Advisory Committee Chair
Adrie J C Steyn
Advisory Committee Members
Louis B Justement
Date of Award
Degree Name by School
Doctor of Philosophy (PhD) School of Medicine
Despite curative treatment, tuberculosis remains a leading cause of death around the world. As such, there is great interest in novel therapeutic approaches to treat this disease. One such approach aims to enhance the efficacy of host immune cells in responding to the pathogen, Mycobacterium tuberculosis—so called host-directed therapies. The metabolism of immune cells has been a central focus in the search for hostdirected therapies, and the role of glycolysis in myeloid cells, in particular, has received much attention. However, the role of glycolysis in myeloid cells in the context of tuberculosis has not yet been made clear. Here we show that glycolysis in myeloid cells is essential for host protection in TB. We observed that mice with glycolytically deficient myeloid cells (LDHALysM-/-) are more susceptible to TB and exhibit a delayed immune response to infection with M. tuberculosis. This is associated with their inability to respond metabolically to the key antimycobacterial cytokine interferon-γ. We demonstrate that this defect can be rescued through the supplementation of pyruvate, glucogenic amino acids, or nicotinamide. Of these compounds, nicotinamide protected mice from TB in models of early and established infection. We argue that this effect is due to the enhancement of glycolysis in immune cells following treatment, and that nicotinamide should be revisited as a therapy for TB.
Pacl, Hayden Thomas, "Glycolytic Myeloid Cells Protect the Host in Tuberculosis" (2021). All ETDs from UAB. 628.