title: LPS remodeling is an evolved survival strategy for bacteria.
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.
authors.affiliation: State Key Laboratory of Food Science and Technology, School of Biotechnology, Jiangnan University, Wuxi 214211, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Li
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Powell
authors.forename: Scott A
authors.initials: SA
authors.lastname: Shaffer
authors.forename: David A
authors.initials: DA
authors.lastname: Rasko
authors.forename: Mark R
authors.initials: MR
authors.lastname: Pelletier
authors.forename: John D
authors.initials: JD
authors.lastname: Leszyk
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Scott
authors.forename: Ali
authors.initials: A
authors.lastname: Masoudi
authors.forename: David R
authors.initials: DR
authors.lastname: Goodlett
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Wang
authors.forename: Christian R H
authors.initials: CR
authors.lastname: Raetz
authors.forename: Robert K
authors.initials: RK
authors.lastname: Ernst
mesh_terms: D000217:Acyltransferases / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D005075:Biological Evolution; D001831:Body Temperature; D002463:Cell Membrane Permeability / Q000235:genetics; D005603:Francisella / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D016905:Gram-Negative Bacterial Infections / Q000382:microbiology / Q000503:physiopathology; D054884:Host-Pathogen Interactions; D007700:Kinetics; D008050:Lipid A / Q000737:chemistry / Q000378:metabolism; D008070:Lipopolysaccharides / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability; D009154:Mutation; D010802:Phylogeny; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013696:Temperature; D014774:Virulence / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D008050:Lipid A; D008070:Lipopolysaccharides; D000217:Acyltransferases