Cellular and genetic basis for the resistance of BALB/cJ and 129S1/SvImJ mice to Yersinia pestis

Yersinia pestis, the causative agent of plague, has been well studied at the molecular and genetic level, but little is known about the role that host genes play in combating this highly lethal pathogen. We challenged several inbred strains of mice with Y. pestis and found that BALB/cJ mice are highly resistant compared to susceptible strains such as C57BL/6J. Resistance is seen within 24 hours post infection. In an effort to identify gene(s) responsible for resistance we performed QTL mapping with F2 mice and discovered a single resistance locus on chromosome 17. Eighth generation backcrossed mice harboring prl1 were found to maintain resistance in the susceptible C57BL/6J background. Resistance appears to be due to an ability of BALB/cJ macrophages and neutrophils to better kill the bacteria. Interleukin (IL)-10 deficient mice are resistant to Y. pestis. Surprisingly, heterozygous IL-10+/- mice also survive high dose infection with Y. pestis KIM5. Analysis of commercial IL-10-/- mice revealed that at least 30 cM of genomic DNA from the original 129 strain remains, including a functional Slc11a1 (Nramp1) gene. Interestingly, two substrains of 129 mice were resistant to high dose Y. pestis KIM5. Resistance does not appear to be recessive as F1 mice (C57BL/6J x 129) also survived a high dose challenge. A QTL-based genetic scan of chromosome 1 with 35 infected F1 backcrossed mice revealed that resistance to KIM5 maps to a region near IL-10. Two novel IL-10+/+ mouse strains, that each possess most of the original 30 cM stretch of 129 DNA, maintained resistance to high dose infection with Y. pestis KIM5 even in a heterozygous state. Conversely, a novel IL-10-/- mouse strain, in which most of the 129 DNA has been crossed out exhibited intermediate resistance to KIM5, while the corresponding IL-10+/- strain was completely susceptible. Taken together, these results demonstrate that 129-derived genomic DNA near IL-10 confers resistance to Y. pestis KIM5 and contributes to the observed resistance of IL-10-/- mice.