Blood-brain barrier invasion by group B Streptococcus depends upon proper cell-surface anchoring of lipoteichoic acid
Blood-brain barrier invasion by group B Streptococcus depends upon proper cell-surface anchoring of lipoteichoic acid
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DOI：
10.1172/jci23829
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发表时间：
2005-09-01
影响因子：
15.9
通讯作者：
Nizet, V
中科院分区：
文献类型：
--
作者：
Doran, KS;Engelson, EJ;Nizet, V
B族链球菌是新生儿脑膜炎的主要致病菌。GBS通过穿透血脑屏障（BBB）进入CNS，血脑屏障由特化的人脑微血管内皮细胞（hBMEC）组成。为了鉴定BBB穿透所需的GBS因子，我们产生了一种强毒株的随机突变体文库，并筛选了hBMEC体外侵袭的丧失。两个独立的低侵袭性突变体在同一基因中具有破坏，侵袭相关基因（iagA），其编码糖基转移酶同源物。GBS染色体中iagA的等位基因替换使hBMEC侵袭性降低4倍。用GBS Delta IagA突变体攻击的小鼠发展了比WT小鼠更快的菌血症，但死亡率显著更低（20%对90%），脑膜炎的发生率也是如此。糖脂二葡糖基二酰基甘油，脂磷壁酸（LTA）的细胞膜锚和IagA糖基转移酶的预测产物，是不存在的Delta IagA突变体，因此脱落到媒体LTA。发现Δ lagA突变体的毒力减弱不依赖于TLR 2介导的信号传导，但是来自Δ lagA突变体的含有释放的LTA的细菌上清液抑制WT GBS对hBMEC的侵袭。我们的数据表明，GBS表面的LTA表达在细菌与血脑屏障内皮细胞的相互作用和新生儿脑膜炎的发病机制中发挥作用。
Group B streptococci (GBSs) are the leading cause of neonatal meningitis. GBSs enter the CNS by penetrating the blood-brain barrier (BBB), which consists of specialized human brain microvascular endothelial cells (hBMECs). To identify GBS factors required for BBB penetration, we generated random mutant libraries of a virulent strain and screened for loss of hBMEC invasion in vitro. Two independent hypo-invasive mutants possessed disruptions in the same gene, invasion associated gene (iagA), which encodes a glycosyltransferase homolog. Allelic replacement of iagA in the GBS chromosome produced a 4-fold decrease in hBMEC invasiveness. Mice challenged with the GBS Delta iagA mutant developed bacteremia comparably to WT mice, yet mortality was significantly lower (20% vs. 90%), as was the incidence of meningitis. The glycolipid diglucosyldiacylglycerol, a cell membrane anchor for lipoteichoic acid (LTA) and predicted product of the IagA glycosyltransferase, was absent in the Delta iagA mutant, which consequently shed LTA into the media. Attenuation of virulence of the Delta iagA mutant was found to be independent of TLR2-mediated signaling, but bacterial supernatants from the Delta iagA mutant containing released LTA inhibited hBMEC invasion by WT GBS. Our data suggest that LTA expression on the GBS surface plays a role in bacterial interaction with BBB endothelium and the pathogenesis of neonatal meningitis.