Analyses of the NRAMP1 and IFN- γ R1 Genes in Women with Mycobacterium avium-intracellulare Pulmonary Disease

Abstract

Mycobacterium avium-intracellulare (MAI) pulmonary disease causes substantial morbidity in a population of older, HIV-negative women without preexisting lung disease. The cause for disease susceptibility in these patients is unknown, although their relative phenotypic homogeneity suggests the existence of a common, subtle immune deficiency. An investigation was undertaken to determine if these patients have a defect in their natural resistance-associated macrophage protein (NRAMP1) or interferon gamma receptor 1 (IFN-gammaR1) genes. A point mutation in murine nramp, an autosomal recessive gene controlling resistance to intracellular organisms, correlates with overwhelming Mycobacterium bovis infection in mice. The corresponding region in human NRAMP1, two coding polymorphisms and one promoter NRAMP1 polymorphism, as well as two IFN-gammaR1 polymorphisms, were analyzed to determine if an allele was present to correlate with disease. Genomic DNA was purified from eight women with MAI pulmonary disease and four controls. Regions of interest were amplified by PCR; three sites were analyzed by restriction fragment length polymorphisms, and three were analyzed using denaturing high-performance liquid chromatography. The NRAMP1 promoter polymorphism of 18 additional random controls was analyzed by microsatellite sizing. No allelism was found in NRAMP1 corresponding to the murine mutation, or in the two coding regions. In the NRAMP1 promoter microsatellite, 3 of 8 patients were heterozygous for a dinucleotide sequence insertion, as were 10 of 22 controls. None of the patients had either of the two known IFN-gammaR1 mutations. In conclusion, in women with MAI pulmonary disease, there is no evidence for a genetic defect in NRAMP1 or IFN-gammaR1 to correlate with disease.

PulmonaryMycobacterium aviumcomplex infection: association withNRAMP1polymorphisms

“…A human homologue, NRAMP1, recently designated as solute carrier 11a1, was identified in the region of 2q35, and variations of the NRAMP1 gene were studied for mycobacterial diseases including TB and leprosy [12][13][14][15][16]. In cases of MAC infection, the number of subjects is small [10,17,18], and, to date, no population-based studies have investigated the contribution of NRAMP1 to pulmonary MAC infection with a relatively large sample size. As other candidate genes, polymorphisms of the vitamin D receptor (VDR ) and mannose binding lectin (MBL) genes are known to be associated with TB [19,20], presumably playing an important role in intracellular growth of the pathogen.…”

Genetic Resistance of Mice toMycobacterium paratuberculosisIs Influenced bySlc11a1at the Early but Not at the Late Stage of Infection

“…Bacteria were very rapidly eliminated from the lungs of both susceptible and resistant mice, indicating that Slc11a1-independent mechanisms are involved in the antimycobacterial defense of pulmonary macrophages. Interestingly, a study of women suffering from M. avium-M. intracellulare pulmonary disease also failed to find a correlation with Slc11a1 polymorphisms (16).…”

Nontuberculous Mycobacterial Lung Disease: An Emerging Disease in the Elderly

“…In contrast to the previously described studies, a large cohort of 63 prospectively enrolled patients with NTM lung disease was found to have normal CD4(+), CD8(+), B, and natural killer cell numbers, and similar stimulated cytokine production compared with healthy control subjects (including the IFN-γ/IL-12 pathway) [27], albeit these investigations utilized less specific antigenic stimuli versus some of the prior studies that did demonstrate differences [51]. Another evaluation of 8 women with MAC lung disease found no evidence of mutations affecting the IFN-γ receptor or NRAMP1 [54]. Furthermore, intact granuloma formation capability has been demonstrated on histopathologic analysis of transbronchial lung biopsies among more than half of individuals with MAC lung disease in another series [55].…”