Group B Streptococcus engages an inhibitory Siglec through sialic acid mimicry to blunt innate immune and inflammatory responses in vivo.
Group B Streptococcus engages an inhibitory Siglec through sialic acid mimicry to blunt innate immune and inflammatory responses in vivo.
复制标题
DOI：
10.1371/journal.ppat.1003846
复制
发表时间：
2014-01
期刊：
影响因子：
6.7
通讯作者：
Nizet V
中科院分区：
文献类型：
--
作者：
Chang YC;Olson J;Beasley FC;Tung C;Zhang J;Crocker PR;Varki A;Nizet V
B族链球菌（GBS）是新生儿细菌性败血症和脑膜炎的常见病原。GBS表面被膜含有唾液酸（Sia），其与白细胞上的Sia结合免疫球蛋白样凝集素（Siglecs）结合。在这里，我们使用缺乏Siglec-E（骨髓单核细胞的抑制性Siglec）的小鼠来研究体内感染期间GBS Siglec接合的意义。我们发现GBS以Sia特异性的方式与Siglec-E结合，从而钝化NF-κB和MAPK活化。因此，Siglec-E缺陷型巨噬细胞具有增强的促炎性细胞因子分泌、吞噬作用和针对病原体的杀菌活性。在肺部或低剂量静脉内GBS激发后，Siglec-E KO小鼠产生更多的促炎细胞因子，并表现出GBS对中枢神经系统的侵袭减少。相比之下，在高剂量致死性攻击后，Siglec-E KO小鼠中的细胞因子风暴与加速死亡相关。我们得出结论，GBS Sia模拟通过抑制性Siglec的参与影响体内宿主的先天免疫和炎症反应，宿主反应的最终结果取决于感染的部位、阶段和程度。细菌B族链球菌（GBS）导致严重的感染，例如人类新生婴儿的脑膜炎。GBS的表面覆盖着一层由糖分子组成的胶囊。其中最突出的是唾液酸（Sia），这是一种与人类相似的糖，它与我们白色血细胞表面上称为Siglecs的蛋白质受体相互作用。在试管中，GBS Sia与人Siglecs结合可以抑制白色血细胞活化，降低其细菌杀伤能力;然而，这在实际感染期间的意义尚不清楚。为了回答这个问题，我们研究了一种关键的白色血细胞Siglec被基因删除的小鼠。当感染GBS时，突变小鼠的白色血细胞不会被病原体的含Sia的糖囊关闭。来自Siglec缺陷小鼠的白色血细胞更善于杀死GBS，并且能够比正常小鼠更快地清除感染。然而，如果小鼠被给予压倒性剂量的GBS细菌，过度的白色血液激活会引发休克和更快的死亡。这些研究显示了宿主中糖分子的“分子模拟”如何影响细菌病原体与免疫系统的相互作用以及感染的结果。
Group B Streptococcus (GBS) is a common agent of bacterial sepsis and meningitis in newborns. The GBS surface capsule contains sialic acids (Sia) that engage Sia-binding immunoglobulin-like lectins (Siglecs) on leukocytes. Here we use mice lacking Siglec-E, an inhibitory Siglec of myelomonocytic cells, to study the significance of GBS Siglec engagement during in vivo infection. We found GBS bound to Siglec-E in a Sia-specific fashion to blunt NF-κB and MAPK activation. As a consequence, Siglec-E-deficient macrophages had enhanced pro-inflammatory cytokine secretion, phagocytosis and bactericidal activity against the pathogen. Following pulmonary or low-dose intravenous GBS challenge, Siglec-E KO mice produced more pro-inflammatory cytokines and exhibited reduced GBS invasion of the central nervous system. In contrast, upon high dose lethal challenges, cytokine storm in Siglec-E KO mice was associated with accelerated mortality. We conclude that GBS Sia mimicry influences host innate immune and inflammatory responses in vivo through engagement of an inhibitory Siglec, with the ultimate outcome of the host response varying depending upon the site, stage and magnitude of infection. The bacterium Group B Streptococcus (GBS) causes serious infections such as meningitis in human newborn babies. The surface of GBS is coated with a capsule made of sugar molecules. Prominent among these is sialic acid (Sia), a human-like sugar that interacts with protein receptors called Siglecs on the surface of our white blood cells. In a test tube, GBS Sia binding to human Siglecs can suppress white blood cell activation, reducing their bacterial killing abilities; however, the significance of this during actual infection was unknown. To answer this question, we studied mice for which a key white blood cell Siglec has been genetically deleted. When infected with GBS, white blood cells from the mutant mice are not shut off by the pathogen's Sia-containing sugar capsule. The white blood cells from the Siglec-deficient mice are better at killing GBS and are able to clear infection more quickly than a normal mouse. However, if the mice are given an overwhelming dose of GBS bacteria, exaggerated white blood activation can trigger shock and more rapid death. These studies show how “molecular mimicry” of sugar molecules in the host can influence a bacterial pathogen's interaction with the immune system and the outcome of infection.
登录
查看更多内容
影响因子：
4.4
作者：
Gergely, J;Pecht, I;Sármay, G
通讯作者：
Sármay, G
影响因子：
--
作者：
Bedford, H;de Louvois, J;Harvey, D
通讯作者：
Harvey, D
影响因子：
46.9
作者：
通讯作者：
--
DOI：
10.1016/j.bpobgyn.2007.01.003
发表时间：
2007-06-01
影响因子：
5.5
作者：
Heath, Paul T.;Schuchat, Anne
通讯作者：
Schuchat, Anne
影响因子：
14.5
作者：
Malipiero, Ursula;Koedel, Uwe;Fontana, Adriano
通讯作者：
Fontana, Adriano