Research Article: Uropathogenic E. coli Exploit CEA to Promote Colonization of the Urogenital Tract Mucosa

Date Published: May 12, 2016

Publisher: Public Library of Science

Author(s): Petra Muenzner, Arnaud Kengmo Tchoupa, Benedikt Klauser, Thomas Brunner, Johannes Putze, Ulrich Dobrindt, Christof R. Hauck, Steven R. Blanke.


Attachment to the host mucosa is a key step in bacterial pathogenesis. On the apical surface of epithelial cells, members of the human carcinoembryonic antigen (CEA) family are abundant glycoproteins involved in cell-cell adhesion and modulation of cell signaling. Interestingly, several gram-negative bacterial pathogens target these receptors by specialized adhesins. The prototype of a CEACAM-binding pathogen, Neisseria gonorrhoeae, utilizes colony opacity associated (Opa) proteins to engage CEA, as well as the CEA-related cell adhesion molecules CEACAM1 and CEACAM6 on human epithelial cells. By heterologous expression of neisserial Opa proteins in non-pathogenic E. coli we find that the Opa protein-CEA interaction is sufficient to alter gene expression, to increase integrin activity and to promote matrix adhesion of infected cervical carcinoma cells and immortalized vaginal epithelial cells in vitro. These CEA-triggered events translate in suppression of exfoliation and improved colonization of the urogenital tract by Opa protein-expressing E. coli in CEA-transgenic compared to wildtype mice. Interestingly, uropathogenic E. coli expressing an unrelated CEACAM-binding protein of the Afa/Dr adhesin family recapitulate the in vitro and in vivo phenotype. In contrast, an isogenic strain lacking the CEACAM-binding adhesin shows reduced colonization and does not suppress epithelial exfoliation. These results demonstrate that engagement of human CEACAMs by distinct bacterial adhesins is sufficient to blunt exfoliation and to promote host infection. Our findings provide novel insight into mucosal colonization by a common UPEC pathotype and help to explain why human CEACAMs are a preferred epithelial target structure for diverse gram-negative bacteria to establish a foothold on the human mucosa.

Partial Text

During evolution bacteria have developed fascinating strategies to colonize multicellular organisms. A first critical step, which in many cases determines the outcome of the microbe-host encounter, is the ability of the microorganisms to establish themselves on mucosal surfaces [1,2]. Attachment to the mucosa is facilitated by specific bacterial adhesins, which firmly connect the microbe to the tissue [3,4]. Indeed, adhesin-mediated bacteria-host interactions prevent mechanical removal of the microbes via mucociliary cleansing or urinary flow, and can be seen as a prerequisite for efficient colonization. However, mucosal epithelia have several additional tissue-intrinsic defense mechanisms that protect the surface from adherent pathogens [5]. For example, in both stratified as well as single-layered epithelia the superficial cells are constantly replaced from a stem cell population. This tissue turnover also leads to shedding of cell-associated microbes from the epithelium reducing the bacterial burden. Epithelial tissue turnover can be very fast, as in the intestinal epithelium, where the superficial cells on the exposed villus folds are continuously replaced every day and where this process helps to maintain intestinal homeostasis. Indeed, slowing down tissue turnover in the intestinal tract can facilitate pathogen colonization [6,7]. Similar to the single-layered epithelium of the gut, stratified epithelia of the urogenital tract are also subject to continuous tissue renewal, albeit at a lower rate. However, exposure to high numbers of bacteria can trigger an accelerated turnover, whereby large amounts of superficial epithelial cells are released, a mechanism also known as exfoliation [8–12]. Exfoliation is an innate protective mechanism that, via rapid detachment and shedding of the infected superficial cells, limits colonization of the tissue by the microflora and ultimately prohibits further penetration of the bacteria [13]. By this process, even cell-associated bacteria can be removed from the tissue surface together with the infected cells.

Regulation of epithelial exfoliation is a particularly effective and rapid innate defense mechanism modulating mucosal colonization by microorganisms. However, there is only limited knowledge how pathogens themselves regulate this process and which molecular factors affect cell exfoliation during the course of an infection.




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