title: Bordetella pertussis naturally occurring isolates with altered lipooligosaccharide structure fail to fully mature human dendritic cells.
abstract: Bordetella pertussis is a Gram-negative bacterium and the causative agent of whooping cough. Despite high vaccination coverage, outbreaks are being increasingly reported worldwide. Possible explanations include adaptation of this pathogen, which may interfere with recognition by the innate immune system. Here, we describe innate immune recognition and responses to different B. pertussis clinical isolates. By using HEK-Blue cells transfected with different pattern recognition receptors, we found that 3 out of 19 clinical isolates failed to activate Toll-like receptor 4 (TLR4). These findings were confirmed by using the monocytic MM6 cell line. Although incubation with high concentrations of these 3 strains resulted in significant activation of the MM6 cells, it was found to occur mainly through interaction with TLR2 and not through TLR4. When using live bacteria, these 3 strains also failed to activate TLR4 on HEK-Blue cells, and activation of MM6 cells or human monocyte-derived dendritic cells was significantly lower than activation induced by the other 16 strains. Mass spectrum analysis of the lipid A moieties from these 3 strains indicated an altered structure of this molecule. Gene sequence analysis revealed mutations in genes involved in lipid A synthesis. Findings from this study indicate that B. pertussis isolates that do not activate TLR4 occur naturally and that this phenotype may give this bacterium an advantage in tempering the innate immune response and establishing infection. Knowledge on the strategies used by this pathogen in evading the host immune response is essential for the improvement of current vaccines or for the development of new ones.
authors.affiliation: Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
authors.forename: Jolanda
authors.initials: J
authors.lastname: Brummelman
authors.affiliation: Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
authors.forename: Rosanne E
authors.initials: RE
authors.lastname: Veerman
authors.affiliation: Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
authors.forename: Hendrik Jan
authors.initials: HJ
authors.lastname: Hamstra
authors.affiliation: Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
authors.forename: Anna J M
authors.initials: AJ
authors.lastname: Deuss
authors.affiliation: Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Schuijt
authors.affiliation: Institute for Translational Vaccinology, Bilthoven, The Netherlands.
authors.forename: Arjen
authors.initials: A
authors.lastname: Sloots
authors.affiliation: Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
authors.forename: Betsy
authors.initials: B
authors.lastname: Kuipers
authors.affiliation: Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
authors.forename: Cécile A C M
authors.initials: CA
authors.lastname: van Els
authors.affiliation: Institute for Translational Vaccinology, Bilthoven, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: van der Ley
authors.affiliation: Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
authors.forename: Frits R
authors.initials: FR
authors.lastname: Mooi
authors.affiliation: Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
authors.forename: Wanda G H
authors.initials: WG
authors.lastname: Han
authors.affiliation: Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands elena.pinelli.ortiz@rivm.nl.
authors.forename: Elena
authors.initials: E
authors.lastname: Pinelli
mesh_terms: D053898:Biosynthetic Pathways / Q000235:genetics; D001886:Bordetella pertussis / Q000737:chemistry* / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000382:microbiology*; D006801:Humans; D057131:Immune Evasion; D008070:Lipopolysaccharides / Q000737:chemistry* / Q000276:immunology*; D013058:Mass Spectrometry; D009154:Mutation; D017422:Sequence Analysis, DNA; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014917:Whooping Cough / Q000382:microbiology
chemical_list: D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4; C023023:lipid-linked oligosaccharides