Unique Host Iron Utilization Mechanisms of Helicobacter pylori Revealed with Iron-Deficient Chemically Defined Media

Abstract

Helicobacter pylori chronically infects the gastric mucosa, where it can be found free in mucus, attached to cells, and intracellularly. H. pylori requires iron for growth, but the sources of iron used in vivo are unclear. In previous studies, the inability to culture H. pylori without serum made it difficult to determine which host iron sources might be used by H. pylori. Using iron-deficient, chemically defined medium, we determined that H. pylori can bind and extract iron from hemoglobin, transferrin, and lactoferrin. H. pylori can use both bovine and human versions of both lactoferrin and transferrin, contrary to previous reports. Unlike other pathogens, H. pylori preferentially binds the iron-free forms of transferrin and lactoferrin, which limits its ability to extract iron from normal serum, which is not iron saturated. This novel strategy may have evolved to permit limited growth in host tissue during persistent colonization while excessive injury or iron depletion is prevented.

Change Is Good: Variations in Common Biological Mechanisms in the Epsilonproteobacterial GeneraCampylobacterandHelicobacter

“…In contrast, as the lone known bacterial resident of the gastric mucosa, H. pylori competes for iron solely with the human host. Thus, H. pylori has evolved specific iron acquisition mechanisms that primarily allow the bacterium to compete for hostderived sources of iron (134,533). Regardless of the colonization site, both C. jejuni and H. pylori tightly control the expression of iron uptake and storage systems by using Fur.…”

“…are capable of utilizing hemoglobin. For H. pylori, the hemoglobin receptor was identified as FrpB2 and specific hemoglobin utilization was clearly confirmed using a chemically defined growth medium (212,533). Analysis of the predicted FrpB2 structure revealed an overall similarity to the hemoglobinbinding protein, ChuA, of E. coli O157:H7 strains (212).…”

“…Among the gastric Helicobacter spp., H. pylori appears unique in its ability to utilize host lactoferrin (274). In addition, a recent study using defined minimal media showed that H. pylori is also able to utilize both human and bovine forms of lactoferrin and transferrin (533). Interestingly, H. pylori preferentially binds the apo forms of lactoferrin and transferrin, which may suggest that preferential binding to the apo forms limits H. pylori pathogenicity to allow for a persistent infection without excessive damage to the host (533).…”

Novel Insights into Fur Regulation in Helicobacter pylori

“…Within the human host, H. pylori is able to obtain and utilize free ferrous iron, as well as iron from host-derived hemoglobin, transferrin, and lactoferrin molecules (reviewed in (69)). In addition, H. pylori binds the iron-free forms of these host molecules, which is hypothesized to limit host iron utilization (139). To date, all of the components of these iron acquisition systems that have been characterized are regulated by Fur.…”

“…During infection, these iron-containing molecules represent a readily available iron source for bacteria. Consequently, H. pylori has evolved the ability to obtain iron from host lactoferrin, transferrin, hemoglobin, and heme (48, 80,139,175). In addition to these iron uptake systems, the H. pylori genome also encodes multiple fec genes, which facilitate ferric citrate uptake (9,39,155) from the extracellular environment.…”