Characterization of FtrABCD: a ferrous iron-specific transporter that is required for the virulence of Brucella abortus 2308 in mice

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Ahmed E. M. Elhassanny (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: Brucella strains are Gram-negative bacteria that cause abortion and infertility in their natural animal hosts resulting in extensive economic losses. Humans can acquire a chronic, debilitating febrile illness known as brucellosis as the result of contact with infected animals or consumption of their products. The brucellae live mainly inside phagosomal compartments in host macrophages where they struggle to acquire enough of the essential micronutrient iron to meet their physiological needs. Brucella spp. have evolved multiple strategies to overcome iron limitation in their mammalian hosts, including siderophore-dependent ferric iron-specific transport and heme acquisition systems. The work presented in this dissertation characterized a ferrous iron (Fe2+) specific transporter encoded by the genes designated bab2_0837-0840 in the Brucella abortus 2308 genome sequence. This transporter is homologous to the FtrABCD transporter recently described in Bordetella. Interestingly, this transporter is required for the virulence of B. abortus 2308 in experimentally infected mice, supporting the proposition that ferrous iron is a critical iron source for these bacteria in the mammalian host. The iron response regulator (Irr), the predominant iron-responsive regulator in Brucella and the other alpha-proteobacteria, activates the expression of the ftrABCD operon in response to iron deprivation by binding a consensus Irr binding site in the promoter region of these genes. These genes are also activated by exposure to acidic pH, which is important because it potentially allows the brucellae to fine-tune the expression of their iron acquisition genes to adapt to the acidic environment they encounter in the phagosomal compartment of host macrophages, where Fe2+ is thought to be a biologically relevant iron source. The ftr locus is also regulated by the Zn finger protein MucR which belongs to the Ros/MucR family of transcriptional regulators that function as global transcriptional regulators in the [alpha]-proteobacteria. MucR has a secondary role in regulating the expression of the ftr genes in B. abortus 2308 by binding to a region very near to the Irr binding site and the acid-responsive regulatory element in the promoter region of these genes. MucR potentially interacts with Irr and the as yet unidentified acid-responsive transcriptional regulator, thus modulating the capacity of these regulators to bind to their target sites in the promoter region of the ftr locus. This type of secondary regulatory function is consistent with what has described for several MucR-regulated genes in other [alpha]-proteobacteria. In conclusion, the work presented in this dissertation showed that the ferrous iron specific transporter FtrABCD is required for Brucella abortus 2308 to survive and replicate in the host macrophage where Fe2+ is an essential and relevant micronutrient. The regulation of the expression of the ftrABCD genes by Irr, the acid-responsive transcriptional regulator and MucR is important because it potentially allows the brucellae to adapt to the environmental niches they inhabit during their residence in host macrophages.

Additional Information

Publication

Dissertation

Language: English

Date: 2016

Keywords

MucR, ferrous iron transporter, FtrABCD, Irr

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