Rapidly Escalating Hepcidin and Associated Serum Iron Starvation Are Features of the Acute Response to Typhoid Infection in Humans

Background Iron is a key pathogenic determinant of many infectious diseases. Hepcidin, the hormone responsible for governing systemic iron homeostasis, is widely hypothesized to represent a key component of nutritional immunity through regulating the accessibility of iron to invading microorganisms during infection. However, the deployment of hepcidin in human bacterial infections remains poorly characterized. Typhoid fever is a globally significant, human-restricted bacterial infection, but understanding of its pathogenesis, especially during the critical early phases, likewise is poorly understood. Here, we investigate alterations in hepcidin and iron/inflammatory indices following experimental human typhoid challenge. Methodology/Principal Findings Fifty study participants were challenged with Salmonella enterica serovar Typhi and monitored for evidence of typhoid fever. Serum hepcidin, ferritin, serum iron parameters, C-reactive protein (CRP), and plasma IL-6 and TNF-alpha concentrations were measured during the 14 days following challenge. We found that hepcidin concentrations were markedly higher during acute typhoid infection than at baseline. Hepcidin elevations mirrored the kinetics of fever, and were accompanied by profound hypoferremia, increased CRP and ferritin, despite only modest elevations in IL-6 and TNF-alpha in some individuals. During inflammation, the extent of hepcidin upregulation associated with the degree of hypoferremia. Conclusions/Significance We demonstrate that strong hepcidin upregulation and hypoferremia, coincident with fever and systemic inflammation, are hallmarks of the early innate response to acute typhoid infection. We hypothesize that hepcidin-mediated iron redistribution into macrophages may contribute to S. Typhi pathogenesis by increasing iron availability for macrophage-tropic bacteria, and that targeting macrophage iron retention may represent a strategy for limiting infections with macrophage-tropic pathogens such as S. Typhi.
Author Summary An adequate supply of iron is essential for both human hosts and their infecting pathogens. Hepcidin is the human hormone that controls the quantity and distribution of iron throughout the body. During infections, hepcidin activity may redistribute iron away from serum and into macrophages, potentially affecting pathogen replication, depending on the niche of the invading microbe. However, the involvement of hepcidin in human bacterial infections remains poorly investigated. Similarly, the pathogenesis of typhoid fever, caused by infection with Salmonella Typhi is also poorly understood. We therefore investigated the behaviour of hepcidin and other iron/inflammation-related parameters during the course of typhoid fever in human volunteers challenged experimentally with Salmonella Typhi. Hepcidin concentrations rose rapidly during acute typhoid infection, in parallel with fever. Hepcidin induction was accompanied by a rapid decline in serum iron concentrations, likely reflecting iron sequestration in macrophages (a preferred replication site of Salmonella Typhi). The extent of hepcidin upregulation associated with the extent of serum iron starvation. We hypothesize that hepcidin activity during acute typhoid infection in humans may elevate iron levels in the niche used by the pathogen for replication. Targeting macrophage iron retention should be evaluated as a potential strategy for limiting typhoid fever.