Efficacy of Resistance to Imparted by ITY/NRAMP/SLC11A1 Depends on Route of Infection.

Natural resistance-associated macrophage protein (NRAMP) encoded by the gene is a membrane-associated transporter of divalent metal ions. Murine has two known alleles, a functional , which is found in DBA2/J, NOD/LtJ, and 129p3/J and related mouse strains, and a non-functional , that is found in C56Bl/6J (B6) and BALB/cJ mice. B6 mice congenic for (B6- ) are markedly resistant to the intracellular pathogens , and . We examined the host cell response and replication of in B6- mice. Bone marrow-derived macrophages from either B6- or B6 mice were both effectively invaded by live vaccine strain (LVS). However, at 16 hours post-infection (hpi), the number of LVS bacteria recovered from B6 macrophages had increased roughly 100-fold, while in B6- mice the number decreased 10-fold. When the mice were challenged intranasally (i.n.) B6 mice lost significant amounts (15%) of weight, where as B6- mice lost no weight. Three days after infection in B6- mice, we failed to recover viable from the lungs, livers, or spleens. By contrast, B6 mice had bacterial burdens approaching 1 × 10 CFU/organ in all three organs. To further examine the degree of resistance imparted by expression, we challenged mice deficient in TLR2, TLR4, and TLR9, but expressing the functional Slc11a1 (B6- ). Surprisingly, B6- mice had no notable weight loss. Eighty percent of B6- mice yielded no detectable in any organ tested. Additionally, produced little detectable cytokine either in the lung or serum compared to B6 mice. Mice expressing survived even high doses (80 LD) of LVS inoculation. These data taken together serve to highlight that functional can compensate the lack of TLR2/4/9. Thus is a critical player in murine resistance to pulmonary infection, but not footpad infection.