Hypoxia abrogates antichlamydial properties of IFN-[gamma] in human fallopian tube cells in vitro and ex vivo

• Published in: Proceedings of the National Academy of Sciences - PNAS 2010-11, Vol.107 (45), p.19502
• Main Authors: Roth, Anna, van Zandbergen, Peter Köer, Klinger, Matthias, Hellwig-Brügel, Thomas, Däubener, Walter, Bohlmann, Michael K, Rupp, Jan
• Format: Article
• Language: English
• Subjects: Bacterial infections; Cells; Hypoxia; Pathogens; Proteins; Urinary tract diseases
• ISSN: 0027-8424; 1091-6490

IFN-γ has an important role in the adaptive immune response against intracellular pathogens. In urogenital tract (UGT) infections with the obligate intracellular pathogen Chlamydia trachomatis, IFN-γ-mediated control of chlamydial growth implies the JAK-STAT signaling cascades and subsequent induction of the indoleamine 2,3-dioxygenase (IDO). As oxygen concentrations in the UGT are low under physiological conditions (O2 < 5%) and further decrease during an inflammatory process, we wondered whether antibacterial properties of IFN-γ are maintained under hypoxic conditions. Using primary cells that were isolated from human fallopian tubes and an ex vivo human fallopian tube model (HFTM), we found that even high IFN-γ concentrations (200 units/mL) were not sufficient to limit growth of C. trachomatis under hypoxia. Reduced antibacterial activity of IFN-γ under hypoxia was restricted to the urogenital serovars D and L2, but was not observed with the ocular serovar A. Impaired effectiveness of IFN-γ on chlamydial growth under hypoxia was accompanied by reduced phosphorylation of Stat-1 on Tyr701 and diminished IDO activity. This study shows that IFN-γ effector functions on intracellular C. trachomatis depend on the environmental oxygen supply, which could explain inadequate bacterial clearance and subsequent chronic infections eventually occurring in the UGT of women. [PUBLICATION ABSTRACT]