Brucella abortus is a Gram-negative, α-proteobacterium that causes bovine brucellosis, a prevalent zoonotic disease in many areas of the world. Brucella abortus is an intracellular pathogen that survives and replicates in the phagosomal compartment of host macrophages, a property that is critical for virulence. In this environment, Brucella abortus requires manganese, but the availability of this essential micronutrient is restricted in the phagosomal compartment. Host cells resist bacterial infection by limiting the availability of metals in the phagosome employing what is known as the metal withholding defense, a process mediated by Nramp1 (Natural resistance associated macrophage protein). To counter this, pathogenic bacteria produce high-affinity manganese transporters, and these transporters have been shown to be necessary for virulence.
MntH is the bacterial homolog of the eukaryotic Nramp and is the only identified high affinity manganese transporter in Brucella strains. In this study, the function and the metal-specificity of this protein was examined. Studies employing a genetically defined Brucella abortus mntH mutant show that MntH-mediated manganese acquisition is critical for normal in vitro growth and the establishment of infection in mice. The α-proteobacteria employ a structural homolog of the ferric uptake regulator Fur which is Mn-responsive (and thus designated Mur for manganese uptake regulator) to control the expression of their manganese acquisition genes. Phenotypic analysis of a mur mutant showed that Mur is responsible for the Mn-responsive regulation of mntH expression in B. abortus 2308 and biochemical studies defined the Mur binding site in the mntH promoter.
|Advisor:||Roop, Roy M., II|
|Commitee:||Hager, Paul, Martin, Daniel, Putnam-Evans, Cindy|
|School:||East Carolina University|
|School Location:||United States -- North Carolina|
|Source:||MAI 49/06M, Masters Abstracts International|
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