Helicobacter pylori persistence: an overview of interactions between H. pylori and host immune defenses

Abstract

Helicobacter pylori is a gram-negative bacterium that persistently colonizes more than half of the global human population. In order to successfully colonize the human stomach, H. pylori must initially overcome multiple innate host defenses. Remarkably, H. pylori can persistently colonize the stomach for decades or an entire lifetime despite development of an acquired immune response. This review focuses on the immune response to H. pylori and the mechanisms by which H. pylori resists immune clearance. Three main sections of the review are devoted to (i) analysis of the immune response to H. pylori in humans, (ii) analysis of interactions of H. pylori with host immune defenses in animal models, and (iii) interactions of H. pylori with immune cells in vitro. The topics addressed in this review are important for understanding how H. pylori resists immune clearance and also are relevant for understanding the pathogenesis of diseases caused by H. pylori (peptic ulcer disease, gastric adenocarcinoma, and gastric lymphoma).

FIG. 1.

Antibacterial properties of the stomach. The stomach is intrinsically resistant to bacterial colonization. Factors which contribute to this resistance include gastric acidity, lactoferrin, and antibacterial peptides (LL-37, β-defensin 1, and β-defensin 2). The gastric epithelial layer constitutes a physical barrier that prevents entry of bacteria into the gastric mucosa. Ribbon diagrams of lactoferrin, β-defensins, and LL-37 are derived from published structures (24, 200, 218).

FIG. 2.

Colonization factors of H. pylori. Multiple bacterial factors contribute to the ability of H. pylori to colonize the stomach. Urease contributes to the acid resistance of H. pylori. Flagella permit bacterial motility, which allows bacterial penetration of the mucus layer. Several outer membrane proteins, including BabA, SabA, AlpA, AlpB, and HopZ, can mediate bacterial adherence to gastric epithelial cells.

FIG. 3.

Innate immune recognition of H. pylori. Innate immune recognition of H. pylori leads to production of proinflammatory cytokines by macrophages (Mφ), DCs, mast cells, and gastric epithelial cells. Innate immune recognition of H. pylori is mediated at least in part through TLRs. In addition, H. pylori peptidoglycan (PG) can be recognized by intracellular Nod receptors (239). Interactions between H. pylori and gastric epithelial cells lead to activation of NF-κB and alteration in gene transcription in the epithelial cells. Production of IL-8 by epithelial cells leads to recruitment of neutrophils (polymorphonuclear leukocytes [PMNs]), which can phagocytose opsonized bacteria and produce reactive oxygen species (ROI) or reactive nitrogen species (RNI). The activation of mast cells results in degranulation and production of proinflammatory cytokines and chemokines.

FIG. 4.

Effects of H. pylori on T lymphocytes. Multiple H. pylori factors can suppress T-cell activity. VacA inhibits NFAT activity in T cells, leading to diminished IL-2 production, and also inhibits T-cell proliferation (37, 77, 219). Arginase inhibits T-cell receptor (TCR) signaling (256). An unidentified low-molecular-weight protein has been reported to inhibit T-cell proliferation by blocking cell cycle progression (78).