The stomach is an especially hostile environment for pathogens. Besides the thick layer of mucus and peristaltic washing, it is filled with acid (average pH ≈2), which is lethal to almost all bacteria ingested in food. Yet, it is home to a microbiota of hundreds of resident species, including the bacterium H. pylori, which, as we discussed earlier, is the major cause of stomach ulcers and some stomach cancers. The hypothesis that a persistent bacterial infection could cause stomach ulcers was initially met with skepticism. The young Australian doctor who made the initial discovery finally proved the point: he drank a pure culture of H. pylori and developed inflammation of the stomach, which often precedes the development of ulcers. A short course of antibiotics can now effectively cure a patient of recurrent stomach ulcers. Remarkably, H. pylori is able to persist for life as a commensal in most humans. One way in which it survives in the stomach is by producing the enzyme urease, which converts urea to ammonia that neutralizes the acid in its immediate vicinity. The bacterium also uses its flagellum for chemotactic motility, allowing it to seek out the more neutral pH near the surface of gastric epithelial cells. H. pylori virulence proteins that target both epithelial and immune cells help H. pylori persist in the stomach, but they can also induce chronic inflammation, alteration in host gene expression, changes in cell proliferation and apoptosis, and disruption of cell–cell junctions, all of which are predisposing factors for stomach cancer.
Extracellular pathogens can cause serious disease without entering host cells. Bordetella pertussis, the bacterium that causes whooping cough, for example, colonizes the respiratory epithelium and circumvents the normal mechanism that
Figure 23–15 Pathogenic E. coli in the infected bladder of a mouse.
(A) Scanning electron micrograph of uropathogenic E. coli, a common cause of bladder and kidney infections. The bacteria are attached to the surface of epithelial cells lining the infected bladder. (B) A closeup view of one of the bacteria showing the pili on its surface. (C) An E. coli pilus has adaptor proteins on its tip that bind to glycolipids on the surface of kidney cells. (A, from G.E. Soto and S.J. Hultgren,  J. Bacteriol. 181:1059–1071, 1999. With permission from the American Society for Microbiology; B, courtesy of D.G. Thanassi and S.J. Hultgren, Methods 20:111–126, 2000. With permission from Academic Press.) (A) P P P Tir injected Tir inserts and folds in plasma membrane HOST CELL type III secretion system enteropathogenic E. coli outer membrane inner membrane intimin intimin actin flaments pedestal phosphorylated Tir host proteins that promote actin polymerization clears the respiratory tract by expressing adhesins that bind ciliated epithelial cells. The adherent bacteria produce toxins that eventually kill the ciliated cells, compromising the host’s ability to clear the infection. The most familiar of these is pertussis toxin, which, like the cholera toxin discused above, has an A subunit that ADP-ribosylates the α subunit of the G protein Gi, inhibiting the G protein from suppressing the activity of the host cell’s adenylyl cyclase, thereby increasing the production of cyclic AMP (see Figure 23–6). This toxin also interferes with the chemotactic pathway that neutrophils use to seek out and destroy invading bacteria (see Figures 16–3 and 16–86). B. pertussis colonization of the respiratory tract causes severe coughing, which helps spread the infection.