Studies on the immunological and genetic properties of sensitive hosts for the pathogenic mycobacteria

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The murine natural resistance-associated macrophage protein, NRAMP1 has multiple pleiotropic effects on macrophage activation and regulates survival of intracellular pathogens. Genetic analyses have now linked polymorphisms in and around the NRAMP1 locus with susceptibility to some mycobacterial species in humans. In this time, the expression of NRAMP-1 proteins and mRNAs in the human macrophage cell line THP-1 was investigated by western blot analysis and real time-polymerase chain reaction(RT-PCR), respectively. Phorbol myristate acetate(PMA)- differentiated THP-1 cells were used in these studies. Unstimulated (without PMA) THP-1 cells constitutively expressed a low level of NRAMP1 mRNA and proteins. Both PMA and live bacteria stimulation (M.avium) could slightly accelerate the mRNA synthesis. The amount of NRAMP1 mRNA dramatically increased (>10 times) if THP-1 cells were stimulated with recombinant human IFN-γ(200U/ml). The growth of M.avium in THP-1 cells was inhibited if cells had been stimulated with PMA, and IFN-γ did not affect the growth of M.avium. This in vitro infection model seems to be a useful tool for studying the function of human NRAMP1. Next we examined the NRAMP-1 function in Mycobacterium lepraemurium(MLM) infected mice. Although NRAMP1 did not affect the susceptibility/resistance to the MLM infection among mouse strains, female mice were more sensitive than male mice if they were received with 10^8 bacteria intravenously. Finally, we tried to clarify the relationship between NRAMP1 and NK cells and their roles in M.avium infected mice. NK cell deficient beige mice increased their susceptibility to M.avium. Anti-NK cell antibody treatment in vivo decreased total number of NK cells in the mouse and reduced the ability to produce IFN-γ dramatically. However no relationship was observed between natural resistance to the infection by the NRAMP1 and NK cell function.