Contributions of diverse models of the female reproductive tract to the study of Chlamydia trachomatis-host interactions

Abstract

Chlamydia trachomatis is a common cause of sexually transmitted infections in humans with devastating sequelae. Understanding of disease on all scales, from molecular details to the immunology underlying pathology, is essential for identifying new ways of preventing and treating chlamydia. Infection models of various complexity are essential to understand all aspects of chlamydia pathogenesis. Cell culture systems allow for research into molecular details of infection, including characterization of the unique biphasic Chlamydia developmental cycle and the role of type-III-secreted effectors in modifying the host environment to allow for infection. Multicell type and organoid culture provide means to investigate how cells other than the infected cells contribute to the control of infection. Emerging comprehensive three-dimensional biomimetic systems may fill an important gap in current models to provide information on complex phenotypes that cannot be modeled in simpler in vitro models.

Figure 1.

Current models of the female genital tract to study Chlamydia infections. (a) The human female reproductive tract. Organs relevant to Chlamydia infection are labeled, with overall cellular composition of the cervix, uterus, and fallopian tube lining shown at right. The cervix contains squamous (light orange, at left) and columnar (orange, at right) epithelial cells, a layer of mucus (green), the cervicovaginal microbiota (red), and a layer of fibroblasts (brown) containing blood vessels lined with endothelial cells (red) and containing various immune cells (purple). The uterus includes columnar epithelial cells (orange), endometrial stromal cells (brown), muscle cells of the myometrium (dark purple), and spiral arteries (red). The fallopian tube lining contains secretory (orange) and ciliated (yellow) epithelial cells as well as fibroblasts (brown). Chlamydia inclusions containing infectious (green) and replicative (red) bacteria are depicted in some of the epithelial cells. (b) Top panel: The most common in vitro immortalized cell culture model of the female reproductive tract, consisting of a monolayer of immortalized epithelial cells (orange) on the bottom of a plastic dish (gray) covered in cell culture media (pink). Such systems are used to gain insights into molecular details of Chlamydia infection (bottom panel): at left, the developmental cycle of Chlamydia elementary bodies (green) and reticulate bodies (red) within the lumen of the inclusion and, at right, the secretion of various type 3 secretion system (black) effectors (teal). (c) Top left panel: Common in vitro co-culture models include immortalized epithelial cells (orange), sometimes on a porous transwell membrane (black dashed line), with fibroblasts (brown) at the bottom of the plastic dish (gray), all within cell culture media (pink). Top right panel: Other co-culture models include organoid systems, containing spheroids of stem cell-derived epithelial cells (orange) within a gel matrix (pink) in a plastic dish (gray), with the potential addition of other components such as immune cells (purple). Bottom panel: Co-culture systems are useful to investigate proposed cell-cell interactions during infection, such as the role of stromal cells (brown) as intermediates in relaying signals, such as (left) hormones (grey spheres) to modulate Chlamydia infection in epithelial cells (orange) or (right) investigating how Chlamydia impedes neutrophil (purple) recruitment and activation to the site of infection. (d) Top panel: An in vitro explant model of fallopian tube, consisting of excised pieces of fallopian tube in a dish (gray) within cell culture media (pink). Bottom panel: Explant models have allowed for proposed insights into complex phenotypes, such as tissue damage, caused by infection.

Figure 2.

Key features of future biomimetic models to study Chlamydia infections. (a) A representative biomimetic chip containing two stacked channels (red and blue, respectively) separated by a porous membrane (not shown). Inlets and outlets allow for the introduction and/or removal of media to/from the channels. (b) Longitudinal side view through the center of the biomimetic chip shown in (a). An upper layer of columnar epithelial cells (orange) with mucus (green) are separated from a lower layer of fibroblasts (brown) via a porous membrane (black dashed line). Each channel can be supplied with a distinct media type (pink and blue), with additional biological or chemical alterations as needed. Here, the upper channel contains bacterial members of the microbiota (red), while the lower channel contains an assortment of immune cells (purple).