Powell Daniel A, Frelinger Jeffrey A
Department of Immunobiology, University of Arizona , Tucson, AZ , USA.
Front Immunol. 2017 Mar 15;8:206. doi: 10.3389/fimmu.2017.00206. eCollection 2017.
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.
由该基因编码的天然抗性相关巨噬细胞蛋白（NRAMP）是一种与膜相关的二价金属离子转运蛋白。小鼠的该基因有两个已知等位基因，一个是功能性的Slc11a1，存在于DBA2/J、NOD/LtJ和129p3/J及相关小鼠品系中；另一个是非功能性的Slc11a1，存在于C56Bl/6J（B6）和BALB/cJ小鼠中。携带功能性Slc11a1的B6小鼠（B6-Slc11a1）对细胞内病原体土拉弗朗西斯菌和结核分枝杆菌具有显著抗性。我们研究了B6-Slc11a1小鼠的宿主细胞反应及土拉弗朗西斯菌的复制情况。来自B6-Slc11a1或B6小鼠的骨髓源性巨噬细胞均能被土拉弗朗西斯菌活疫苗株（LVS）有效侵袭。然而，在感染后16小时（hpi），从B6巨噬细胞中回收的LVS细菌数量增加了约100倍，而在B6-Slc11a1小鼠中数量减少了10倍。当经鼻内（i.n.）攻击小鼠时，B6小鼠体重显著减轻（约15%），而B6-Slc11a1小鼠体重未减轻。在B6-Slc11a1小鼠感染三天后，我们未能从其肺、肝或脾中回收活的土拉弗朗西斯菌。相比之下，B6小鼠在所有三个器官中的细菌载量接近1×10⁶CFU/器官。为了进一步研究Slc11a1表达所赋予的抗性程度，我们攻击了缺乏TLR2、TLR4和TLR9但表达功能性Slc11a1的小鼠（B6-Slc11a1）。令人惊讶的是，B6-Slc11a1小鼠没有明显的体重减轻。80%的B6-Slc11a1小鼠在任何测试器官中均未检测到土拉弗朗西斯菌。此外，与B6小鼠相比，土拉弗朗西斯菌在肺或血清中产生的可检测细胞因子也很少。表达Slc11a1的小鼠即使接种高剂量（约80 LD）的LVS也能存活。这些数据共同表明功能性Slc11a1可以弥补TLR2/4/9的缺失。因此，Slc11a1是小鼠抵抗肺部土拉弗朗西斯菌感染的关键因素，但不是抵抗足垫感染的关键因素。
