Lipopolysaccharide from Coxiella burnetii is involved in bacterial phagocytosis, filamentous actin reorganization, and inflammatory responses through Toll-like receptor 4.
The role of Toll-like receptors (TLRs) in the recognition of extracellular and facultative intracellular bacteria by the innate immune system has been extensively studied, but their role in the recognition of obligate intracellular organisms remains unknown. Coxiella burnetii, the agent of Q fever, is an obligate intracellular bacterium that specifically inhabits monocytes/macrophages. We showed in this study that C. burnetii LPS is involved in the uptake of virulent organisms by macrophages but not in that of avirulent variants. The uptake of virulent organisms was dependent on TLR4 because it was reduced in macrophages from TLR4(-/-) mice. In addition, LPS was responsible for filamentous actin reorganization induced by virulent C. burnetii, which was prevented in TLR4(-/-) macrophages. In contrast, the intracellular fate of C. burnetii was not affected in TLR4(-/-) macrophages, suggesting that TLR4 does not control the maturation of C. burnetii phagosome and the microbicidal activity of macrophages. These results are consistent with in vivo experiments because the pattern of tissue infection and the clearance of C. burnetii were similar in wild-type and TLR4(-/-) mice. We also showed that the number of granulomas was decreased in the liver of infected TLR4(-/-) mice, and the formation of splenic granulomas was only transient. The impaired formation of granulomas was associated with decreased production of IFN-gamma and TNF. Taken together, these results demonstrate that TLR4 controls early events of C. burnetii infection such as macrophage phagocytosis, granuloma formation, and cytokine production.
Unité des Rickettsies, Centre National de la Recherche Scientifique Unité Mixte de Recherche 6020, Institut Federatif de Recherche 48 Université de la Méditerranée, Marseille, France.
Amélie
A
Honstettre
Eric
E
Ghigo
Alix
A
Moynault
Christian
C
Capo
Rudolf
R
Toman
Shizuo
S
Akira
Osamu
O
Takeuchi
Hubert
H
Lepidi
Didier
D
Raoult
Jean-Louis
JL
Mege
D000199:Actins / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D016997:Coxiella burnetii / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D007424:Intracellular Fluid / Q000276:immunology / Q000382:microbiology; D008070:Lipopolysaccharides / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D010587:Phagocytosis / Q000276:immunology*; D011778:Q Fever / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014774:Virulence
D000199:Actins; D016207:Cytokines; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors