Pathology after Chlamydia trachomatis infection is driven by nonprotective immune cells that are distinct from protective populations

Abstract

Infection with drives severe mucosal immunopathology; however, the immune responses that are required for mediating pathology vs. protection are not well understood. Here, we employed a mouse model to identify immune responses required for-induced upper genital tract pathology and to determine whether these responses are also required for bacterial clearance. In mice as in humans, immunopathology was characterized by extravasation of leukocytes into the upper genital tract that occluded luminal spaces in the uterus and ovaries. Flow cytometry identified these cells as neutrophils at early time points and CD4 and CD8 T cells at later time points. To determine what draws these cells to -infected tissue, we measured the expression of 700 inflammation-related genes in the upper genital tract and found an up-regulation of many chemokines, including a node of interaction between CXCL9/10/11 and their common receptor CXCR3. Either depleting neutrophils or reducing T-cell numbers by CXCR3 blockade was sufficient to significantly ameliorate immunopathology but had no effect on bacterial burden, demonstrating that these responses are necessary for mucosal pathology but dispensable for clearance. Therapies that specifically target these host responses may therefore prove useful in ameliorating -induced pathology without exacerbating infection or transmission.

Gamma Interferon Is Required forChlamydiaClearance but Is Dispensable for T Cell Homing to the Genital Tract

“…We have previously established one such transgenic mouse, denoted the NR1 mouse, in which CD4 ϩ T cells are specific for the C. trachomatis protein Cta1 (6). Following C. trachomatis infection, NR1 T cells can home to the genital tract using specific chemokine receptors (9) and host integrins (10) that are similar to those used by endogenous T cells (11)(12)(13). NR1 T cell homing to the genital tract is essential for C. trachomatis clearance, as T cells that cannot home to the genital tract are unable to clear infection (9,10).…”

Shift work influences the outcomes of Chlamydia infection and pathogenesis

“…The similarity in uterine necrosis noticed in all mice groups could be due to histological and functional remodeling of the endometrium during the estrous cycle 21 , 22 . The lymphocytic inflammation contained increased numbers of CD4-positive lymphocytes, which are associated with Chalmydia l 23 – 26 . In this study we housed the ECD mice under normal LD conditions after infection.…”

“…Pathology from chlamydial infection is associated with host immune response to Chalmydia 20 , 23 , 27 . Cytokines and chemokines are important mediators of this immune response 28 – 30 .…”

Early Colonization of the Upper Genital Tract by Chlamydia muridarum Is Associated with Enhanced Inflammation Later in Infection

“…Given that there are greater numbers of CD4 ϩ T cells in the genital tracts of mice following transcervical infection, it is likely that this enhanced population contributes significantly to higher levels of IFN-␥ in the upper genital tract. While CD4 ϩ T cells are necessary for Chlamydia clearance (5,22), antigen-nonspecific bystander CD4 ϩ T cells have been found to contribute to immunopathology in mice infected with C. trachomatis serovar D (23). Furthermore, it has been recently demonstrated that CD4 ϩ T cells can induce pathology in mice deficient in CD8 ϩ T cells, following C. muridarum infection (24).…”

“…Tissues were sent to the Rodent Histopathology Core Facility at Harvard Medical School for sectioning and hematoxylin and eosin (H&E) staining. Sections were assessed for immunopathology as described previously (23).…”