Role of innate immunity in Helicobacter pylori-induced gastric malignancy

Abstract

Helicobacter pylori colonizes the majority of persons worldwide, and the ensuing gastric inflammatory response is the strongest singular risk factor for peptic ulceration and gastric cancer. However, only a fraction of colonized individuals ever develop clinically significant outcomes. Disease risk is combinatorial and can be modified by bacterial factors, host responses, and/or specific interactions between host and microbe. Several H. pylori constituents that are required for colonization or virulence have been identified, and their ability to manipulate the host innate immune response will be the focus of this review. Identification of bacterial and host mediators that augment disease risk has profound ramifications for both biomedical researchers and clinicians as such findings will not only provide mechanistic insights into inflammatory carcinogenesis but may also serve to identify high-risk populations of H. pylori-infected individuals who can then be targeted for therapeutic intervention.

FIG. 1

Progression to intestinal-type gastric adenocarcinoma. Helicobacter pylori colonization typically occurs during childhood and leads to superficial gastritis. The presence of genes such as the cag island and vacA that encode bacterial virulence factors augment the risk for progression to gastric atrophy and gastric adenocarcinoma.

FIG. 2

The H. pylori cag pathogenicity island. The H. pylori cag island encodes a type IV secretion system that protrudes from the bacterial surface and is induced upon contact with host cells. The cag pilus is covered on its surface by CagY and CagL. CagY is a large protein that contains two transmembrane domains, and CagY can differ in size due to in-frame deletions or duplications resulting in reduced host antibody recognition that may allow immune evasion. CagL binds to α₅β₁-integrins on host cells to facilitate translocation of CagA. CagA is present at the tip of the pilus, and delivery of CagA into host cells proceeds in an energy-dependent manner driven by NTPases such as CagE.

FIG. 3

CagA phosphorylation motifs and cellular morphogenic alterations induced by intracellular CagA. A: tyrosine phosphorylation of EPIYA sites within the COOH terminus of CagA leads to alterations in host epithelial cells. Variation in the number and sequence of these sites determines the degree of CagA phosphorylation and the intensity of cellular changes. H. pylori strains colonizing individuals in Western countries typically have Western-type CagA (C) motifs, whereas those from East Asia have Eastern-Asian CagA (D) motifs. B: CagA (depicted as “A”) is phosphorylated by Src and Abl kinases, which is followed by a decrease in levels of phospho-CagA via the inhibitory kinase c-src kinase (csk). Phosphorylated CagA activates SHP-2 and ERK also leading to cellular morphological changes. Unphosphorylated CagA associates with the tight junction proteins ZO-1 and JAM-A leading to dysregulated apical junctional complexes. Unmodified CagA can also lead to changes in motility and proliferation through binding Grb2 and activation of the Raf/Mek/Erk pathway.

FIG. 4

Structure of VacA. A: allelic diversity of vacA is found near the 5′ end (types s1a, s1b, s1c, and s2), the intermediate region (types i1 and i2), and the mid-region (types m1 and m2). B: VacA is secreted and cleaved to yield an 88-kDa protein (p88) and a 10.5-kDa protein (p10). p88 is further processed to yield two functional fragments, p55 and p33, which function in cell binding and pore formation, respectively.

FIG. 5

Toll-like receptors and pathogen recognition. Activation of Toll-like receptors (TLRs) and intracellular receptors (e.g., Nod1) by pathogen-associated molecular patterns (PAMPs) triggers multiple intracellular signaling pathways that culminate in NF-κB activation and subsequent production of inflammatory and immune effectors, such as interleukin-8.

FIG. 6

Regulation of inducible nitric oxide (NO) synthase (iNOS) synthesis and NO production. Pathways involved in the regulation of macrophage iNOS synthesis and NO production in response to H. pylori are depicted, in conjunction with the proposed pathogenic role of the generation of the polyamine spermine by induction of arginase and ODC that results in inhibition of iNOS protein translation.

FIG. 7

Model depicting mechanisms involved in the induction of macrophage apoptosis by H. pylori. H. pylori induces macrophage apoptosis through the generation of polyamines and increased expression and nuclear translocation of c-Myc.

FIG. 8

Schematic demonstarting how dendritic cells may bridge the innate and adaptice immune response directed against H. pylori within the gastric mucosa. Dendritic cells can penetrate the epithelial barrier in vivo and sample H. pylori antigens directly. Dendritic cells, in turn, activate T cells in different ways, being capable of inducing either a Th1, Th2/regulatory T cell (Treg), or a Th17 response by generation of interleukin (IL)-12, IL-10, or IL-23, respectively. Direct interactions between H. pylori and gastric epithelial cells or H. pylori constituents such as urease can also activate polymorphonuclear (PMN) cells and/or macrophages, which further amplifies the T-cell response to this pathogen.