The lipopolysaccharide core of Brucella abortus acts as a shield against innate immunity recognition.
The lipopolysaccharide core of Brucella abortus acts as a shield against innate immunity recognition.
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DOI：
10.1371/journal.ppat.1002675
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Gorvel JP
中科院分区：
文献类型：
--
作者：
Conde-Álvarez R;Arce-Gorvel V;Iriarte M;Manček-Keber M;Barquero-Calvo E;Palacios-Chaves L;Chacón-Díaz C;Chaves-Olarte E;Martirosyan A;von Bargen K;Grilló MJ;Jerala R;Brandenburg K;Llobet E;Bengoechea JA;Moreno E;Moriyón I;Gorvel JP
先天免疫识别带有病原体相关分子模式的细菌分子，从而启动炎症反应，从而激活适应性免疫。然而，革兰氏阴性菌布氏菌的脂多糖（LPS）缺乏明显的病原体相关分子模式，据推测，这延迟了免疫的发展，造成了细菌到达细胞内复制生态位的关键间隙。研究人员发现，在保留LPS o -多糖和脂质a的同时，流产芽孢杆菌的wadC基因突变体显示出LPS核心被破坏，在小鼠中，wadC突变体诱导了促炎反应，并被减弱。此外，它对非免疫血清和杀菌肽的杀伤敏感，并且不会在靶向溶酶体室的树突状细胞中繁殖。与野生型B. abortus相比，wadC突变体诱导树突状细胞成熟和分泌促炎细胞因子。所有这些特性都是由wadC突变体纯化的LPS以tlr4依赖的方式再现的。此外，核心突变的LPS与TLR4共受体MD-2的结合增加，导致随后细胞内信号传导增加。在这里，我们发现布鲁氏菌在感染的早期阶段通过在其脂多糖核心表达抵抗先天免疫识别的屏障来逃避识别，并在细胞内致病性革兰氏阴性菌中确定了一种新的毒力机制。这些结果也鼓励改进新型细菌疫苗的产生。布鲁氏菌病是世界上传播最广的细菌性人畜共患病之一，也是造成经济损失和人类痛苦的重要原因。病原体属于布鲁氏菌属，这是一组具有高度传染性的革兰氏阴性菌，其特点是能够逃避先天免疫的早期检测。这种隐蔽的行为有效地延缓了免疫力的发展，创造了一个间隙，细菌利用这个间隙渗透到各种细胞中，并激活互补的毒力机制，如IV型分泌系统。通过这种方式，布鲁氏菌转移细胞内运输，以达到安全的增殖生态位并建立慢性感染。我们的研究结果表明，布鲁氏菌LPS（一种大多数细菌被先天免疫检测到的分子）的内部部分有效地阻止了宿主先天免疫系统的可溶性分子和细胞受体的识别。因此，一个突变破坏了内部而不是其他脂多糖部分，通过损害这种病原体的隐身特性产生衰减。这是第一个布鲁氏菌突变体，其衰减与增强对该病原体的免疫力特别相关。因此，这种新的毒力机制为改进细菌疫苗的开发开辟了道路。
Innate immunity recognizes bacterial molecules bearing pathogen-associated molecular patterns to launch inflammatory responses leading to the activation of adaptive immunity. However, the lipopolysaccharide (LPS) of the gram-negative bacterium Brucella lacks a marked pathogen-associated molecular pattern, and it has been postulated that this delays the development of immunity, creating a gap that is critical for the bacterium to reach the intracellular replicative niche. We found that a B. abortus mutant in the wadC gene displayed a disrupted LPS core while keeping both the LPS O-polysaccharide and lipid A. In mice, the wadC mutant induced proinflammatory responses and was attenuated. In addition, it was sensitive to killing by non-immune serum and bactericidal peptides and did not multiply in dendritic cells being targeted to lysosomal compartments. In contrast to wild type B. abortus, the wadC mutant induced dendritic cell maturation and secretion of pro-inflammatory cytokines. All these properties were reproduced by the wadC mutant purified LPS in a TLR4-dependent manner. Moreover, the core-mutated LPS displayed an increased binding to MD-2, the TLR4 co-receptor leading to subsequent increase in intracellular signaling. Here we show that Brucella escapes recognition in early stages of infection by expressing a shield against recognition by innate immunity in its LPS core and identify a novel virulence mechanism in intracellular pathogenic gram-negative bacteria. These results also encourage for an improvement in the generation of novel bacterial vaccines. Brucellosis is one of the most extended bacterial zoonosis in the world and an important cause of economic losses and human suffering. The causative agents belong to the genus Brucella, a group of highly infectious gram-negative bacteria characterized by their ability to escape early detection by innate immunity. This stealthy behavior effectively delays the development of immunity, creating a gap that is used by the bacterium to penetrate into a variety of cells and to activate complementary virulence mechanisms such as the type IV secretion system. By this manner, the brucellae divert intracellular trafficking to reach a safe multiplication niche and establish chronic infections. Our results show that an inner section of the Brucella LPS (a molecule that in most bacteria is detected by innate immunity), effectively contributes to block recognition by soluble molecules and cellular receptors of the host innate immune system. Accordingly, a mutation disrupting the inner but no other lipopolysaccharide sections generates attenuation by impairing the stealthiness characteristics of this pathogen. This is the first Brucella mutant in which attenuation is specifically linked to the bolstering of immunity against this pathogen. Therefore, this new virulence mechanism opens the way for the development of improved bacterial vaccines.
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影响因子：
15.3
作者：
Geijtenbeek, TBH;van Vliet, SJ;Koppel, EA;Sanchez-Hernandez, M;Vandenbroucke-Grauls, CMJE;Appelmelk, B;van Kooyk, Y
通讯作者：
van Kooyk, Y
影响因子：
3.7
作者：
González D;Grilló MJ;De Miguel MJ;Ali T;Arce-Gorvel V;Delrue RM;Conde-Alvarez R;Muñoz P;López-Goñi I;Iriarte M;Marín CM;Weintraub A;Widmalm G;Zygmunt M;Letesson JJ;Gorvel JP;Blasco JM;Moriyón I
通讯作者：
Moriyón I
影响因子：
3.1
作者：
Allen, CA;Adams, LG;Ficht, TA
通讯作者：
Ficht, TA
影响因子：
4.4
作者：
Hallez, Regis;Letesson, Jean-Jacques;De Bolle, Xavier
通讯作者：
De Bolle, Xavier
影响因子：
64.8
作者：
Hemmi, H;Takeuchi, O;Akira, S
通讯作者：
Akira, S