LPS remodeling is an evolved survival strategy for bacteria

Proc Natl Acad Sci U S A. 2012 May 29;109(22):8716-21. doi: 10.1073/pnas.1202908109. Epub 2012 May 14.

Abstract

Maintenance of membrane function is essential and regulated at the genomic, transcriptional, and translational levels. Bacterial pathogens have a variety of mechanisms to adapt their membrane in response to transmission between environment, vector, and human host. Using a well-characterized model of lipid A diversification (Francisella), we demonstrate temperature-regulated membrane remodeling directed by multiple alleles of the lipid A-modifying N-acyltransferase enzyme, LpxD. Structural analysis of the lipid A at environmental and host temperatures revealed that the LpxD1 enzyme added a 3-OH C18 acyl group at 37 °C (host), whereas the LpxD2 enzyme added a 3-OH C16 acyl group at 18 °C (environment). Mutational analysis of either of the individual Francisella lpxD genes altered outer membrane (OM) permeability, antimicrobial peptide, and antibiotic susceptibility, whereas only the lpxD1-null mutant was attenuated in mice and subsequently exhibited protection against a lethal WT challenge. Additionally, growth-temperature analysis revealed transcriptional control of the lpxD genes and posttranslational control of the LpxD1 and LpxD2 enzymatic activities. These results suggest a direct mechanism for LPS/lipid A-level modifications resulting in alterations of membrane fluidity, as well as integrity and may represent a general paradigm for bacterial membrane adaptation and virulence-state adaptation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acyltransferases / classification
  • Acyltransferases / genetics
  • Acyltransferases / metabolism*
  • Animals
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Biological Evolution
  • Body Temperature
  • Cell Membrane Permeability / genetics
  • Francisella / genetics
  • Francisella / metabolism*
  • Francisella / pathogenicity
  • Gram-Negative Bacterial Infections / microbiology
  • Gram-Negative Bacterial Infections / physiopathology
  • Host-Pathogen Interactions
  • Kinetics
  • Lipid A / chemistry
  • Lipid A / metabolism
  • Lipopolysaccharides / chemistry
  • Lipopolysaccharides / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Microbial Sensitivity Tests
  • Microbial Viability
  • Mutation
  • Phylogeny
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Temperature
  • Virulence / genetics

Substances

  • Bacterial Proteins
  • Lipid A
  • Lipopolysaccharides
  • Acyltransferases