title: Efficacy of Resistance toFrancisellaImparted by ITY/NRAMP/SLC11A1 Depends on Route of Infection.
abstract: Natural resistance-associated macrophage protein (NRAMP) encoded by theSlc11a1gene is a membrane-associated transporter of divalent metal ions. MurineSlc11a1has two known alleles, a functionalSlc11a1Gly169, which is found in DBA2/J, NOD/LtJ, and 129p3/J and related mouse strains, and a non-functionalSlc11a1Asp169, that is found in C56Bl/6J (B6) and BALB/cJ mice. B6 mice congenic forSlc11a1Gly169(B6-Slc11a1G169) are markedly resistant to the intracellular pathogensSalmonella, Leishmania, andMycobacterium tuberculosis. We examined the host cell response and replication ofFrancisellain B6-Slc11a1G169mice. Bone marrow-derived macrophages from either B6-Slc11a1G169or B6 mice were both effectively invaded byFrancisellalive 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-Slc11a1G169mice the number decreased 10-fold. When the mice were challenged intranasally (i.n.) B6 mice lost significant amounts (~15%) of weight, where as B6-Slc11a1G169mice lost no weight. Three days after infection in B6-Slc11a1G169mice, we failed to recover viableFrancisellafrom the lungs, livers, or spleens. By contrast, B6 mice had bacterial burdens approaching 1 × 106CFU/organ in all three organs. To further examine the degree of resistance imparted bySlc11a1Gly169expression, we challenged mice deficient in TLR2, TLR4, and TLR9, but expressing the functional Slc11a1 (B6-Slc11a1G169Tlr2/4/9-/-). Surprisingly, B6-Slc11a1G169Tlr2/4/9-/-mice had no notable weight loss. Eighty percent of B6-Slc11a1G169Tlr2/4/9-/-mice yielded no detectableFrancisellain any organ tested. Additionally,Slc11a1G169produced little detectable cytokine either in the lung or serum compared to B6 mice. Mice expressingSlc11a1Gly169survived even high doses (~80 LD50) of LVS inoculation. These data taken together serve to highlight that functionalSlc11a1Gly169can compensate the lack of TLR2/4/9. ThusSlc11a1is a critical player in murine resistance to pulmonaryFrancisellainfection, but not footpad infection.
authors.affiliation: Department of Immunobiology, University of Arizona , Tucson, AZ , USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Powell
authors.affiliation: Department of Immunobiology, University of Arizona , Tucson, AZ , USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Frelinger
keywords: Francisella tularensis; SLC11A1; host response; mouse genetics; natural resistance-associated macrophage protein