Tuberculosis (TB) ranks alongside HIV as one of the world’s most deadly infectious diseases. Moreover, the increased prevalence of multi-drug resistant TB has been declared a worldwide threat to public health. New research is thus focusing on therapeutic strategies directed at promoting the host response. Therefore, understanding the mechanisms behind the immune response to Mycobacterium tuberculosis (Mtb) is crucial to developing new adjunctive host-directed therapies and informing vaccine design.
Our group have previously shown that glucose metabolism in the human alveolar macrophage is required for optimal control of intracellular bacillary replication during Mtb infection. IFN-γ plays a critical role in the intracellular killing of Mtb and its use as an aerosolized adjunctive therapy has yielded efficacy in clinical trials. We sought to determine the relationship between IFN-γ priming of macrophages, their ability to switch to aerobic glycolysis and the subsequent ability to exert effector functions to promote immunity to Mtb infection.
Priming with IFN-γ promoted the production of IL-1β, IL-12p70 and TNF from Mtb infected macrophages however; inhibiting glycolysis with 2-deoxyglucose (2DG) blocked this effect. Furthermore, IFN-γ promoted HLA-DR and co-stimulatory molecule expression on infected MDM and this was abrogated in the presence of 2DG. Infected macrophages primed with IFN-γ exhibited increased ability to promote antigen-specific T cell responses and this boost was completely abrogated when IFN-γ primed cells were infected in the presence of 2DG. Moreover, T cells co-cultured with unprimed, infected macrophages that had been metabolically inhibited with 2DG exhibited reduced capacity to produce pro-inflammatory cytokines.
These data indicate that the metabolic profile of the host macrophage has an impact on subsequent adaptive T cell responses and that the anti-bacterial effects of IFN-γ on the macrophage are mediated by changes in cell metabolism. Better understanding of these effects will inform strategies for host-directed therapy.