Abstract
Helicobacter pylori (Hp) injects the CagA effector protein into host epithelial cells and induces growth factor-like signaling, perturbs cell-cell junctions, and alters host cell polarity. This enables Hp to grow as microcolonies adhered to the host cell surface even in conditions that do not support growth of free-swimming bacteria. We hypothesized that CagA alters host cell physiology to allow Hp to obtain specific nutrients from or across the epithelial barrier. Using a polarized epithelium model system, we find that isogenic ΔcagA mutants are defective in cell surface microcolony formation, but exogenous addition of iron to the apical medium partially rescues this defect, suggesting that one of CagA's effects on host cells is to facilitate iron acquisition from the host. Hp adhered to the apical epithelial surface increase basolateral uptake of transferrin and induce its transcytosis in a CagA-dependent manner. Both CagA and VacA contribute to the perturbation of transferrin recycling, since VacA is involved in apical mislocalization of the transferrin receptor to sites of bacterial attachment. To determine if the transferrin recycling pathway is involved in Hp colonization of the cell surface, we silenced transferrin receptor expression during infection. This resulted in a reduced ability of Hp to colonize the polarized epithelium. To test whether CagA is important in promoting iron acquisition in vivo, we compared colonization of Hp in iron-replete vs. iron-deficient Mongolian gerbils. While wild type Hp and ΔcagA mutants colonized iron-replete gerbils at similar levels, ΔcagA mutants are markedly impaired in colonizing iron-deficient gerbils. Our study indicates that CagA and VacA act in concert to usurp the polarized process of host cell iron uptake, allowing Hp to use the cell surface as a replicative niche.
Highlights
Helicobacter pylori (Hp) is a mucosal colonizer that infects the stomachs of more than half of the world’s population [1]
We previously reported that wild type (WT) Hp are able to colonize the apical cell surface of polarized Madin-Darby Canine Kidney II (MDCK) monolayers when the apical medium bathing the cells contains only DMEM, a medium that cannot support Hp growth in vitro [8]
The rescue of DcagA growing on the cell surface by iron suggests that CagA affects host epithelial cell function to allow Hp access to micronutrients that are found in the epithelium or across its barrier
Summary
Helicobacter pylori (Hp) is a mucosal colonizer that infects the stomachs of more than half of the world’s population [1]. The contact-dependent Hp virulence factor CagA, which is injected directly into host cells via the bacterium’s type IV secretion system, plays an important role in enabling Hp colonization of the epithelium [8]. This occurs via a local perturbation of epithelial polarity, and can occur without gross disruption of epithelial integrity [8]. Since an important role of the epithelial barrier is to sequester and compartmentalize molecules that may be useful for colonizing microbes, we speculated that Hp has evolved specialized mechanisms to perturb cell polarity to acquire essential factors directly from the polarized epithelium. The nature of the factors transferred from the host cells to the bacteria and the molecular mechanisms involved remain unclear
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