The Resistance of BALB/cJ Mice toYersinia pestisMaps to the Major Histocompatibility Complex of Chromosome 17

Abstract

Yersinia pestis, the causative agent of plague, has been well studied at the molecular and genetic levels, 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. This resistance was observed only in BALB/cJ mice and not in other BALB/c substrains. Compared to C57BL/6J mice, the BALB/cJ strain exhibited reduced bacterial burden in the spleen and liver early after infection as well as lower levels of serum interleukin-6. These differences were evident 24 h postinfection and became more pronounced with time. Although a significant influx of neutrophils in the spleen and liver was exhibited in both strains, occlusive fibrinous thrombi resulting in necrosis of the surrounding tissue was observed only in C57BL/6J mice. In an effort to identify the gene(s) responsible for resistance, we measured total splenic bacteria in 95 F 2 mice 48 h postinfection and performed quantitative trait locus mapping using 58 microsatellite markers spaced throughout the genome. This analysis revealed a single nonrecessive plague resistance locus, designated prl1 (plague resistance locus 1), which coincides with the major histocompatibility complex of chromosome 17. A second screen of 95 backcrossed mice verified that this locus confers resistance to Y. pestis early in infection. Finally, eighth generation backcrossed mice harboring prl1 were found to maintain resistance in the susceptible C57BL/6J background. These results identify a novel genetic locus in BALB/cJ mice that confers resistance to Y. pestis.

Resistance of Mice of the 129 Background to Yersinia pestis Maps to Multiple Loci on Chromosome 1

“…We therefore chose to use inbred mice as a model to identify genes that may confer resistance against plague. We and others subsequently identified several inbred strains of mice that are resistant (11)(12)(13)(14). Resistance of the 129 line was first identified by Congleton et al in a pigmentation locus-negative (pgm Ϫ ) infection model of plague (11) but not for a fully virulent Y. pestis strain.…”

Mus spretus SEG/Pas mice resist virulent Yersinia pestis, under multigenic control

“…Using a combination of backcrossing and intercrossing, a QTL was mapped in the H2 region on proximal chromosome 17. 10 However, both studies were performed using the attenuated Y. pestis strain KIM5 which lacks the pgm locus, an important virulence factor. 16 This deletion requires that inoculation of Y. pestis be performed intravenously, a route that ensures rapid dissemination of the bacteria, but one that also bypasses several important processes, in particular those deployed in the skin and the draining lymph node.…”

“…10 These results were obtained upon intravenous injection of the Y. pestis mutant strain KIM5, which lacks the chromosomal pgm locus. As this strain is highly attenuated, it has to be given intravenously to cause a lethal infection.…”

Resistance to Yersinia pestis Infection Decreases with Age in B10.T(6R) Mice

“…Most BALB/c strains of mice are susceptible to plague infection. However, BALB/cJ mice are also highly resistant to plague (42). This resistance was mapped to a region that coincided with the major histocompatibility complex on chromosome 17.…”

“…Several laboratories (2,8,41,42) have reported different mouse strains intrinsically resistant to plague. Resistance does not appear to be conferred by one specific strain or genetic background.…”