Siderophore-mediated iron acquisition in Campylobacter
Jun Lin, Professor and PhD
Department of Animal Science
The University of Tennessee, Knoxville, USA
Iron acquisition is critical for bacterial pathophysiology and thus has been proposed as attractive targets for iron-dependent pathogen control. The high-affinity iron acquisition mediated by siderophores is the most efficient and common iron scavenging mechanism in Gram-negative bacteria. Campylobacter has emerged as the leading bacterial cause of foodborne human diseases in many industrialized countries. While Campylobacter does not produce any siderophores, siderophore piracy is evident in various Campylobacter species. To date, enterobactin (Ent), a triscatecholate siderophore with the highest affinity for ferric iron, is the only known physiologically relevant siderophore utilized by Campylobacter for in vivo colonization. The high affinity Ent-mediated iron scavenging is tightly linked to Campylobacter pathogenesis; inactivation of ferric Ent (FeEnt) receptor CfrA or CfrB dramatically reduced and even abolished intestinal colonization by Campylobacter (> 5 log units reduction). Our recent studies have revealed novel features of FeEnt acquisition systems in Campylobacter, and provided new insights into the evolution of FeEnt acquisition in different Campylobacter species. These studies also suggested that Campylobacter is an ideal model organism to examine key issues of Ent-mediated iron scavenging due to its small genome (1.6-1.8 Mbp), inability to synthesize any siderophores, low redundancy of iron acquisition systems, and enormous strain diversity. Salmochelin, the glucosylated enterobactin, is likely another significant iron source for Campylobacter during infection. Various vaccination strategies have been developed and evaluated by targeting FeEnt receptor CfrA; however, these approaches did not provide significant protection against Campylobacter colonization in the intestine. Recently, we have started to explore innovative technology of iron-dependent control. Specifically, using Campylobacter as a model organism, we will use Ent specific antibodies as lipocalin-like agent to inhibit catecholates-mediated iron uptake and starve pathogen out of iron. Evaluation of the in vitro and in vivo efficacy of Ent antibodies in our ongoing studies is expected to result in major conceptual advances in the development of new vaccine and therapeutics to control effectively control the infections caused by Campylobacter and likely other Gram-negative pathogens.