Interferon-γ interferes with host cell metabolism during intracellular Chlamydia trachomatis infection

Interferon-gamma (IFN-gamma) is a central mediator of host immune responses including T-cell differentiation and activation of macrophages for the control of bacterial pathogens. Anti-bacterial mechanisms of IFN-gamma against the obligate intracellular bacteria Chlamydia trachomatis in epithelial cells have been intensively investigated in the past, focusing on cellular tryptophan depletion by an IFN-gamma induced expression of the indoleamine 2, 3-deoxygenase (IDO). In this study, we could show that IFN-gamma treatment caused a significant reduction of the host cell glycolysis that was accompanied by a reduction of glucose transporter-1 (GLUT1) and hypoxia inducible factor-1 alpha (HIF-1 alpha) expression. Furthermore, C. trachomatis induced enhancement of glycolytic and mitochondrial activation were significantly suppressed by IFN-gamma treatment. We could further show that glucose starvation, as observed under IFN-gamma treatment, was associated with an attenuated antimicrobial efficacy of doxycycline (DOX) against C. trachomatis. In conclusions, anti-chlamydial activity of IFN-gamma goes beyond tryptophan depletion including interference with cellular energy metabolism resulting reduced progeny, but also impaired antimicrobial susceptibility of C. trachomatis.