Discovery and characterization of sialic acid O-acetylation in group B Streptococcus
Discovery and characterization of sialic acid O-acetylation in group B Streptococcus
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DOI：
10.1073/pnas.0403010101
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发表时间：
2004-07-27
影响因子：
11.1
通讯作者：
Varki, A
中科院分区：
文献类型：
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作者：
Lewis, AL;Nizet, V;Varki, A
B族链球菌（GBS）是导致人类新生儿败血症和脑膜炎的主要原因。GBS荚膜多糖是一种主要的毒力因子，也是II期试验中疫苗的活性成分。所有GBS胶囊均具有末端α 2 -3连接的唾液酸[N-乙酰神经氨酸（Neu 5Ac）]，其干扰补体介导的杀伤。我们在这里表明，一些Neu 5Ac残基的GBS III型胶囊O-乙酰化的碳位置7，8，或9，一个主要的修改显然错过了在以前的研究。数据与位置7处的初始O-乙酰化以及位置8和9处的O-乙酰酯的后续迁移一致。O-乙酰化也存在于其他几种GBS血清型（Ia、Ib、II、V和VI）上。通过精确、符合读码框的等位基因替换来删除CMP-Neu 5Ac合酶基因neuA，会导致O-乙酰化Neu 5Ac在细胞内积累，而过表达则显着减少O-乙酰化。鉴于已知的GBS Neu 5Ac生物合成途径，这些数据表明O-乙酰化发生在游离Neu 5Ac上，与CMP-Neu 5Ac合酶竞争。O-乙酰化通常在细菌荚膜多糖上产生免疫原性表位，并且可以调节人替代途径补体激活。因此，我们的发现对GBS致病性、免疫原性和疫苗设计具有重要意义。
Group B Streptococcus (GBS) is the leading cause of human neonatal sepsis and meningitis. The GBS capsular polysaccharide is a major virulence factor and the active principle of vaccines in phase II trials. All GBS capsules have a terminal alpha2-3-linked sialic acid [N-acetylneuraminic acid (Neu5Ac)], which interferes with complement-mediated killing. We show here that some of the Neu5Ac residues of the GBS type III capsule are O-acetylated at carbon position 7, 8, or 9, a major modification evidently missed in previous studies. Data are consistent with initial O-acetylation at position 7, and subsequent migration of the O-acetyl ester at positions 8 and 9. O-acetylation was also present on several other GBS serotypes (Ia, Ib, II, V, and VI). Deletion of the CMP-Neu5Ac synthase gene neuA by precise, in-frame allelic replacement gave intracellular accumulation of O-acetylated Neu5Ac, whereas overexpression markedly decreased O-acetylation. Given the known GBS Neu5Ac biosynthesis pathway, these data indicate that O-acetylation occurs on free Neu5Ac, competing with the CMP-Neu5Ac synthase. O-acetylation often generates immunogenic epitopes on bacterial capsular polysaccharides and can modulate human alternate pathway complement activation. Thus, our discovery has important implications for GBS pathogenicity, immunogenicity, and vaccine design.