Impaired Stimulation of p38α-MAPK/Vps41-HOPS by LPS from Pathogenic Coxiella burnetii Prevents Trafficking to Microbicidal Phagolysosomes

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 p38 alpha-MAPK signaling required for proper trafficking of bacteria containing compartments to lysosomes for destruction, pathogenic C. bumetii LPS (vLPS) does not. The defect in vLPS and pathogenic C. bumetii targeting to degradative compartments involves an antagonistic engagement of TLR4 by vLPS, lack of p38 alpha-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 p38 alpha-MAPK or phosphomimetic mutant Vps41-S796E expression overrides the inhibition, allowing vLPS and pathogenic C. bumetii targeting to phagolysosomes. Thus, p38 alpha-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.