Chlamydia trachomatis disturbs epithelial tissue homeostasis in fallopian tubes via paracrine Wnt signaling.

The obligate intracellular pathogen Chlamydia trachomatis (Ctr) is a major cause of sexually transmitted disease and infertility worldwide. Ascending genital infections cause inflammation of fallopian tubes and subsequent scarring and occlusion. The cellular basis for such sequelae remains undetermined. We used confocal immunofluorescence microscopy to show that Ctr disrupts epithelial homeostasis in an ex vivo infection model of human fallopian tubes. Ctr triggered loss of polarity of inclusion harboring cells and of neighboring uninfected cells, as shown by subcellular redistribution of adhesion and polarity (occludin) markers. ß-catenin (a component of the adherens junction and a Wnt signaling transducer) was recruited to the bacterial inclusion, suggesting a role for Wnt signaling in Ctr-mediated tissue damage. Comparative microarray analysis of infected epithelium in the presence of the Wnt secretion inhibitor (IWP2) demonstrated that the transcriptional response to Ctr infection was highly dependent on active Wnt secretion, moreover IWP2 reversed Ctr-induced tissue phenotypes. Notably, we observed the up-regulation of differentiation and proliferation biomarkers olfactomedin 4 and epithelial cell adhesion molecule, and also Ctr-induced proteolytic activation of epithelial cell adhesion molecule. Thus, acute Ctr infection activates the paracrine Wnt signaling pathway, leading to profound disruption of epithelial structure and function that facilitates the dissemination of damage beyond that of infected cells.

Tarp regulates early Chlamydia-induced host cell survival through interactions with the human adaptor protein SHC1.

Many bacterial pathogens translocate effector proteins into host cells to manipulate host cell functions. Here, we used a protein microarray comprising virtually all human SRC homology 2 (SH2) and phosphotyrosine binding domains to comprehensively and quantitatively assess interactions between host cell proteins and the early phase Chlamydia trachomatis effector protein translocated actin-recruiting phosphoprotein (Tarp), which is rapidly tyrosine phosphorylated upon host cell entry. We discovered numerous novel interactions between human SH2 domains and phosphopeptides derived from Tarp. The adaptor protein SHC1 was among Tarp's strongest interaction partners. Transcriptome analysis of SHC1-dependent gene regulation during infection indicated that SHC1 regulates apoptosis- and growth-related genes. SHC1 knockdown sensitized infected host cells to tumor necrosis factor-induced apoptosis. Collectively, our findings reveal a critical role for SHC1 in early C. trachomatis-induced cell survival and suggest that Tarp functions as a multivalent phosphorylation-dependent signaling hub that is important during the early phase of chlamydial infection.