M. tuberculosis infection. Thus, GSK3a/b balances the
cellular response to IFNγ to protect against infection without driving inflammatory tissue damage. These data lead to
the hypothesis that GSK3a/b is a critical mediator of the IFNγ response during TB in vivo. This proposal will use
genetic approaches combined with in vivo models to dissect the role of GSK3a/b-mediated control of IFNγ responses
and TB. Aim 1 will understand the mechanisms that regulate GSK3a/b control of IFNγ responses and determine how
M. tuberculosis modulates GSK3a/b activity. In Aim 2, we will use unique models of bacterial control and inflammation
to examine how the loss of myeloid-specific GSK3a and/or GSK3b disrupts the IFNγ-mediated control of M.
tuberculosis growth and tissue damage. Finally, in Aim 3 we will use M. tuberculosis specific TCR-transgenic T cell
mice to test the hypothesis that the loss of myeloid GSK3a and/or GSK3b results in reduced T cell responses and
ineffective protection against TB. Together these aims will dissect the role of GSK3a/b in controlling IFNγ-responses
and protecting against TB. These mechanisms can then be leveraged to develop new therapies that may shorten
treatment times and prevent TB disease progression.
Terms: <1,2,3-Propanetriol><1,2,3-Trihydroxypropane><Address><Antigen Presentation><Antigen-Presenting Cells><Automobile Driving><Bacterial Model><Body Tissues><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CRISPR editing screen><CRISPR screen><CRISPR-based screen><CRISPR/Cas9 screen><Cause of Death><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Function><Cell Interaction><Cell Physiology><Cell Process><Cell Signaling><Cell-to-Cell Interaction><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cessation of life><Chemicals><Chronic><Communicable Diseases><Complex><Coupled><Data><Death><Development><Disease><Disease Progression><Disorder><Disputes><Epidemic><Equilibrium><Generalized Growth><Genes><Genetic Screening><Glycerin><Glycerol><Glycogen Synthase Kinases><Goals><Growth><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><Immune><Immune Evasion><Immune Interferon><Immune response><Immunes><Immunity><Immunological response><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammation><Inflammatory><Inflammatory Response><Innate Immune Response><Interferon Gamma><Interferon Type II><Intracellular Communication and Signaling><Kinases><Kinetics><Knowledge><Lead><Lung><Lung Diseases><Lung Parenchyma><Lung Respiratory System><Lung Tissue><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><Macrophage Activation><Mediating><Mediator><Metabolic><Mice><Mice Mammals><Murine><Mus><Mycobacterium tuberculosis><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><Myelogenous><Myeloid><Mφ><Outcome><Pathogenesis><Pathologic><Pathway interactions><Pb element><Phosphotransferase Gene><Phosphotransferases><Play><Production><Public Health><Pulmonary Diseases><Pulmonary Disorder><Regulation><Role><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Structure of parenchyma of lung><Subcellular Process><Surface><T cell response><T-Cell Activation><T4 Cells><T4 Lymphocytes><TB infection><Teff cell><Testing><Time><Tissue Growth><Tissues><Transphosphorylases><Tuberculosis><Vaccines><Virulence><accessory cell><activate T cells><adaptive immune response><balance><balance function><biological signal transduction><clustered regularly interspaced short palindromic repeats screen><cytokine><developmental><disease of the lung><disorder of the lung><disseminated TB><disseminated tuberculosis><driving><effective therapy><effective treatment><effector T cell><engineered T cells><genetic approach><genetic strategy><genetically engineered T-cells><genome scale><genome-wide><genomewide><global gene expression><global transcription profile><heavy metal Pb><heavy metal lead><host response><immune evasive><immune system response><immunoresponse><in vivo><in vivo Model><infection due to Mycobacterium tuberculosis><interdisciplinary approach><lFN-Gamma><lung disorder><mtb><multidisciplinary approach><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><ontogeny><paralog><paralogous gene><pathogen><pathway><prevent><preventing><protection pathway><protective pathway><pulmonary><response><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><transcriptome><transgenic T- cells><tuberculosis infection><tuberculous spondyloarthropathy>