Chlamydia trachomatis Disrupts N-Cadherin-Dependent Cell-Cell Junctions and Sequesters β-Catenin in Human Cervical Epithelial Cells

Abstract

The cadherin/catenin complex serves as an important structural component of adherens junctions in epithelial cells. Under certain conditions, ␤-catenin can be released from this complex and interact with transcription factors in the nucleus to stimulate the expression of genes that regulate apoptosis and cell cycle control. While studying the effects of the bacterial pathogen Chlamydia trachomatis on human cervical epithelial cells in culture, we observed that C. trachomatis caused the epithelial cells to separate from each other without detaching from their growing surface. The objective of the present study was to determine if this effect might involve the disruption of the cadherin/catenin complex. Primary cultures of human cervical epithelial cells or HeLa cells were infected with C. trachomatis serovar E. Cadherin-like immunoreactive materials and ␤-catenin were visualized by immunofluorescence. Preliminary studies showed that N-cadherin was the primary cadherin expressed in both the primary cultures and the HeLa cells. In noninfected cells, N-cadherin and ␤-catenin were colocalized at the intercellular junctional complexes. By contrast, the infected cells showed a marked loss of both N-cadherin and ␤-catenin labeling from the junctional complexes and the concomitant appearance of intense ␤-catenin labeling associated with the chlamydial inclusion. The results of Western blot analyses of extracts of C. trachomatis showed no evidence of cross-reactivity with the ␤-catenin antibody. These results indicate that C. trachomatis causes the breakdown of the N-cadherin/␤-catenin complex and that the organism can sequester ␤-catenin within the chlamydial inclusion. This could represent an important mechanism by which C. trachomatis alters epithelial cell function.Chlamydia trachomatis is an obligate intracellular bacterial pathogen that typically infects columnar epithelial cells but which may also infect a variety of other types of mammalian cells (24). The organism can exist as a metabolically dormant elementary body and an active reticulate body. The initial infection involves the attachment of the elementary body to the cell surface and the subsequent internalization of the organism. Inside the cell, the elementary body differentiates to form reticulate bodies that replicate within a vacuole, or "inclusion," in the cytoplasm. Chlamydiae depend on their host cell for nutritional support and can alter cellular function to evade various intracellular defense mechanisms, inhibit apoptosis, direct vesicular traffic, disrupt cytoskeletal arrangements, and alter host cell signaling mechanisms (for reviews, see references 24 and 25).Despite extensive research efforts, the exact mechanisms by which C. trachomatis causes derangements of host cell physiology remain poorly understood. During the course of studies to address this problem, we observed that infection of primary cultures of human cervical epithelial cells with C. trachomatis caused the cells to separate from each other without detaching from their growing surfa...

Potential Mechanisms for Increased HIV-1 Transmission Across the Endocervical Epithelium During C. trachomatis Infection

“…That said, preliminary results in A2EN endocervical cells grown under strict polarizing conditions indicate that infection with C. trachomatis serovar D exerts quite minimal and transient effects on endocervical epithelial integrity (Buckner, Schust and Quayle, unpublished observations). This possible discrepancy between our current findings and those of others [31],[33] may be due to the infected cell type, C. trachomatis serovar choice (see above), and/or chlamydial preference for an exocytic versus a lytic exit strategy [17, 81]. These issues are currently under further investigation in our polarized model.…”

“…Since infection of immune cells expressing the primary HIV receptor, CD4, and HIV’s chemokine co-receptors, CXCR4 or CCR5, is known to cause the major disease manifestations of HIV infection, a local increase in HIV target cells in the presence of chlamydial infection could be assumed to be a primary factor linking increased HIV transmissibility to C. trachomatis infection. C. trachomatis infection has also been shown to decrease epithelial integrity in vitro , as evidenced by decreased transepithelial resistance and cervical epithelial cell shedding in selected C. trachomatis -infected genital epithelial models [31–33]. This could facilitate movement of HIV-1 between mucosal epithelial cells and allow direct contact with infiltrating immune cells.…”

“…They and others [33, 78–80] have demonstrated that the ability of fluid and small particles contained within that fluid to traverse the space between these epithelial cells is influenced by the function of several of the molecular components in intercellular junctional complexes, including the N-cadherin/catenin complex and the nectin-afadin complex. Both complexes have been shown to be disrupted by C. trachomatis infection in vitro [31, 33]. These reports were generated using C. trachomatis serovar E to infect cervical adenocarcinoma cell lines [HeLa cells grown in monolayers [31, 33] or under polarizing conditions [33]] or using primary cervical epithelial cells cultured under non-polarizing conditions [31].…”

“…Both complexes have been shown to be disrupted by C. trachomatis infection in vitro [31, 33]. These reports were generated using C. trachomatis serovar E to infect cervical adenocarcinoma cell lines [HeLa cells grown in monolayers [31, 33] or under polarizing conditions [33]] or using primary cervical epithelial cells cultured under non-polarizing conditions [31]. They have never been performed on cells derived from the endocervix.…”

Chlamydiae and polymorphonuclear leukocytes: unlikely allies in the spread of chlamydial infection

“…Chlamydial infection in epithelial cells has also been reported to disrupt the cadherin‐dependent epithelial cell lateral junctional complexes, which leads to host cell rounding and retraction from neighboring epithelia (Fig. 5a, top monolayer) (Prozialeck et al , 2002) and more release of intact infected epithelial cells into the lumen. In addition, lysis of some infected cells occurs with release of chlamydiae into the extracellular milieu (Figs 5b and 7a).…”