Attenuated virulence of a Francisella mutant lacking the lipid A 4′-phosphatase

被引:101
作者
Wang, Xiaoyuan
Ribeiro, Anthony A.
Guan, Ziqiang
Abraham, Soman N.
Raetz, Christian R. H.
机构
[1] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA
[2] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA
关键词
antimicrobial pepticles; outer membrane; innate immunity; polymyxin; tularemia;
D O I
10.1073/pnas.0611606104
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Francisella tularensis causes tularemia, a highly contagious disease of animals and humans, but the virulence features of F. tularensis are poorly defined. F. tularensis and the related mouse pathogen Francisella novicida synthesize unusual lipid A molecules lacking the 4'-monophosphate group typically found in the lipid A of Gram-negative bacteria. LpxF, a selective phosphatase located on the periplasmic surface of the inner membrane, removes the 4'-phosphate moiety in the late stages of F. novicida lipid A assembly. To evaluate the relevance of the 4'-phosphatase to pathogenesis, we constructed a deletion mutant of lpxF and compared its virulence with wild-type F. novicida. Intradermal injection of 106 wild-type but not 108 mutant F novicida cells is lethal to mice. The rapid clearance of the lpxF mutant is associated with a stronger local cytokine response and a greater influx of neutrophils compared with wild-type. The F. novicida mutant was highly susceptible to the cationic antimicrobial peptide polymyxin. LpxF therefore represents a kind of virulence factor that confers a distinct lipid A phenotype, preventing Francisella from activating the host innate immune response and preventing the bactericidal actions of cationic peptides. Francisella lpxF mutants may be useful for immunization against tularemia.
引用
收藏
页码:4136 / 4141
页数:6
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