title: Differential Toll-Like Receptor-Signalling of Burkholderia pseudomallei Lipopolysaccharide in Murine and Human Models.
abstract: The Gram-negative bacterium Burkholderia pseudomallei causes melioidosis and is a CDC category B bioterrorism agent. Toll-like receptor (TLR)-2 impairs host defense during pulmonary B.pseudomallei infection while TLR4 only has limited impact. We investigated the role of TLRs in B.pseudomallei-lipopolysaccharide (LPS) induced inflammation. Purified B.pseudomallei-LPS activated only TLR2-transfected-HEK-cells during short stimulation but both HEK-TLR2 and HEK-TLR4-cells after 24 h. In human blood, an additive effect of TLR2 on TLR4-mediated signalling induced by B.pseudomallei-LPS was observed. In contrast, murine peritoneal macrophages recognized B.pseudomallei-LPS solely through TLR4. Intranasal inoculation of B.pseudomallei-LPS showed that both TLR4-knockout(-/-) and TLR2x4-/-, but not TLR2-/- mice, displayed diminished cytokine responses and neutrophil influx compared to wild-type controls. These data suggest that B.pseudomallei-LPS signalling occurs solely through murine TLR4, while in human models TLR2 plays an additional role, highlighting important differences between specificity of human and murine models that may have important consequences for B.pseudomallei-LPS sensing by TLRs and subsequent susceptibility to melioidosis.
authors.affiliation: Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, the Netherlands.|Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Tassili A F
authors.initials: TA
authors.lastname: Weehuizen
authors.affiliation: Defence Science and Technology Laboratory, Porton Down, Salisbury, United Kingdom.
authors.forename: Joann L
authors.initials: JL
authors.lastname: Prior
authors.affiliation: Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, the Netherlands.|Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: van der Vaart
authors.affiliation: Defence Science and Technology Laboratory, Porton Down, Salisbury, United Kingdom.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Ngugi
authors.affiliation: John Innes Centre, Norwich Research Park, Colney, United Kingdom.
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Nepogodiev
authors.affiliation: John Innes Centre, Norwich Research Park, Colney, United Kingdom.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Field
authors.affiliation: Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, the Netherlands.|Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Liesbeth M
authors.initials: LM
authors.lastname: Kager
authors.affiliation: Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, the Netherlands.|Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Cornelis
authors.initials: C
authors.lastname: van 't Veer
authors.affiliation: Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, the Netherlands.|Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Alex F
authors.initials: AF
authors.lastname: de Vos
authors.affiliation: Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, the Netherlands.|Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, Amsterdam, the Netherlands.|Department of Internal Medicine, Division of Infectious Diseases, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: W Joost
authors.initials: WJ
authors.lastname: Wiersinga
mesh_terms: D000818:Animals; D016957:Burkholderia pseudomallei / Q000378:metabolism / Q000472:pathogenicity*; D057809:HEK293 Cells / Q000378:metabolism / Q000382:microbiology; D054884:Host-Pathogen Interactions; D006801:Humans; D008070:Lipopolysaccharides / Q000302:isolation & purification / Q000378:metabolism* / Q000633:toxicity; D008554:Melioidosis / Q000378:metabolism / Q000382:microbiology; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018410:Pneumonia, Bacterial / Q000139:chemically induced / Q000378:metabolism / Q000382:microbiology; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D037521:Virulence Factors / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D037521:Virulence Factors