title: Impaired stimulation of p38α-MAPK/Vps41-HOPS by LPS from pathogenic Coxiella burnetii prevents trafficking to microbicidal phagolysosomes.
abstract: Variations in lipopolysaccharide (LPS), a bacterial outer membrane component, determine virulence of the obligate intracellular bacterium Coxiella burnetii, but the underlying mechanisms are unknown. We find that while avirulent C. burnetii LPS (avLPS) stimulates host p38α-MAPK signaling required for proper trafficking of bacteria containing compartments to lysosomes for destruction, pathogenic C. burnetii LPS (vLPS) does not. The defect in vLPS and pathogenic C. burnetii targeting to degradative compartments involves an antagonistic engagement of TLR4 by vLPS, lack of p38α-MAPK-driven phosphorylation, and block in recruitment of the homotypic fusion and protein-sorting complex component Vps41 to vLPS-containing vesicles. An upstream activator of p38α-MAPK or phosphomimetic mutant Vps41-S796E expression overrides the inhibition, allowing vLPS and pathogenic C. burnetii targeting to phagolysosomes. Thus, p38α-MAPK and its crosstalk with Vps41 play a central role in trafficking bacteria to phagolysosomes. Pathogenic C. burnetii has evolved LPS variations to evade this host response and thrive intracellularly.
authors.affiliation: CNRS UMR 7278, IRD198, INSERM U1095, Aix-Marseille Université, 27 Bd Jean Moulin 13385 Marseille Cedex 05, France.
authors.forename: Abdoulaye Oury
authors.initials: AO
authors.lastname: Barry
authors.forename: Nicolas
authors.initials: N
authors.lastname: Boucherit
authors.forename: Giovanna
authors.initials: G
authors.lastname: Mottola
authors.forename: Pavol
authors.initials: P
authors.lastname: Vadovic
authors.forename: Virginie
authors.initials: V
authors.lastname: Trouplin
authors.forename: Philippe
authors.initials: P
authors.lastname: Soubeyran
authors.forename: Christian
authors.initials: C
authors.lastname: Capo
authors.forename: Stefano
authors.initials: S
authors.lastname: Bonatti
authors.forename: Angel
authors.initials: A
authors.lastname: Nebreda
authors.forename: Rudolf
authors.initials: R
authors.lastname: Toman
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Lemichez
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mege
authors.forename: Eric
authors.initials: E
authors.lastname: Ghigo
mesh_terms: D016997:Coxiella burnetii / Q000276:immunology* / Q000472:pathogenicity; D054884:Host-Pathogen Interactions; D057131:Immune Evasion; D008070:Lipopolysaccharides / Q000276:immunology* / Q000378:metabolism; D010588:Phagosomes / Q000276:immunology* / Q000382:microbiology; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors*; D033921:Vesicular Transport Proteins / Q000276:immunology / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C549959:VPS41 protein, human; D033921:Vesicular Transport Proteins; D048051:p38 Mitogen-Activated Protein Kinases