Role of toll-like receptor 4 in induction of cell-mediated immunity and resistance to Brucella abortus infection in mice
Role of toll-like receptor 4 in induction of cell-mediated immunity and resistance to Brucella abortus infection in mice
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DOI：
10.1128/iai.72.1.176-186.2004
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发表时间：
2004-01-01
影响因子：
3.1
通讯作者：
Oliveira, SC
中科院分区：
文献类型：
--
作者：
Campos, MA;Rosinha, GMS;Oliveira, SC
宿主对细菌感染的初始防御是由先天免疫执行的，因此本研究的主要目的是检查Toll样受体（TLR）在布鲁氏菌感染过程中的作用。转染CD 14和TLR的CHO报告细胞系显示B.流产会触发TLR 2和TLR 4。相比之下，来自布鲁氏杆菌粗糙（R）和光滑（S）菌株的脂多糖（LPS）和脂质A仅通过TLR 4激活CHO细胞。一致地，与C3 H/HeJ（TLR 4突变小鼠）相比，来自暴露于R和S菌株及其LPS的C3 H/HePas小鼠的巨噬细胞产生更高水平的肿瘤坏死因子α（TNF-α）和白细胞介素-12。TLR 4诱导促炎细胞因子的重要作用用来自Rhodabacter sphaeroides的二磷酸脂质A证实。此外，为了确定TLR 2和TLR 4在细菌清除中的贡献，在B后1、3和6周监测C3 H/HeJ、C3 H/HePas、TLR 2敲除和野生型小鼠脾脏中的布鲁氏菌数量。流产感染有趣的是，与C3 H/HePas相比，缺乏功能性TLR 4（C3 H/HeJ）的动物在感染后第3周和第6周小鼠布鲁氏菌病明显加重，C3 H/HePas抑制了该小鼠品系的γ干扰素产生减少。最后，通过质谱分析，我们发现R和S菌株的脂质A谱存在显着差异。事实上，在CHO细胞中，S脂质A比R脂质A更有活性地触发TLR 4，并且在诱导树突状细胞成熟方面更有效。总之，这些结果表明TLR 4在对B的抗性中起作用。流产感染，且S脂质A具有有效佐剂活性。
Initial host defense to bacterial infection is executed by innate immunity, and therefore the main goal of this study was to examine the contribution of Toll-like receptors (TLRs) during Brucella abortus infection. CHO reporter cell lines transfected with CD14 and TLRs showed that B. abortus triggers both TLR2 and TLR4. In contrast, lipopolysaccharide (LPS) and lipid A derived from Brucella rough (R) and smooth (S) strains activate CHO cells only through TLR4. Consistently, macrophages from C3H/HePas mice exposed to R and S strains and their LPS produced higher levels of tumor necrosis factor alpha (TNF-alpha) and interleukin-12 compared to C3H/HeJ, a TLR4 mutant mouse. The essential role of TLR4 for induction of proinflammatory cytokines was confirmed with diphosphoryl lipid A from Rhodabacter sphaeroides. Furthermore, to determine the contribution of TLR2 and TLR4 in bacterial clearance, numbers of Brucella were monitored in the spleen of C3H/HeJ, C3H/HePas, TLR2 knockout, and wild-type mice at 1, 3, and 6 weeks following B. abortus infection. Interestingly, murine brucellosis was markedly exacerbated at weeks 3 and 6 after infection in animals that lacked functional TLR4 (C3H/HeJ) compared to C3H/HePas that paralleled the reduced gamma interferon production by this mouse strain. Finally, by mass spectrometry analysis we found dramatic differences on the lipid A profiles of R and S strains. In fact, S lipid A was shown to be more active to trigger TLR4 than R lipid A in CHO cells and more effective in inducing dendritic cell maturation. In conclusion, these results indicate that TLR4 plays a role in resistance to B. abortus infection and that S lipid A has potent adjuvant activity.