Host Cell Antimicrobial Responses against Helicobacter pylori Infection: From Biological Aspects to Therapeutic Strategies

Abstract

The colonization of Helicobacter pylori (H. pylori) in human gastric mucosa is highly associated with the occurrence of gastritis, peptic ulcer, and gastric cancer. Antibiotics, including amoxicillin, clarithromycin, furazolidone, levofloxacin, metronidazole, and tetracycline, are commonly used and considered the major treatment regimens for H. pylori eradication, which is, however, becoming less effective by the increasing prevalence of H pylori resistance. Thus, it is urgent to understand the molecular mechanisms of H. pylori pathogenesis and develop alternative therapeutic strategies. In this review, we focus on the virulence factors for H. pylori colonization and survival within host gastric mucosa and the host antimicrobial responses against H. pylori infection. Moreover, we describe the current treatments for H. pylori eradication and provide some insights into new therapeutic strategies for H. pylori infection.

Keywords: antibiotic-resistance; antimicrobial responses; helicobacter pylori; host cells.

Figure 1

H. pylori infection and host antimicrobial response. H. pylori attach to host cells surface via bacterial outer membrane proteins (OMPs such as BabA, SabA, OipA, et al.) interacting with ligands (Lewis et al. blood group antigen) on cell surface. Once attached, the bacterial type IV secretion system (T4SS) delivers a variety of virulence factors into host cell. The translocated CagA is phosphorylated by c-Src and c-Abl on the inner face of plasma membrane, leading to the change of numerous cellular signaling pathways. Specifically, CagA can activate mTORC1 to enhance cathelicidin/LL-37 expression. Meanwhile, T4SS-dependent internalization of bacterial peptidoglycan (PG) can activate NOD1 pathway to induce hBD-2/β-defensin expression. The attached bacteria induce cellular endocytosis wherein they are surrounded by the double-membrane structure autophagosome. The autophagosome would then fuse with lysosome to form autolysosome, resulting in bacteria degradation by lysosomal hydrolytic enzymes. However, H. pylori could secrete cytotoxin VacA to impair autophagic flux and lysosomal function by inhibiting TRPML1-mediated outflow of Ca2+ on lysosome and suppressing the activity of cathepsin D (CTSD), respectively. Bacterial products can bind to TLRs (Toll-like receptors) to activate NF-κB signaling, resulting in induction of NOX and iNOS and subsequent ROS and RNS generation to kill H. pylori. The autophagosome membrane-located NOX and iNOS are also involved in the clearance of intracellular H. pylori. Nevertheless, H. pylori could produce SOD and catalase to attenuate ROS damage. Moreover, the release of bacterial arginase can eliminate RNS to protect H. pylori.