ChePep Controls Helicobacter pylori Infection of the Gastric Glands and Chemotaxis in the Epsilonproteobacteria

Abstract

Microbes use directed motility to colonize harsh and dynamic environments. We discovered that Helicobacter pylori strains establish bacterial colonies deep in the gastric glands and identified a novel protein, ChePep, necessary to colonize this niche. ChePep is preferentially localized to the flagellar pole. Although mutants lacking ChePep have normal flagellar ultrastructure and are motile, they have a slight defect in swarming ability. By tracking the movement of single bacteria, we found that ∆ChePep mutants cannot control the rotation of their flagella and swim with abnormally frequent reversals. These mutants even sustain bursts of movement backwards with the flagella pulling the bacteria. Genetic analysis of the chemotaxis signaling pathway shows that ChePep regulates flagellar rotation through the chemotaxis system. By examining H. pylori within a microscopic pH gradient, we determined that ChePep is critical for regulating chemotactic behavior. The chePep gene is unique to the Epsilonproteobacteria but is found throughout this diverse group. We expressed ChePep from other members of the Epsilonproteobacteria, including the zoonotic pathogen Campylobacter jejuni and the deep sea hydrothermal vent inhabitant Caminibacter mediatlanticus, in H. pylori and found that ChePep is functionally conserved across this class. ChePep represents a new family of chemotaxis regulators unique to the Epsilonproteobacteria and illustrates the different strategies that microbes have evolved to control motility.

Bacterial chemotaxis modulates host cell apoptosis to establish a T-helper cell, type 17 (Th17)-dominant immune response in Helicobacter pylori infection

“…Our model fits well with previous H. pylori experiments that demonstrated chemotaxis is needed for normal bacterial positioning within the gastric epithelium (4,6). Here we show that appropriate localization allows H. pylori to increase VacA expression (Fig.…”

“…Therefore, our results suggest Che − bacteria express or deliver less proapoptotic virulence factors in vivo. Che − H. pylori localize farther from the gastric epithelial cell surface than does wild type (4,6) suggesting Che − either may be too spatially distant from the target cells for efficient delivery of virulence factors or may experience a different microenvironment that does not trigger appropriate expression of apoptosis-inducing proteins. Supporting this latter idea, chemotaxis regulates virulence factor expression in Vibrio cholerae (31).…”

“…The expression of UreA is regulated by the acid-responsive signaling regulator/sensor (ArsRS) twocomponent system, which prompts pH-controlled gene expression (32). Therefore, because Che − bacteria are farther from the epithelial cells (4,6) where they may encounter a more acidic pH, it is not surprising that they have slightly increased expression of UreA. The slightly lower expression of VacA along with a greater delivery distance may contribute to reduced apoptosis through reduced delivery of VacA to the epithelial cells.…”

“…In mouse models, these mutants have a marginal colonization defect (4-6) but induce less overall chronic inflammation (4). Specifically, Che − mutants localize far from the epithelial surface and do not colonize the gastric glands robustly (4,6), suggesting that chemotaxis-driven contact with epithelial cells, resident dendritic cells, or monocytes promotes the inflammatory response to H. pylori.…”

A supplemented soft agar chemotaxis assay demonstrates the Helicobacter pylori chemotactic response to zinc and nickel

“…Other reported attractants include bicarbonate (Cerda et al, 2003;Mizote et al, 1997), NaCl (Mizote et al, 1997), cholesterol (Wunder et al, 2006), and the amino acids aspartate, serine and arginine (Cerda et al, 2003). H. pylori is repelled by NiCl 2 (Cerda et al, 2003), low pH (Croxen et al, 2006;Howitt et al, 2011;Rader et al, 2011) and autoinducer-2 (Rader et al, 2011), the latter two via the TlpB chemoreceptor. Alterations in proton motive force trigger both attractant and repellent responses (Schweinitzer et al, 2008).…”