The Regulatory Protein ChuP Connects Heme and Siderophore-Mediated Iron Acquisition Systems Required for Virulence.

is an environmental Gram-negative beta-proteobacterium that causes systemic infections in humans. uses siderophore-based iron acquisition systems to overcome the host-imposed iron limitation, but its capacity to use other iron sources is unknown. In this work, we characterized ChuPRSTUV as a heme utilization system employed by to explore an important iron reservoir in mammalian hosts, free heme and hemoproteins. We demonstrate that the genes comprise a Fur-repressed operon that is expressed under iron limitation. The operon potentially encodes a small regulatory protein (ChuP), an outer membrane TonB-dependent receptor (ChuR), a heme degradation enzyme (ChuS), and an inner membrane ABC transporter (ChuTUV). Our nutrition growth experiments using deletion mutants revealed that, with the exception of , all genes of the operon are required for heme and hemoglobin utilization in . The mutant strains without displayed increased siderophore halos on CAS plate assays. Significantly, we demonstrate that ChuP connects heme and siderophore utilization by acting as a positive regulator of and , which encode the TonB-dependent receptors for the uptake of heme (ChuR) and the siderophore viobactin (VbuA). Our data favor a model of ChuP as a heme-binding post-transcriptional regulator. Moreover, our virulence data in a mice model of acute infection demonstrate that uses both heme and siderophore for iron acquisition during infection, with a preference for siderophores over the Chu heme utilization system.