EVALUATION OF: Tan S, Noto JM, Romero-Gallo J, Peek RM Jr, Amieva MR. Helicobacter pylori perturbs iron trafficking in the epithelium to grow on the cell surface. PLoS Pathog. 7(5), E1002050 (2011). The effects of Helicobacter pylori virulence factors on gastric epithelial cells are topics open to many studies. Major virulence factors, cytotoxin-associated gene A (CagA) and vacuolating cytotoxin (VacA), predict severe infection outcomes in many countries. H. pylori possesses various proteins for iron transport/storage, however, mechanisms of iron acquisition are not fully evaluated. The study by Tan et al. reveals a concurrent CagA/VacA activity for micronutrient acquisition and host tissue colonization. The virulence factors possess new activities, involving VacA-induced apical mislocalization of transferrin receptors to regions of H. pylori attachment and effects of both factors on polarized uptake and recycling of transferrin. The authors used many in vitro methods and an animal model. Iron acquisition by CagA was proven in vitro and in vivo by strain colonization of the gastric mucosa in iron-depleted conditions. CagA EPIYA motifs were associated with increased host internalization of transferrin. Importantly, CagA and VacA were involved in iron acquisition and colonization without severely damaging the host cells, thus favoring the infection chronicity. Further studies should assess molecular mechanisms of H. pylori iron acquisition, comparative activities of contact-dependent/soluble VacA and Eastern/Western CagA on the polarized epithelium and long-term effects of iron deficiency by virulent versus less virulent H. pylori strains. An interesting topic is the association of virulent strains with iron deficiency anemia but also with various H. pylori-induced diseases, in different populations and, possibly, for other bacterial infections. In conclusion, H. pylori iron acquisition is multifaceted. CagA and VacA work concurrently to provide both iron acquisition from interstitial holotransferrin and enhanced bacterial colonization of host cells apically. The new activities of the major virulence factors of adherent H. pylori are important both to research and in a clinical setting.