Helicobacter pylori is invasive and it may be a facultative intracellular organism

Abstract

The pathogenicity of many bacteria colonizing the gastrointestinal tract often depends on their ability to gain access to cells that are normally non-phagocytic. Helicobacter pylori colonizes the stomach of over half the world population and is the main cause of peptic ulcer disease and gastric cancer. It is generally considered to be a non-invasive pathogen present only in the lumen of the stomach and attached to gastric epithelial cells although a number of in vivo and in vitro studies have demonstrated that H. pylori is in fact invasive. In addition, H. pylori can repopulate the extracellular environment after complete elimination of extracellular bacteria with gentamicin, suggesting it may be considered a facultative intracellular bacterium. This review examines the validity of these observations and describes the evidence suggesting that the intracellular presence of H. pylori plays a role in the induction of diseases, in immune evasion, and in life-long persistence of the bacterium in the stomach of a majority of humans.

Fig. 1

Gastric biopsy of a patient with intestinal metaplasia (Genta stain, original magnification ×1000). A blue-stained goblet cell is surrounded by more or less normal epithelial cells. Intraluminal H. pylori are either free-floating (1) or adherent to epithelial cells (2), but not to the goblet cell. Rod-, comma- and spiral-shaped H. pylori are visible in the goblet cell (3), in epithelial cells (4), in inflammatory cells (5), in the lamina propria (6), and in a post-capillary venule, where they are closely associated with erythrocytes (7). Interestingly, the silver straining of intraluminal H. pylori appears to be stronger than for intracellular and interstitial bacteria.

Fig. 2

A. SEM picture of H. pylori entry in an HEp2 cell (with permission from M. Block, after Engstrand and Graham, 1997). B and C. Time-lapse observation of two H. pylori outlined in red showing the progressive entry into an HEp2 cell over a 49 s time. Adapted by permission from Macmillan Publishers Ltd. Nature Medicine 3: 930–931, copyright 1997.

Fig. 3

SEM and TEM analyses of H. pylori 26695 adherence to, and entry into, AGS cells. AGS cells infected with H. pylori 26695 at a multiplicity of infection of 100 for 12 h at 37°C. Samples obtained at various times were analysed by SEM and TEM. H. pylori adhered to AGS cells by intimate contact with the host cell microvilli (30 min, arrows). Features of zipper-like engulfment are observed at 1 h, 90 min and 3 h post infection. Bars, 1.5 μm. With permission from Kwok et al. (2002).

Fig. 4

Illustration of differential immunostaining of AGS cells cocultured with H. pylori. As illustrated by the yellow arrow, most H. pylori are stained yellow and are located outside the cells. One of the H. pylori is intracellular (red arrow) and is stained red (after Amieva et al., 2002 with permission).