Ascension of Chlamydia is moderated by uterine peristalsis and the neutrophil response to infection.

Chlamydia trachomatis is a common sexually transmitted infection that is associated with a range of serious reproductive tract sequelae including in women Pelvic Inflammatory Disease (PID), tubal factor infertility, and ectopic pregnancy. Ascension of the pathogen beyond the cervix and into the upper reproductive tract is thought to be necessary for these pathologies. However, Chlamydia trachomatis does not encode a mechanism for movement on its genome, and so the processes that facilitate ascension have not been elucidated. Here, we evaluate the factors that may influence chlamydial ascension in women. We constructed a mathematical model based on a set of stochastic dynamics to elucidate the moderating factors that might influence ascension of infections in the first month of an infection. In the simulations conducted from the stochastic model, 36% of infections ascended, but only 9% had more than 1000 bacteria ascend. The results of the simulations indicated that infectious load and the peristaltic contractions moderate ascension and are inter-related in impact. Smaller initial loads were much more likely to ascend. Ascension was found to be dependent on the neutrophil response. Overall, our results indicate that infectious load, menstrual cycle timing, and the neutrophil response are critical factors in chlamydial ascension in women.

Sortilin is associated with the chlamydial inclusion and is modulated during infection.

Chlamydia species are obligate intracellular pathogens that have a major impact on human health. The pathogen replicates within an intracellular niche called an inclusion and is thought to rely heavily on host-derived proteins and lipids, including ceramide. Sortilin is a transmembrane receptor implicated in the trafficking of acid sphingomyelinase, which is responsible for catalysing the breakdown of sphingomyelin to ceramide. In this study, we examined the role of sortilin in Chlamydia trachomatis L2 development. Western immunoblotting and immunocytochemistry analysis revealed that endogenous sortilin is not only associated with the inclusion, but that protein levels increase in infected cells. RNAi-mediated depletion of sortilin, however, had no detectable impact on ceramide delivery to the inclusion or the production of infectious progeny. This study demonstrates that whilst Chlamydia redirects sortilin trafficking to the chlamydial inclusion, RNAi knockdown of sortilin expression is insufficient to determine if this pathway is requisite for the development of the pathogen.

Evidence of a conserved role for Chlamydia HtrA in the replication phase of the chlamydial developmental cycle.

Identification of the HtrA inhibitor JO146 previously enabled us to demonstrate an essential function for HtrA during the mid-replicative phase of the Chlamydia trachomatis developmental cycle. Here we extend our investigations to other members of the Chlamydia genus. C. trachomatis isolates with distinct replicative phase growth kinetics showed significant loss of viable infectious progeny after HtrA was inhibited during the replicative phase. Mid-replicative phase addition of JO146 was also significantly detrimental to Chlamydia pecorum, Chlamydia suis and Chlamydia cavie. These data combined indicate that HtrA has a conserved critical role during the replicative phase of the chlamydial developmental cycle.