Attenuated virulence of a Francisella mutant lacking the lipid A 4'-phosphatase.
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 10(6) wild-type but not 10(8) 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.
Wang
Xiaoyuan
X
Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.
Ribeiro
Anthony A
AA
Guan
Ziqiang
Z
Abraham
Soman N
SN
Raetz
Christian R H
CR
D000818:Animals; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism; D002240:Carbohydrate Sequence; D005604:Francisella tularensis / Q000201:enzymology / Q000235:genetics* / Q000472:pathogenicity*; D006801:Humans; D007113:Immunity, Innate; D008050:Lipid A / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009154:Mutation; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D011113:Polymyxins / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism
D001425:Bacterial Outer Membrane Proteins; D008050:Lipid A; D011113:Polymyxins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C095015:lipid A 4'-phosphatase; D010744:Phosphoric Monoester Hydrolases