Abstract
The human pathogen Helicobacter pylori acquires cholesterol from membrane raft domains in eukaryotic cells, commonly known as “lipid rafts.” Incorporation of this cholesterol into the H. pylori cell membrane allows the bacterium to avoid clearance by the host immune system and to resist the effects of antibiotics and antimicrobial peptides. The presence of cholesterol in H. pylori bacteria suggested that this pathogen may have cholesterol-enriched domains within its membrane. Consistent with this suggestion, we identified a hypothetical H. pylori protein (HP0248) with homology to the flotillin proteins normally found in the cholesterol-enriched domains of eukaryotic cells. As shown for eukaryotic flotillin proteins, HP0248 was detected in detergent-resistant membrane fractions of H. pylori. Importantly, H. pylori HP0248 mutants contained lower levels of cholesterol than wild-type bacteria (P < 0.01). HP0248 mutant bacteria also exhibited defects in type IV secretion functions, as indicated by reduced IL-8 responses and CagA translocation in epithelial cells (P < 0.05), and were less able to establish a chronic infection in mice than wild-type bacteria (P < 0.05). Thus, we have identified an H. pylori flotillin protein and shown its importance for bacterial virulence. Taken together, the data demonstrate important roles for H. pylori flotillin in host-pathogen interactions. We propose that H. pylori flotillin may be required for the organization of virulence proteins into membrane raft-like structures in this pathogen.
Highlights
The human gastric pathogen Helicobacter pylori induces chronic gastric inflammation that usually remains asymptomatic
Given that H. pylori cell membranes are highly enriched in cholesterol, a feature of membrane rafts, we speculated that H. pylori may have a flotillin-like protein
The data demonstrate that HP0248 plays a role in chronic colonization of the mouse gastric mucosa. It has been known for some time that H. pylori obtains host cell-derived cholesterol to generate cholesteryl glucosides which the bacterium incorporates into its own membrane (Ansorg et al, 1992; Hirai et al, 1995)
Summary
The human gastric pathogen Helicobacter pylori induces chronic gastric inflammation that usually remains asymptomatic. In 10–20% of infections, individuals develop either peptic ulceration or gastric cancer (The EUROGAST Study Group, 1993) These severe forms of disease are more commonly associated with infection by H. pylori strains which harbor a cag pathogenicity. The H. pylori T4SS system mediates the induction of pro-inflammatory (e.g., interleukin-8, IL-8) responses (Viala et al, 2004) and a cell scattering or socalled “hummingbird” phenotype in epithelial cells (Segal et al, 1999). These responses are mediated by the T4SS-dependent delivery of cell wall peptidoglycan (Viala et al, 2004) and the effector protein, CagA (Odenbreit et al, 2000), respectively. The H. pylori T4SS appears to be dispensable for the induction of cytokine responses in macrophages and monocytes (Maeda et al, 2001; Gobert et al, 2004; Koch et al, 2016)
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