Effects of lipid A acyltransferases on the pathogenesis of F. novicida

Microb Pathog. 2017 Aug;109:313-318. doi: 10.1016/j.micpath.2017.04.040. Epub 2017 May 4.

Abstract

Francisella novicida is a gram-negative pathogen commonly used to study infections by the potential bioterrorism agent, Francisella tularensis. The Francisella lipid A structure has been well characterized and showed to affect the pathogenesis of F. novicida. Previous work characterized two lipid A acyltransferases, LpxD1 and LpxD2, and constructed the lpxD1-null and lpxD2-null mutants. Mutational analysis showed the lpxD1-null mutant was attenuated in mice and subsequently exhibited protection against a lethal WT challenge. However, details as how the virulence has been changed have remained elusive. This study aims to analyze effects of lipid A acyltransferases on the pathogenesis of F. novicida. MS and MSn were conducted to confirm the lipid A structures of lpxD1-null and lpxD2-null mutants. The stress tolerance, Toll-like receptor 4 (TLR4) stimulation level, intracellular survival and replication ability and cytotoxicity of lpxD1-null and lpxD2-null mutants were analyzed. The results suggested the lpxD1-null mutant with shorter acyl chains in lipid A is more sensitive to various environmental stresses than F. novicida and lpxD2-null mutant. In addition, the lpxD1-null mutant fails to survive and replicate in cells and shows lower cytotoxicity to infected cells. This study provides insights into the pathogenesis of F. novicida.

Keywords: Acyltransferases; Francisella novicida; Lipid A; lpxD-null mutants.

MeSH terms

  • Acyltransferases / pharmacology*
  • Animals
  • Bacterial Proteins / genetics
  • Cell Line
  • Francisella / chemistry
  • Francisella / drug effects*
  • Francisella / genetics
  • Francisella / pathogenicity*
  • Genes, Bacterial / genetics
  • Humans
  • Lipid A / chemistry*
  • Lipid A / isolation & purification
  • Lipid A / metabolism
  • Mice
  • Mutation
  • RAW 264.7 Cells
  • THP-1 Cells
  • Toll-Like Receptor 4
  • Virulence*

Substances

  • Bacterial Proteins
  • Lipid A
  • Toll-Like Receptor 4
  • Acyltransferases