Helicobacter pylori Perturbs Iron Trafficking in the Epithelium to Grow on the Cell Surface

PLoS Pathogens

Manuel R. Amieva¹  Jennifer M. Noto²  Judith Romero-Gallo²  Richard M. Peek Jr.²  Shumin Tan³ 

[1] Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, United States of America;Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America;Department of Microbiology and Immunology, Stanford University, Stanford, California, United States of America

关键词: Host cells;    Epithelium;    Small interfering RNAs;    Cell polarity;    Fluorescence imaging;    Epithelial cells;    Cell staining;    Virulence factors;   

DOI  :  10.1371/journal.ppat.1002050

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY