IFNg at the frontline of tuberculosis control : investigating the dynamic responses to IFNg in distinct macrophage populations
Tuberculosis (TB) is a major public health concern, affecting millions of people worldwide. Current Mycobacterium tuberculosis (Mtb) treatment strategies have many limitations including long treatment duration, drug toxicity, emergence of drug-resistant strains, and inadequate efficacy. One new strategy to eradicate Mtb is the use of host directed therapy; however, we must first gain a better understanding of how the host responds to Mtb infection. Understanding that IFNγ is critical for Mtb control, we used IFNγ to dissect macrophage responses. Here, we used a CRISPR Cas9 screen to broadly understand genes necessary for IFNγ-dependent MHCII expression. MHCII drives T-cell activation needed for pathogen clearance. Additionally, we took advantage of a new alveolar macrophage model, known as FLAMs, that was optimized by our lab, to better understand AM IFNγ-responses. Our findings reveal that IFNγ robustly activates both macrophage types; however, the profile of activated IFNγ-stimulated genes varies significantly. Notably, FLAMs show limited activation of costimulatory markers essential for T cell activation upon IFNγ stimulation alone. However, with the inhibition of GSK3α/β, a well-conserved multifunctional kinase, FLAMs express a high amount of co-stimulatory molecules, particularly CD40. We also discovered that TNF and IFNγ contribute to the increase in costimulatory molecules during GSK3α/β inhibition and IFNγ stimulation. Together, these data suggest that AMs' capacity to respond to IFNγ is restricted in a GSK3α/β dependent manner and that IFNγ responses differ across distinct macrophage populations.
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- In Collections
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Electronic Theses & Dissertations
- Copyright Status
- In Copyright
- Material Type
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Theses
- Authors
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Ankley, Laurisa M.
- Thesis Advisors
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Olive, Andrew
- Committee Members
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Pyeon, Dohun
Petroff, Margaret
Rockwell, Cheryl
Crosson, Sean
- Date Published
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2023
- Subjects
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Microbiology
Immunology
- Program of Study
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Microbiology and Molecular Genetics - Doctor of Philosophy
- Degree Level
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Doctoral
- Language
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English
- Pages
- 177 pages
- ISBN
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9798379530136
- Permalink
- https://doi.org/doi:10.25335/wvze-b749