Figure 8 Infection with the galU Selleckchem PCI-34051 mutant of FT LVS elicits protective immunity WT FT LVS. C57Bl/6J mice (n = 5) that had survived intranasal challenge with the galU mutant FT strain and naïve control mice (n = 5) were challenged intranasally with 5 × 104 CFU (50 × LD50) of WT FT LVS eight weeks following the initial infection. The body weight (Panel A) and survival (Panel B) of mice were monitored for survival for 30 days. Statistical analyses of changes in body weight were performed via two-way ANOVA

using a Bonferroni multiple comparisons post-test and p-values are indicated as follows: * P < 0.05 and *** P < 0.001. Statistical analysis of the survival data was GSK2118436 price performed using a Gehan-Breslow-Wilcoxon test (** indicates a p-value of 0.0043). Discussion A major focus of FT research continues to be the identification of virulence-mechanisms used by this extremely virulent pathogen. A number of virulence determinants have been identified, but there remains much to discover regarding the virulence mechanisms used by FT to survive and cause disease within its mammalian hosts. In this report we show that mutation of galU results in a dramatic

attenuation of FTLVS virulence that appears to be unrelated to any in vivo infectivity or growth defects. Although it is known that mutation of the galU gene leaves some other bacterial pathogens attenuated for virulence [27, 32, 43, 44], this is the first report examining the role of galU in the pathogenesis of FT. Neutrophils are a critical component of the innate immune responses to bacterial infection, and the recruitment of these cells into the lungs following pneumonic infection typically peaks by 48-hours post-infection click here [45–47]. However, it has been reported elsewhere [22, 25] and confirmed here that neutrophil recruitment following wild type FT infection in the lungs is not detected until approximately Dolichyl-phosphate-mannose-protein mannosyltransferase 72 h post-infection. Because it is known that neutrophils are required for control of FT infection [48], it is reasonable to speculate that the ability of FT to delay the kinetics

of neutrophil recruitment into the lungs following pulmonary infection may be an important virulence determinant. Interestingly, a comparative analysis following pulmonary infection of mice with the galU mutant and WT strains of FT revealed that the kinetics of neutrophil recruitment (and production of chemokines/cytokines involved in neutrophil recruitment) occurs much more rapidly following infection with the galU mutant (peaks at 48 h post-infection). Kinetic analyses of bacterial burdens in the lungs, spleens, and livers of mice following infection with the galU mutant and WT strains of FT revealed that the two strains disseminated and replicated at comparable rates, but the bacterial burdens in galU-infected animals became significantly lower than in WT-infected animals by 72 h post-infection. The significant difference in bacterial burdens observed in galU mutant- vs.