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Control of Mycobacterium tuberculosis infection by the macrophage Glycogen Synthase Kinase-3

University of British Columbia

Tuberculosis, an infectious disease caused by Mycobacterium tuberculosis, ranks as the leading cause of mortality worldwide from a single infectious agent. The high global burden of this disease, together with the emergence of drug resistant strains, necessitates new approaches for the development of novel therapies. Amongst these new approaches are host-directed therapies, which target the human host rather than the bacterium in order to enhance the host immune response to clear the invading pathogen. M. tuberculosis is a prime candidate for host-directed therapies as it is an intracellular pathogen that primarily infects the human alveolar macrophage, where it survives and replicates intracellularly by evading the macrophage’s defence mechanisms. In this work, we used two screening assays to test libraries of human kinase inhibitors for their ability to restrict the growth of M. tuberculosis in the THP-1 human macrophage-like cell line. These screening methods identified a variety of Glycogen Synthase Kinase-3 (GSK3) inhibitor compounds that restrict the intracellular growth of M. tuberculosis, suggesting GSK3 as a potential target to restrict the growth of intracellular M. tuberculosis. GSK3 was genetically validated as a host target using siRNA mediated gene silencing and CRISPR interference in THP-1 cells infected with M. tuberculosis, highlighting its role in the control of the intracellular growth of the bacteria. In agreement with previous studies, we showed that the M. tuberculosis secreted protein, PtpA, participates in the blocking of apoptosis in the infected macrophage. Finally, we demonstrated that GSK3 inhibition induces apoptosis in infected THP-1 cells and developed a molecular model describing the induction of apoptosis in infected cells in response to mycobacterial infection. In conclusion, my studies demonstrated that GSK3 is involved in the regulation of apoptosis in infected macrophages and identified GSK3 inhibitors as potent small molecules with the ability to restrict the intracellular growth of M. tuberculosis. These findings highlight the potential of GSK3 inhibitors to be developed as host-directed therapies which could improve the outcome of the existing treatment against tuberculosis.

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2024-04-30

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http://hdl.handle.net/2429/77990

Microbiology and Immunology

University of British Columbia

UBCV

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