Abstract
Genital tract infections with Chlamydia trachomatis (C. trachomatis) are the most frequent sexually transmitted disease worldwide. Severe clinical sequelae such as pelvic inflammatory disease (PID), tubal occlusion, and tubal infertility are linked to inflammatory processes of chronically infected tissues. The oxygen concentrations in the female urogenital tract are physiologically low and further diminished (0.5–5% O2, hypoxia) during an ongoing inflammation. However, little is known about the effect of a low oxygen environment on genital C. trachomatis infections. In this study, we investigated the host immune responses during reactivation of IFN-γ induced persistent C. trachomatis infection under hypoxia. For this purpose, the activation of the MAP-kinases p44/42 and p38 as well as the induction of the pro-inflammatory cytokines IL-1β, IL-6, IL-8, and MCP-1 were analyzed. Upon hypoxic reactivation of IFN-γ induced persistent C. trachomatis infection, the phosphorylation of the p44/42 but not of the p38 MAP-kinase was significantly diminished compared to IFN-γ induced chlamydial persistence under normoxic condition. In addition, significantly reduced IL-6 and IL-8 mRNA expression levels were observed for reactivated Chlamydiae under hypoxia compared to a persistent chlamydial infection under normoxia. Our findings indicate that hypoxia not only reactivates IFN-γ induced persistent C. trachomatis infections resulting in increased bacterial growth and progeny but also dampens inflammatory host immune signaling responses that are normally observed in a normoxic environment.
Highlights
Chlamydia trachomatis (C. trachomatis) is an obligate intracellular pathogen and the most frequent sexually transmitted bacterium worldwide
TRACHOMATIS INFECTION UNDER HYPOXIA To further investigate the influence of reactivated C. trachomatis on host cell immune responses under hypoxia, we analyzed the activation of the MAP-kinases p44/42 and p38 (Figure 3) which were described to be activated during productive infection under normoxic conditions
This is the first report showing that the activation of the MAP-kinase p44/42 and the expression of the pro-inflammatory cytokines IL-6 and IL-8 were diminished in reactivated C. trachomatis infection under hypoxia compared to persistently infected cells under normoxia
Summary
Chlamydia trachomatis (C. trachomatis) is an obligate intracellular pathogen and the most frequent sexually transmitted bacterium worldwide. Reoccurrence or a chronic infection with C. trachomatis are discussed to be central mediators of disease progression and final outcome (Dean et al, 2000) It is not clear whether chlamydial reoccurrence after a symptomatic episode with/without antibiotic treatment occurs mainly due to reinfection transferred from the sexual partner or due to reactivation of persistent C. trachomatis from a silent state (Golden et al, 2005; Geisler, 2007). Phillips et al could show a reduced number of infectious Chlamydiae in persistent infection while pre-16s rRNA expression was not changed, indicating a viable but not infectious chlamydial form (Phillips et al, 2012) They could show chlamydial inclusions with abnormal reticulate bodies but without elementary bodies (EBs) via transmission electron microscopy (Phillips et al, 2012). These findings were in line with the observations of in vitro persistence models
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