Innate host resistance to infectious agents plays an important role in determining whether infection by pathogenic microorganisms progresses to disease or whether the microorganisms are eliminated. Resistance to the growth of several intracellular pathogens, including Mycobacteria, Salmonella and Leishmania is mediated by the macrophage and is controlled by a gene, now called Nramp1, a natural resistance associated macrophage protein. The gene appears to control the functional capacity of macrophages such that macrophages that express the functional protein appear to be at a more heightened state of activation than are macrophages that do not express a functional protein. The function of the gene product in controlling resistance is not known. Based on nucleotide sequence analysis the deduced protein appears to be a transport protein.
The specific aims are to: 1) correlate mycobacterial resistance, using lung and splenic macrophages, with stable expression of mRNA and the intracellular iron with Nramp1 using both congenic and transgenic mice; 2) determine the role of Nramp1Gly169 in transition metal transport; 3) determine the role of intracellular iron and Nramp1 in mRNA stability and protein synthesis using cell lines transfected with Nramp1Gly169 and Nramp1Asp169; and 4) determine the mechanism of mRNA stability induced by iron.
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