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May, 2011;7 (5): e1002050.

Helicobacter pylori perturbs iron trafficking in the epithelium to grow on the cell surface.

Shumin Tan, Jennifer M Noto, Judith Romero-Gallo, Richard M Peek, Manuel R Amieva
Author Information
  1. Shumin Tan: Department of Microbiology and Immunology, Stanford University, Stanford, California, United States of America.
PMID: 21589900 DOI: 10.1371/journal.ppat.1002050

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.

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Grants

  1. R01 CA077955/NCI NIH HHS
  2. R01 CA092229/NCI NIH HHS
  3. CA77955/NCI NIH HHS
  4. CA92229/NCI NIH HHS
  5. R01 AI038459/NIAID NIH HHS
  6. R01 DK058587/NIDDK NIH HHS
  7. R29 CA077955/NCI NIH HHS
  8. AI038459/NIAID NIH HHS
  9. DK58587/NIDDK NIH HHS
  10. CA116837/NCI NIH HHS

MeSH Term

Adaptation, Physiological
Animals
Antigens, Bacterial
Bacterial Adhesion
Bacterial Proteins
Caco-2 Cells
Cell Line
Cell Membrane
Cell Polarity
Dogs
Down-Regulation
Epithelium
Gastric Mucosa
Gerbillinae
Helicobacter Infections
Helicobacter pylori
Humans
Intercellular Junctions
Iron
Receptors, Transferrin
Sequence Deletion
Signal Transduction
Transcytosis
Transferrin

Chemicals

Antigens, Bacterial
Bacterial Proteins
Receptors, Transferrin
Transferrin
VacA protein, Helicobacter pylori
cagA protein, Helicobacter pylori
Iron
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't
Article has an altmetric score of 13

Word Cloud

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