Coadaptation of Helicobacter pylori and humans: ancient history, modern implications
John C. Atherton, Martin J. Blaser
John C. Atherton, Martin J. Blaser
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Coadaptation of Helicobacter pylori and humans: ancient history, modern implications

Abstract

Humans have been colonized by Helicobacter pylori for at least 50,000 years and probably throughout their evolution. H. pylori has adapted to humans, colonizing children and persisting throughout life. Most strains possess factors that subtly modulate the host environment, increasing the risk of peptic ulceration, gastric adenocarcinoma, and possibly other diseases. H. pylori genes encoding these and other factors rapidly evolve through mutation and recombination, changing the bacteria-host interaction. Although immune and physiologic responses to H. pylori also contribute to pathogenesis, humans have evolved in concert with the bacterium, and its recent absence throughout the life of many individuals has led to new human physiological changes. These may have contributed to recent increases in esophageal adenocarcinoma and, more speculatively, other modern diseases.

Authors

John C. Atherton, Martin J. Blaser

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Figure 2

CagA phenotypes and variation.

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CagA phenotypes and variation. Local and whole-cell effects of the H. py...
Local and whole-cell effects of the H. pyloricag–encoded T4SS and its major effector protein, CagA. H. pylori, with an intact cag PaI, forms a T4SS, which injects CagA into epithelial cells (10). The T4SS tip protein, CagL, binds to and activates integrin α5β1, resulting in local activation of focal adhesion kinase (FAK) and then Src kinase (11). Activated kinases phosphorylate CagA at specific tyrosine residues, in turn activating local Src homology 2 domain–containing tyrosine phosphatase 2 (SHP-2) and therefore local signaling (12, 13, 125). A soluble component of bacterial peptidoglycan, γ-D-glutamyl-meso-diaminopimelic acid (ie-DAP) also enters the cell and is recognized by the intracellular innate immune pattern-recognition receptor Nod1, leading to stimulation of NF-κB (14). Furthermore, phosphorylated CagA itself, possibly when in excess or when trafficked deeper into the cell, also may activate NF-κB and have other whole-cell effects (8, 15–17). Blue arrows indicate H. pylori components, black arrows indicate epithelial cell components, and red text indicates cellular effects.