Abstract
Host-pathogen interactions that allow Helicobacter pylori to survive and persist in the stomach of susceptible individuals remain unclear. Human beta-defensins (hBDs), epithelial-derived antimicrobial peptides are critical components of host-defense at mucosal surfaces. The role of H. pylori-mediated NF-kappaB and epidermal growth factor receptor (EGFR) activation on beta-defensin expression was investigated. Transient transfection studies utilizing beta-defensin promoter constructs were conducted in gastric cells with contribution of individual signaling events evaluated by the addition of specific inhibitors, small interference nucleotide-binding oligomerization domain 1 (NOD1) RNA or plasmids encoding Vaccinia virus proteins that interrupt interleukin-1 and Toll-like receptor signaling. The role of individual MAPK pathways was further delineated in HEK-293 cells expressing conditional MAPK mutants. We found hBD2 expression exclusively dependent on the presence of the bacterial cag pathogenicity island, with NOD1 a critical host sensor. Impairment of murinebeta-defensin 4 (an orthologue of hBD2) expression in NOD1-deficient mice 7-days post-infection further confirmed the role of this cytoplasmic pattern-recognition receptor in eliciting host innate immunity. In contrast to hBD2, hBD3 expression was NOD1-independent but EGFR and ERK pathway-dependent. Importantly, Toll-like receptor signaling was not implicated in H. pylori-mediated hBD2 and hBD3 gene expression. The divergent signaling events governing hBD2 and hBD3 expression suggest temporal functional variation, such that hBD2 may contribute to antimicrobial barrier function during the inflammatory phase with hBD3 playing a greater role during the repair, wound healing phase of infection.
Highlights
Host-pathogen interactions that allow Helicobacter pylori to survive and persist in the stomach of susceptible individuals remain unclear
Transient transfection studies utilizing -defensin promoter constructs were conducted in gastric cells with contribution of individual signaling events evaluated by the addition of specific inhibitors, small interference nucleotide-binding oligomerization domain 1 (NOD1) RNA or plasmids encoding Vaccinia virus proteins that interrupt interleukin-1 and Toll-like receptor signaling
Activation of hBD2 and hBD3 Promoter-Reporter Constructs during Infection with Wild-type and Isogenic Mutant H. pylori Strains—We and others (36 – 40, 50) have previously shown modulation of both hBD2 and hBD3 mRNA and peptide expression during H. pylori infection, most studies to date have been confined to the effect of cytotoxic type I strains
Summary
Host-pathogen interactions that allow Helicobacter pylori to survive and persist in the stomach of susceptible individuals remain unclear. Impairment of murine -defensin 4 (an orthologue of hBD2) expression in NOD1-deficient mice 7-days post-infection further confirmed the role of this cytoplasmic pattern-recognition receptor in eliciting host innate immunity. Toll-like receptor signaling was not implicated in H. pylori-mediated hBD2 and hBD3 gene expression. Who develops disease depends upon the virulence of the infecting strain, the ability of the host to mount a robust innate/acquired immune response, and environmental cofactors (6 –9). The bacterium is known to attach and activate key gastric epithelial cell signaling pathways that lead to phenotypic and genotypic changes, including modulation of host innate immunity, proliferation, and apoptosis [13,14,15]. Pattern recognition receptors are known to play a crucial role in host innate and adaptive immune responses to microbial pathogens and their products [21,22,23].
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