RRC ID 35650
Author Rasmussen JA, Post DM, Gibson BW, Lindemann SR, Apicella MA, Meyerholz DK, Jones BD.
Title Francisella tularensis Schu S4 lipopolysaccharide core sugar and O-antigen mutants are attenuated in a mouse model of tularemia.
Journal Infect Immun
Abstract The virulence factors mediating Francisella pathogenesis are being investigated, with an emphasis on understanding how the organism evades innate immunity mechanisms. Francisella tularensis produces a lipopolysaccharide (LPS) that is essentially inert and a polysaccharide capsule that helps the organism to evade detection by components of innate immunity. Using an F. tularensis Schu S4 mutant library, we identified strains that are disrupted for capsule and O-antigen production. These serum-sensitive strains lack both capsule production and O-antigen laddering. Analysis of the predicted protein sequences for the disrupted genes (FTT1236 and FTT1238c) revealed similarity to those for waa (rfa) biosynthetic genes in other bacteria. Mass spectrometry further revealed that these proteins are involved in LPS core sugar biosynthesis and the ligation of O antigen to the LPS core sugars. The 50% lethal dose (LD50) values of these strains are increased 100- to 1,000-fold for mice. Histopathology revealed that the immune response to the F. tularensis mutant strains was significantly different from that observed with wild-type-infected mice. The lung tissue from mutant-infected mice had widespread necrotic debris, but the spleens lacked necrosis and displayed neutrophilia. In contrast, the lungs of wild-type-infected mice had nominal necrosis, but the spleens had widespread necrosis. These data indicate that murine death caused by wild-type strains occurs by a mechanism different from that by which the mutant strains kill mice. Mice immunized with these mutant strains displayed >10-fold protective effects against virulent type A F. tularensis challenge.
Volume 82(4)
Pages 1523-39
Published 2014-4-1
DOI 10.1128/IAI.01640-13
PII IAI.01640-13
PMID 24452684
PMC PMC3993386
MeSH Amino Acid Sequence Animals Bacterial Capsules / physiology Disease Models, Animal Female Francisella tularensis / genetics Francisella tularensis / immunology Francisella tularensis / pathogenicity* Lipopolysaccharides / immunology Macrophages / cytology Mice Mice, Inbred C57BL Mutation O Antigens / chemistry O Antigens / genetics* O Antigens / immunology Sequence Analysis, DNA Tularemia / genetics Tularemia / immunology Tularemia / microbiology* Virulence / genetics Virulence / immunology Virulence Factors / genetics Virulence Factors / immunology Virulence Factors / metabolism
IF 3.201
Times Cited 16
Prokaryotes E. coli Keio collection