The Ferric Enterobactin Transporter Fep Is Required for Persistent Salmonella enterica Serovar Typhimurium Infection

Abstract

ABSTRACTMost bacterial pathogens require iron to grow and colonize host tissues. The Gram-negative bacteriumSalmonella entericaserovar Typhimurium causes a natural systemic infection of mice that models acute and chronic human typhoid fever.S. Typhimurium resides in tissues within cells of the monocyte lineage, which limit pathogen access to iron, a mechanism of nutritional immunity. The primary ferric iron import system encoded bySalmonellais the siderophore ABC transporter FepBDGC. The Fep system has a known role in acute infection, but it is unclear whether ferric iron uptake or the ferric iron binding siderophores enterobactin and salmochelin are required for persistent infection. We defined the role of the Fep iron transporter and siderophores in the replication ofSalmonellain macrophages and in mice that develop acute followed by persistent infections. Replication of wild-type and iron transporter mutantSalmonellastrains was quantified in cultured macrophages, fecal pellets, and host tissues in mixed- and single-infection experiments. We show that deletion offepBattenuatedSalmonellareplication and colonization within macrophages and mice. Additionally, the genes required to produce and transport enterobactin and salmochelin across the outer membrane receptors,fepAandiroN, are needed for colonization of all tissues examined. However, salmochelin appears to be more important than enterobactin in the colonization of the spleen and liver, both sites of dissemination. Thus, the FepBDGC ferric iron transporter and the siderophores enterobactin and salmochelin are required bySalmonellato evade nutritional immunity in macrophages and cause persistent infection in mice.