An O antigen capsule modulates bacterial pathogenesis in Shigella sonnei.
An O antigen capsule modulates bacterial pathogenesis in Shigella sonnei.
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DOI：
10.1371/journal.ppat.1004749
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发表时间：
2015-03
期刊：
影响因子：
6.7
通讯作者：
Gerke C
中科院分区：
文献类型：
--
作者：
Caboni M;Pédron T;Rossi O;Goulding D;Pickard D;Citiulo F;MacLennan CA;Dougan G;Thomson NR;Saul A;Sansonetti PJ;Gerke C
志贺氏菌是世界范围内痢疾的主要原因。在致病过程中，内毒素O抗原(OAG)的存在和长度与多种毒力因子一起起着关键作用。福氏2a双峰OAG链长度分布受生长调节，而宋内氏志贺氏菌LPS为单峰OAG。在这里，我们揭示了宋内氏志贺氏菌，而不是福氏志贺氏菌2a，具有高分子量的免疫原性第4组衣壳，其结构特征与内毒素OAG相似。我们发现宋内氏沙门氏菌的Galu突变体仍能在细胞表面组装OAG物质，而福氏2a沙门氏菌的Galu突变体不能在细胞表面组装OAG物质。从松内沙门氏菌中提纯了与内毒素无关的高分子量物质，并经核磁共振证实含有宋内氏沙门氏菌OAG的特定糖类。与先前在大肠杆菌中描述的第4组胶囊合成簇同源的基因的缺失消除了高分子量OAG材料的产生。该OAG胶囊强烈影响宋内氏葡萄球菌的毒力。未被囊化的敲除细菌在体外具有高度侵袭性，在兔肠道中具有强烈的炎症作用。但是，缺乏被膜降低了宋内氏葡萄球菌抵抗补体介导的杀伤和从肠道向外周器官扩散的能力。相反，与野生型相比，过表达的胶囊在体外减少了侵袭性，在体内减少了炎症。综上所述，数据表明，在宋内氏葡萄球菌中，衣壳的表达调节了细菌的致病机制，导致了入侵和在宿主环境中持续存在的平衡能力。志贺氏菌病是一个主要的全球卫生问题。最近，人们观察到引起疾病的志贺氏菌类型的优势发生了变化，宋内氏志贺氏菌的流行率在社会经济条件改善的情况下增加，导致福氏志贺氏菌的替代。有关志贺氏菌致病机制的大部分知识都是从福氏志贺氏菌的研究中获得的。我们发现宋内氏志贺氏菌具有福氏2a志贺氏菌所没有的高分子量糖囊。胶囊的去除使宋内氏葡萄球菌在体外具有高侵袭性，在体内具有强烈的炎症反应，但与之相反，这些突变细菌从兔的肠道向外周器官的传播减少，对补体介导的溶解更敏感。因此，该胶囊既起到了入侵细菌的作用，又起到了保护细菌免受宿主在感染过程中的先天性免疫防御的作用。这些发现表明，该衣壳是宋内氏葡萄球菌的一个重要毒力因子。根据观察到的被膜去除和过度表达在发病机制上的实质性变化，我们推测其表达水平可能处于显著的进化压力之下。
Shigella is the leading cause for dysentery worldwide. Together with several virulence factors employed for invasion, the presence and length of the O antigen (OAg) of the lipopolysaccharide (LPS) plays a key role in pathogenesis. S. flexneri 2a has a bimodal OAg chain length distribution regulated in a growth-dependent manner, whereas S. sonnei LPS comprises a monomodal OAg. Here we reveal that S. sonnei, but not S. flexneri 2a, possesses a high molecular weight, immunogenic group 4 capsule, characterized by structural similarity to LPS OAg. We found that a galU mutant of S. sonnei, that is unable to produce a complete LPS with OAg attached, can still assemble OAg material on the cell surface, but a galU mutant of S. flexneri 2a cannot. High molecular weight material not linked to the LPS was purified from S. sonnei and confirmed by NMR to contain the specific sugars of the S. sonnei OAg. Deletion of genes homologous to the group 4 capsule synthesis cluster, previously described in Escherichia coli, abolished the generation of the high molecular weight OAg material. This OAg capsule strongly affects the virulence of S. sonnei. Uncapsulated knockout bacteria were highly invasive in vitro and strongly inflammatory in the rabbit intestine. But, the lack of capsule reduced the ability of S. sonnei to resist complement-mediated killing and to spread from the gut to peripheral organs. In contrast, overexpression of the capsule decreased invasiveness in vitro and inflammation in vivo compared to the wild type. In conclusion, the data indicate that in S. sonnei expression of the capsule modulates bacterial pathogenesis resulting in balanced capabilities to invade and persist in the host environment. Shigellosis is a major global health concern. Recently, a shift in the dominance of types of Shigella that cause disease has been observed with S. sonnei increasing in prevalence under improved socio-economic conditions leading to a replacement of S. flexneri. Most of the knowledge of Shigella disease mechanisms has been obtained from studies of S. flexneri. We found that S. sonnei possesses a high molecular weight sugar capsule that is absent in S. flexneri 2a. Removal of the capsule made S. sonnei bacteria highly invasive in vitro and strongly inflammatory in vivo, but in contrast, there was reduced spreading of these mutant bacteria from the gut to peripheral organs in rabbits and higher sensitivity to complement-mediated lysis. Thus, the capsule plays a role in both, invasion and protection of the bacteria against the innate immune defense of the host during the infection. These findings indicate that the capsule is an important virulence factor for S. sonnei. Based on the substantial changes in pathogenesis observed upon removal and overexpression of the capsule, we hypothesize that its level of expression may be under significant evolutionary pressure.
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影响因子：
3.2
作者：
FORMAL, SB;KENT, TH;LABREC, EH
通讯作者：
LABREC, EH
影响因子：
3.1
作者：
KENNE, L;LINDBERG, B;ROMANOWSKA, E
通讯作者：
ROMANOWSKA, E
影响因子：
3.1
作者：
BARZU, S;NATO, F;PHALIPON, A
通讯作者：
PHALIPON, A
影响因子：
2.6
作者：
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通讯作者：
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影响因子：
14.9
作者：
Chaveroche, Marie-Kim;Ghigo, Jean-Marc;d'Enfert, Christophe
通讯作者：
d'Enfert, Christophe