Chemokine Expression Patterns Differ within Anatomically Distinct Regions of the Genital Tract duringChlamydia trachomatisInfection

Abstract

Untreated infections with Chlamydia trachomatis commonly result in ascending infection to fallopian tubes and subsequent immune-mediated tubal pathology in females. The proposed immune-mediated injury may be associated with the increased recruitment of CD4 cells to the upper genital tract (GT) (oviducts) in comparison to the lower GT (cervix) during infection, as shown in animal models. To understand the mechanisms responsible for this biased recruitment of CD4 cells within the GT, we characterized chemokine expression patterns in the upper and lower GTs in mice during infection with the murine pneumonitis biovar of Chlamydia trachomatis. Enzyme-linked immunosorbent assays of supernatants from GT homogenates revealed that the levels of the Th1-associated chemokines CXCL9 (monokine induced by gamma interferon), CXCL10 (interferon-inducible protein 10), and CCL5 (RANTES) were significantly higher in the upper GT than in the lower GT after infection, while the CCL3 (macrophage inflammatory protein 1␣) level was not increased. In contrast, the level of chemokine CCL11 (eotaxin) was significantly elevated in the lower GT later in the course of infection. Increased levels of mRNA confirmed the selective differences in chemokine expression within the upper and lower GTs. The increased levels of Th1-inducible chemokines in the upper GT were not due to differences in the magnitude of infection or progesterone pretreatment. These data demonstrate that the upper and lower regions of the GT respond differently to Chlamydia infection.

The Infecting Dose ofChlamydia muridarumModulates the Innate Immune Response and Ascending Infection

“…Further, investigations have shown that CD4 ϩ Th1 and not Th2 cells are required for Chlamydia resolution in a gamma interferon (IFN-␥)-dependent manner (17,20). Consistent with a predominant role of Th1 cells, Th1-cell-associated chemokines CCL5/RANTES and CXCL10/IFN-␥-inducible protein 10 (IP-10) were shown to be primarily induced in infected genital tissue (6,34). Further, unpublished data from our laboratory demonstrates that the corresponding receptor for CXCL10, CXCR3, plays a role in the recruitment of Th1 cells during chlamydial infection.…”

“…We previously reported that chemokines associated with Th1 cell recruitment are induced in the genital tract within 3 to 7 days after Chlamydia infection and are preferentially expressed in OD tissue compared to CV tissue (34), and we have recently demonstrated a functional role of these chemokines in the chemotaxis of Chlamydia-specific lymphocytes (unpublished data). To determine whether the inoculative dose of Chlamydia affected the distribution or magnitude of induction of Th1-associated chemokines, we measured the CXCR3 ligand CXCL10/IP-10 by ELISA in clarified OD and CV tissue homogenates (Fig.…”

Murine Oviduct Epithelial Cell Cytokine Responses toChlamydia muridarumInfection Include Interleukin-12-p70 Secretion

“…However, the existing data set was notable for the absence of some expected key inflammatory mediators, such as tumor necrosis factor alpha (TNF-␣) (3), IP-10 gamma interferon (IFN-␥)-inducible 10-kDa protein (CXCL10), and RANTES (CCL5) (44). This suggested that existing in vitro models based on epithelial tumor cell lines might not fully mimic the immunobiology of Chlamydia-infected epithelium.…”

REVIEW ARTICLE: Chlamydia trachomatis, a Hidden Epidemic: Effects on Female Reproduction and Options for Treatment

“…Murine studies using Chlamydia muridarum have greatly expanded the knowledge of infection kinetics, including the differential cell infiltration between the lower and upper genital tract, the rate at which this occurs, [18][19][20][21][22][23][24] and also the rate of infection ascension. [24][25][26] The infectious dose of Chlamydia is known to modulate the innate immune response, with greater inoculating doses causing a greater innate immune response.…”