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. 2010 Nov 23;1:115.
doi: 10.3389/fmicb.2010.00115. eCollection 2010.

A Tale of Two Toxins: Helicobacter Pylori CagA and VacA Modulate Host Pathways That Impact Disease

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Free PMC article

A Tale of Two Toxins: Helicobacter Pylori CagA and VacA Modulate Host Pathways That Impact Disease

Kathleen R Jones et al. Front Microbiol. .
Free PMC article

Abstract

Helicobacter pylori is a pathogenic bacterium that colonizes more than 50% of the world's population, which leads to a tremendous medical burden. H. pylori infection is associated with such varied diseases as gastritis, peptic ulcers, and two forms of gastric cancer: gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma. This association represents a novel paradigm for cancer development; H. pylori is currently the only bacterium to be recognized as a carcinogen. Therefore, a significant amount of research has been conducted to identify the bacterial factors and the deregulated host cell pathways that are responsible for the progression to more severe disease states. Two of the virulence factors that have been implicated in this process are cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA), which are cytotoxins that are injected and secreted by H. pylori, respectively. Both of these virulence factors are polymorphic and affect a multitude of host cellular pathways. These combined facts could easily contribute to differences in disease severity across the population as various CagA and VacA alleles differentially target some pathways. Herein we highlight the diverse types of cellular pathways and processes targeted by these important toxins.

Keywords: CagA; Helicobacter; VacA; cell-signaling; gastric cancer; toxin.

Figures

Figure 1
Figure 1
CagA and known host cell targets. (A) A schematic representation of CagA with the polymorphic region containing different EPIYA motif (A, B, C, and D) combinations is shown and is adapted from Hatakeyama and Higashi (2005). (B) A graphic depiction of the gastric mucosa and known host pathways impacted by phosphorylated and non-phosphorylated CagA is shown. Pathways targeted in epithelial cells and B cells are indicated. The actin binding proteins (ABP) affected by CagA include vinculin, cortactin, and ezrin. This figure was adapted from an earlier version by Rieder et al. (2005a).
Figure 2
Figure 2
VacA and known host cell targets. (A) A schematic representation of VacA with the three major regions of polymorphisms (s, i, and m) is shown. Additionally, schematics of the known alleles of each region are shown. The i region contains two important polymorphic regions known as Cluster B and Cluster C, which are designated by a B and C, respectively on the diagram. The activity attributed to each of the regions of the toxin (vacuolating activity or cellular tropism) are indicated, and the impact of each allele on these effects is shown. The highest level of activity or the broadest tropism is defined as ++, intermediate tropism is indicated by a +, low activity is indicated as a +/−, no activity is designated by a −, and incomplete information is indicated by a ?. (B) A depiction of the gastric mucosa and known host pathways targeted by VacA is shown. One of the receptors, sphingomyelin is designated by SM. Pathways targeted in epithelial cells and B and T cells are indicated. Additionally, activation of several pathways by peptidoglycan (PG) and LPS are shown. This figure was adapted from an earlier version by Rieder et al. (2005a).

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