Lipopolysaccharide from Coxiella burnetii is involved in bacterial phagocytosis, filamentous actin reorganization, and inflammatory responses through toll-like receptor 4
Lipopolysaccharide from Coxiella burnetii is involved in bacterial phagocytosis, filamentous actin reorganization, and inflammatory responses through toll-like receptor 4
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DOI：
10.4049/jimmunol.172.6.3695
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发表时间：
2004-03-15
影响因子：
4.4
通讯作者：
Mege, JL
中科院分区：
文献类型：
--
作者：
Honstettre, A;Ghigo, E;Mege, JL
toll样受体（TLRs）在先天免疫系统识别细胞外和兼性细胞内细菌中的作用已被广泛研究，但它们在识别专性细胞内生物中的作用尚不清楚。伯纳蒂Coxiella burnetti是Q热的病原体，是一种专性细胞内细菌，专门栖息于单核细胞/巨噬细胞。我们在这项研究中表明，伯纳蒂C脂多糖参与巨噬细胞对有毒生物的摄取，但不参与无毒变异。毒性生物的摄取依赖于TLR4，因为TLR4在TLR4（-/-）小鼠的巨噬细胞中减少。此外，LPS还参与了强毒伯纳蒂C诱导的丝状肌动蛋白重组，而这种重组在TLR4（-/-）巨噬细胞中被阻止。相比之下，TLR4（-/-）巨噬细胞不影响burnetti的胞内命运，提示TLR4不控制burnetti吞噬体的成熟和巨噬细胞的杀微生物活性。这些结果与体内实验一致，因为野生型和TLR4（-/-）小鼠的组织感染模式和对伯纳蒂菌的清除相似。我们还发现，感染TLR4（-/-）的小鼠肝脏中肉芽肿的数量减少，脾脏肉芽肿的形成只是短暂的。肉芽肿的形成受损与ifn - γ和TNF的产生减少有关。综上所述，这些结果表明TLR4控制伯纳蒂感染的早期事件，如巨噬细胞吞噬、肉芽肿形成和细胞因子的产生。
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 burnetti, the agent of Q fever, is an obligate intracellular bacterium that specifically inhabits monocytes/macrophages. We showed in this study that C burnetti 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 burnetti, which was prevented in TLR4(-/-) macrophages. In contrast, the intracellular fate of C burnetti was not affected in TLR4(-/-) macrophages, suggesting that TLR4 does not control the maturation of C burnetti 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. burnetti infection such as macrophage phagocytosis, granuloma formation, and cytokine production.