Yersinia pestis Lipopolysaccharide in Host-Pathogen Interactions

Abstract

Isogenic Y. pestis strains with a single mutation in 14 genes of lipopolysaccharide (LPS) biosynthetic pathways were constructed. Using high-resolution electrospray ionization mass spectrometry, the full LPS structures were elucidated in each mutant, and the sequence of monosaccharide transfers in the assembly of the LPS core was inferred. Truncation of the core decreased significantly the resistance of bacteria to normal human serum (NHS) and polymyxin B. Impairing of LPS biosynthesis resulted also in reduction of LPS-dependent enzymatic activities of plasminogen activator. A gradual truncation of the LPS core was accompanied by a decrease of virulence in mice and guinea pigs. However, the reduction in virulence remained behind the decrease of bacterial resistance to innate immunity factors. E.g., waaQ mutant deficient in HepIII transferase was highly susceptible to polymyxin B and NHS but was as virulent as the parental strain in both animal models. Y. pestis mutants with two or less sugar residues in the core were not only susceptible to antimicrobial cationic peptides and NHS but also avirulent in animal infection models. This finding demonstrated that the LPS structure is crucial for the lethality of plague infection, and waaC, hldE and waaA or their protein products can be considered as promising candidates for targeting Y. pestis virulence using specific inhibitors.