The language used by Helicobacter pylori to regulate human cells.

Received 29 January 2007; accepted 1 February 2007; electronically published 16 May 2007. Potential conflicts of interest: none reported. Correspondence: Michael Pillinger, Dept. of Medicine 630111J, New York University School of Medicine, Manhattan VA Administration Hospital, 423 E. 23rd St., New York, NY 10010 (michael.pillinger@med.nyu.edu). The Journal of Infectious Diseases 2007;196:6–9 2007 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2007/19601-0003$15.00 DOI: 10.1086/518444 Although it was not isolated in culture until 1982, Helicobacter pylori has colonized the human stomach since ancient times [1]. Moreover, H. pylori has dominated its gastric niche (table 1). On no other internal or external surface of the human body—neither the colon, mouth, esophagus, nor skin—does a single species dominate so overwhelmingly [5–7]. That H. pylori now is disappearing from socioeconomically advantaged human populations (a phenomenon at once multifactorial and modern) [8] does not diminish the powerful biological features that have long made it the dominant member of the gastric biota. How did H. pylori become so successful [9], thwarting both the human immune responses that recognize it readily [10] and the vast competing human microbiota [4]? Evolutionary pressures have selected intrinsic H. pylori phenotypes that protect against gastric acidity, resist the peristalsis that threatens to sweep the bacteria away, and aid in the acquisition of nutrients (reviewed in [11]). Although these are essentially defensive strategies, it is becoming equally clear that H. pylori actively interacts with its host, sending (and receiving) a variety of chemical signals. How such interactions evolved remains uncertain, but H. pylori has been an excellent student of human biology and has developed a complex dialogue with human gastric cells. Among the most important of these signals is the protein CagA, which is introduced by H. pylori into its host cell through a specialized secretion system [11]. The intensity and sophistication of H. pylori–gastric cell interactions imply an extensive coevolution of the 2 species, to the benefit of H. pylori and Homo sapiens alike. For example, if H. pylori helped defend against lethal enteric pathogens or supported the regulation of nutrition, there would be selection for its presence, and if H. pylori could be sustained at low metabolic cost to its host throughout the human reproductive life span, a robust symbiotic relationship would be expected to evolve [8]. Such a model is consistent with H. pylori’s dominance of its niche. In this issue of the Journal, Keates et al. [12] explore a specific facet of the H. pylori–host interaction. Like other epithelia, gastric epithelial cells express the epidermal growth factor receptor (EGFR). Ligation of epithelial EGFR is important in normal gastric physiology, because activation of EGFR initiates signaling pathways (most prominently, Ras-dependent Erk activation) that are at once promitotic and antiapoptotic and may serve to sustain the gastric mucosa. EGFR activation may be a double-edged sword, however, because excessive EGFR signaling (as can be seen in EGFR overexpression) may lead to unrestrained proliferation and has been associated with gastric neoplasia [13]. Because H. pylori persistently colonizes the gastric epithelium and cagA strains in particular increase risk for atrophic gastritis and gastric adenocarcinoma [14, 15], Keates et al. asked whether H. pylori induces EGFR. They demonstrate that this is indeed the case, to a greater extent in cagA strains. Interestingly, the mechanism through which H. pylori induces EGFR expression appears to depend on the presence and indirect activation (transactivation) of preexisting plasma membrane EGFR, which suggests an amplification cycle. Specifically, EGFR up-regulation may act as a mechanism by which H. pylori sensitizes its target host cells for enhanced H. pylori effects. That is, if H. pylori upregulates EGFR via transactivation of the EGFR itself, then the resultant increases in EGFR population would, in turn, likely produce enhanced signaling in response to ongoing H. pylori contact. Presumably, the increased EGFR population also would be