Metabolic barriers underlie interferon gamma-mediated restriction of intracellular bacterial pathogenesis

Abstract

Abstract Interferon gamma (IFNγ) plays a critical role in controlling Legionella pneumophila (L. pneumophila) infection in vivo and in vitro. IFNγ and IFNγ receptor-deficient mice fail to clear L. pneumophila and eventually succumb to infection. In vitro, L. pneumophila replication is restricted in IFNγ-stimulated macrophages; however, the mechanism of IFNγ-dependent restriction of L. pneumophila remains mysterious and does not require most known IFNγ-driven antimicrobial pathways, including induction of autophagy and production of reactive nitrogen. As enhanced glycolysis is a notable metabolic characteristic of IFNγ and toll-like receptor-stimulated macrophages, we hypothesized that changes in macrophage metabolism are required for IFNγ-mediated restriction of L. pneumophila. Using a strain of L. pneumophila that is resistant to the glycolysis inhibitor 2-deoxyglucose (2DG), we were able to rescue bacterial growth in IFNγ-stimulated macrophages treated with 2DG. Interestingly, we observed that 2DG-mediated induction of the unfolded protein response appears to be more important than glycolysis inhibition in terms of interfering with IFNγ-mediated restriction of L. pneumophila. Our data suggest that metabolic shifts in IFNγ-stimulated macrophages could play a role in restriction of intracellular bacterial pathogen replication by altering the pool of available intracellular metabolites.