title: Coxiella burnetii lipopolysaccharide blocks p38α-MAPK activation through the disruption of TLR-2 and TLR-4 association.
abstract: To survive in macrophages, Coxiella burnetii hijacks the activation pathway of macrophages. Recently, we have demonstrated that C. burnetii, via its lipopolysaccharide (LPS), avoids the activation of p38α-MAPK through an antagonistic engagement of Toll-like receptor (TLR)-4. We investigated the fine-tuned mechanism leading to the absence of activation of the p38α-MAPK despite TLR-4 engagement. In macrophages challenged with LPS from the avirulent variants of C. burnetii, TLR-4 and TLR-2 co-immunoprecipitated. This association was absent in cells challenged by the LPS of pathogenic C. burnetii. The disruption makes TLRs unable to signal during the recognition of the LPS of pathogenic C. burnetii. The disruption of TLR-2 and TLR-4 was induced by the re-organization of the macrophage cytoskeleton by C. burnetii LPS. Interestingly, blocking the actin cytoskeleton re-organization relieved the disruption of the association TLR-2/TLR-4 by pathogenic C. burnetii and rescued the p38α-MAPK activation by C. burnetii. We elucidated an unexpected mechanism allowing pathogenic C. burnetii to avoid macrophage activation by the disruption of the TLR-2 and TLR-4 association.
authors.affiliation: CNRS UMR 7278, IRD198, INSERM U1095, Aix-Marseille Université Marseille, France.
authors.forename: Filippo
authors.initials: F
authors.lastname: Conti
authors.affiliation: CNRS UMR 7278, IRD198, INSERM U1095, Aix-Marseille Université Marseille, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Boucherit
authors.affiliation: CNRS UMR 7278, IRD198, INSERM U1095, Aix-Marseille Université Marseille, France.
authors.forename: Veronica
authors.initials: V
authors.lastname: Baldassarre
authors.affiliation: CNRS UMR 7278, IRD198, INSERM U1095, Aix-Marseille Université Marseille, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Trouplin
authors.affiliation: Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Institute of Virology, Slovak Academy of Sciences Bratislava, Slovakia.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Toman
authors.affiliation: UMR MD2, Faculté de Médecine NORD, Aix-Marseille Université and IRBA (Institute of Research in Biology of the French Army) Marseille, France ; Laboratory of Biochemistry, La Timone University Hospital, Assistance Publique Hôpitaux de Marseille Marseille, France.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Mottola
authors.affiliation: CNRS UMR 7278, IRD198, INSERM U1095, Aix-Marseille Université Marseille, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mege
authors.affiliation: CNRS UMR 7278, IRD198, INSERM U1095, Aix-Marseille Université Marseille, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Ghigo
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016997:Coxiella burnetii / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D054884:Host-Pathogen Interactions; D006801:Humans; D008070:Lipopolysaccharides / Q000378:metabolism*; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011778:Q Fever / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D048308:Mitogen-Activated Protein Kinase 14
keywords: Coxiella burnetii; TLR-2; TLR-4; cytoskeleton; macrophages