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Introduction
A monolayered epithelium is a highly organized structure
made of polarized epithelial cells. These cells have an
apical and a basolateral pole, each characterized by a
distinct composition of proteins and lipids, defining different membrane domains with specific functions in
barrier formation and maintenance. In the intestinal
epithelium, the apical surface is made of microvilli that
constitute the exchange surface where nutrients and
fluids are absorbed and where immune system effectors
are secreted. The basolateral pole sits on a basement
membrane in contact with connective tissue, vessels and
cellular effectors of the immune system, and is responsible for the establishment of cellcell and cellmatrix
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Figure 1
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Microbial strategies to target, cross or disrupt epithelia Sousa, Lecuit and Cossart 491
strategies to adhere to, invade or disrupt epithelial barriers [8]. These pathogens have to surmount constant
peristaltic flushing, sloughing of mucus, bile salts and
organic acids, antimicrobial peptides, defensins and competition from the resident microflora. Structural and regulatory components of the intercellular adhesion
structures, as well as matrix-binding proteins, are targets
for pathogens that interact with or cross epithelial barriers.
This review focuses on some of the striking strategies
developed by microbial pathogens to target, cross or
disrupt epithelia.
(Figure 1 Legend) Schematic representation of various strategies developed by bacteria to interact with the intestinal barrier. (a) Representation
of polarized epithelial cells and components of the intercellular junctions. (b) Enteropathogenic (EPEC) adheres to the apical pole via
bundle-forming pili (BFP), resulting in attaching and effacing (A/E) lesions. Via its type-III secretion system (TTSS), it injects into the host cell
cytoplasm bacterial proteins that modify the actin cytoskeleton and interfere with tight junction (TJ) components. (c) Clostridium dificile (C.d.)
secretes two toxins (TcdA and TcdB) that interact with small GTPases and dissociate TJ proteins from the lateral membrane. (d) Helicobacter
pylori (H.p.) adheres to the epithelial apical surface and delivers CagA into the host cytoplasm. CagA interacts with TJ proteins (ZO-1 and JAM)
and activates HGF receptor, leading to the loss of TJs. Intracellular phosphorylated CagA inhibits Src kinases and activates phosphatases.
(e) Vibrio cholerae (V.c.) secretes cholera toxin (CT) that binds GM1 at the host cell surface. Intracellularly, CT stimulates the production of
cAMP, leading to water loss. V. cholerae also secretes the protease HA/P, which degrades the extracellular domain of occludin. (f) Listeria
monocytogenes (L.m.) uses two surface proteins, InlA and InlB, to enter into epithelial cells. InlA binds E-cadherin and requires catenins, vezatin
and myosin VIIa to promote entry. InlB interacts with HGF-R and stimulates the activity of PtdIns-3-kinase and cytoskeleton rearrangements.
The cell-to-cell spread of L. monocytogenes depends on the bacterial protein ActA and ezrin, a regulator of AJs assembly. (g) Bacteroides fragilis
(B.f.) secretes fragilysin, which cleaves the extracellular domain of E-cadherin, disrupting the AJs and activating b-catenin nuclear signaling.
(h) Shigella flexneri (S.f.) crosses the intestinal epithelium through M cells, using its TTSS and injecting bacterial effectors into the host cells.
Once translocated, S. flexneri enters polarized cells via the basal pole and induces the opening of Gap junctions and ATP release. The cell-to-cell
spread depends on E-cadherin and connexin 26.
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Microbial strategies to target, cross or disrupt epithelia Sousa, Lecuit and Cossart 493
Figure 2
Other examples of microbial interactions with epithelia. (a) The reovirus surface protein s1 binds to JAM-1 to promote virus entry. Rotavirus
surface protein VP4 is cleaved into VP5 and VP8 proteins. VP8 displaces ZO-1, claudin-3 and occludin from tight junctions (TJs). NSP4 is a
non-structural virus protein delivered inside the host cells; it induces an increase in calcium concentration and disruption of the actin cytoskeleton.
VP7 interacts with integrins to promote entry. (b) The coxsackievirus protein Fiber interacts with CAR at the AJs during virus entry into epithelial
cells. Fiber released after virus replication binds CAR, disrupts intercellular junctions and allows the migration of new virus to the apical pole.
(c) MIC2, an adhesin of Toxoplasma gondii, interacts with ICAM-1 during its transepithelial paracellular migration. (d) The entry of human herpes
simplex virus in cells of a stratified epithelium depends on the interaction of virus glycoprotein D with nectin, a protein AJ. Human cytomegalovirus
uses two cellular receptors, EGF-R and integrin aVb3, to enter into cells. (e) The exfoliative toxin (ET) of Staphylococcus aureus (S.a.) cleaves
desmoglein1 in the epidermis, thus promoting the loss of intercellular adhesion.
Disrupting desmosomes
Although this review mainly focuses on pathogen interactions with monolayered epithelia, such as the intestinal
epithelium, more complex epithelia such as the epidermal stratified epithelium are also targeted by human
pathogens. This is the case for Staphylococcus aureus, a
bacterium responsible for cutaneomusocal infections.
Exfoliative toxins (ETs) produced by S. aureus rapidly
diffuse into the skin tissue and cleave the cell adhesion
molecule desmoglein 1 (Dsg1), which plays a key role in
maintaining the structure and barrier function of the
epidermis (Figure 2e) [72,73]. ETs cleave a single peptide bond in the extracellular domain of Dsg1 and do not
cleave closely related molecules such as Dsg3 and
E-cadherin [74]. In addition, the specificity of ET cleavage is dependent on the calcium-stabilized structure of
Dsg1 [75]. This highly specific and efficient cleavage of
Dsg1 results in the loss of intercellular adhesion and
allows bacteria to form blisters under the epithelial sheet,
providing protective niches in which they can survive and
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Microbial strategies to target, cross or disrupt epithelia Sousa, Lecuit and Cossart 495
Conclusions
Epithelia are highly organized and sophisticated structures adapted to function as barriers protecting the underlying tissues from external aggressions, including
microbial invasions. Intercellular junctions are the central
players maintaining the epithelial architecture. Apart
from being a physical obstacle, they also play a key role
in the control of cell proliferation, differentiation, migration and death. Microbial pathogens have evolved countless strategies to interfere with cellcell junctions, to
increase epithelium permeability, to destabilize epithelial structure and function and, sometimes, to cross and/or
disrupt the barrier the epithelium constitutes. This barrier is thus not invincible, and in response epithelial cells
have set up extracellular and intracellular sensing systems
(Toll-like receptors and Nods) able to detect microbial
pathogens and react to their intrusion into physiologically
sterile intracellular and extracellular environments.
Engagement of these detecting systems triggers the
recruitment and activation of effectors of the innate
and adaptive immune system at the site of infection.
In turn, these mechanisms may also be exploited by
pathogens to promote their translocation across epithelia,
and it is well known that inflammation favors secondary
infections. It is also important to recall that intestinal
epithelial cells are continuously in contact with billions of
harmless and thus so-called commensal bacteria, which
Current Opinion in Cell Biology 2005, 17:489498
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Microbial strategies to target, cross or disrupt epithelia Sousa, Lecuit and Cossart 497
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