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

Abstract

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 (O 2 < 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 L 2 , 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.Chlamydia trachomatis | hypoxia | persistence | urogenital tract infections

Hypoxia Triggers the Expression of Human β Defensin 2 and Antimicrobial Activity against Mycobacterium tuberculosis in Human Macrophages

“…In contrast, one report demonstrates an opposite effect on epithelial cells (36). Specifically, cells isolated from fallopian tubes and cultured at low oxygen conditions were permissive for the growth of the intracellular bacterium Chlamydia trachomatis.…”

“…Specifically, cells isolated from fallopian tubes and cultured at low oxygen conditions were permissive for the growth of the intracellular bacterium Chlamydia trachomatis. This was shown to be related to an impaired response to IFN-g, resulting in reduced phosphorylation of STAT-1 and activity of indolaminoxygenase (36). These few available studies suggest that antimicrobial defenses in epithelial cells are hampered by the restriction of oxygen, whereas they are strengthened in macrophages, possibly reflecting the elementary role of macrophages in the elimination of intracellular pathogens at inflammatory sites.…”

BCG Vaccination Induces Robust CD4+ T Cell Responses to Mycobacterium tuberculosis Complex–Specific Lipopeptides in Guinea Pigs

“…Although activated T cells patrol the outer layer (49) and keep mycobacteria under control, the inner caseous lesion is devoid of T cells and lined with macrophages in which mycobacteria persist and multiply (50). This failure of immune control results because under hypoxic conditions, as they prevail in the inner area of the granuloma (51), the effectiveness of inflammatory T cell functions is reduced (52). The fact that T cells are capable of eliminating bacteria in the periphery, but are unable to access and exert their effector function inside the granuloma, is reminiscent of what we know about the efficacy of BCG vaccination: in early childhood, BCG reliably protects from mycobacterial dissemination and severe systemic manifestations (53), but no evidence exists that BCG protects from granuloma formation in the lung (54).…”

Impact of a Low-Oxygen Environment on the Efficacy of Antimicrobials against Intracellular Chlamydia trachomatis

“…We and others showed that chlamydiae adapted well to a low-oxygen environment and directly interfered with the stabilization of HIF-1␣, the central mammalian oxygen sensor, to replicate (17,26). In addition, gamma interferon (IFN-␥) could not control intracellular growth of C. trachomatis in human fallopian tube cells in a low-oxygen environment, which can be found in the urogenital tract in women (25).…”