Chapter 114. Molecular Mechanisms of Microbial Pathogenesis (Part 6)

Encounters with Epithelial CellsOver the past decade, many bacterial pathogens have been shown to enter epithelial cells (Fig. 114-2); the bacteria often use specialized surface structures that bind to receptors, with consequent internalization. However, the exact role and the importance of this process in infection and disease are not well defined for most of these pathogens. Bacterial entry into host epithelial cells is seen as a means for dissemination to adjacent or deeper tissues or as a route to sanctuary to avoid ingestion and killing by professional phagocytes. Epithelial cell entry appears, for instance, to be a critical aspect...
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Chapter 114. Molecular Mechanisms of Microbial Pathogenesis (Part 6) Chapter 114. Molecular Mechanisms of Microbial Pathogenesis (Part 6) Encounters with Epithelial Cells Over the past decade, many bacterial pathogens have been shown to enterepithelial cells (Fig. 114-2); the bacteria often use specialized surface structuresthat bind to receptors, with consequent internalization. However, the exact roleand the importance of this process in infection and disease are not well defined formost of these pathogens. Bacterial entry into host epithelial cells is seen as ameans for dissemination to adjacent or deeper tissues or as a route to sanctuary toavoid ingestion and killing by professional phagocytes. Epithelial cell entryappears, for instance, to be a critical aspect of dysentery induction by Shigella.Figure 114-2 Entry of bacteria into epithelial cells. A. Internalization of P. aeruginosa by cultured human airway epithelialcells expressing wild-type cystic fibrosis transmembrane conductance regulator(CFTR), the cell receptor for bacterial ingestion. B. Entry of P. aeruginosa intomurine tracheal epithelial cells after infection by the intranasal route. Curiously, the less virulent strains of many bacterial pathogens are moreadept at entering epithelial cells than are more virulent strains; examples includepathogens that lack the surface polysaccharide capsule needed to cause seriousdisease. Thus, for Haemophilus influenzae, Streptococcus pneumoniae,Streptococcus agalactiae (group B Streptococcus), and Streptococcus pyogenes,isogenic mutants or variants lacking capsules enter epithelial cells better than thewild-type, encapsulated parental forms that cause disseminated disease. Theseobservations have led to the proposal that epithelial cell entry may be primarily amanifestation of host defense, resulting in bacterial clearance by both shedding ofepithelial cells containing internalized bacteria and initiation of a protective andnonpathogenic inflammatory response. However, a possible consequence of thisprocess could be the opening of a hole in the epithelium, potentially allowinguningested organisms to enter the submucosa. This scenario has been documentedin murine S. enterica serovar typhimurium infections and in experimental bladderinfections with uropathogenic E. coli. In the latter system, bacterial pilus–mediated attachment to uroplakins induces exfoliation of the cells with attachedbacteria. Subsequently, infection is produced by residual bacterial cells that invadethe superficial bladder epithelium, where they can grow intracellularly intobiofilm-like masses encased in an extracellular polysaccharide-rich matrix andsurrounded by uroplakin. This mode of growth produces structures that have beenreferred to as bacterial pods. At low bacterial inocula, epithelial cell ingestion andsubclinical inflammation are probably efficient means to eliminate pathogens; incontrast, at higher inocula, a proportion of surviving bacterial cells enter hosttissue through the damaged mucosal surface and multiply, producing disease.Alternatively, failure of the appropriate epithelial cell response to a pathogen mayallow the organism to survive on a mucosal surface where, if it avoids other hostdefenses, it can grow and cause a local infection. Along these lines, as notedabove, P. aeruginosa is taken into epithelial cells by CFTR, a protein missing ornonfunctional in most severe cases of cystic fibrosis. The major clinicalconsequence is chronic airway-surface infection with P. aeruginosa in 80–90% ofpatients with cystic fibrosis. The failure of airway epithelial cells to ingest andpromote the removal of P. aeruginosa via a properly regulated inflammatoryresponse has been proposed as a key component of the hypersusceptibility of thesepatients to chronic airway infection with this organism.