Mutual exclusivity of hyaluronan and hyaluronidase in invasive group A Streptococcus.
Mutual exclusivity of hyaluronan and hyaluronidase in invasive group A Streptococcus.
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浸润性A链球菌中透明质酸和透明质酸酶的相互排他性。
DOI：
10.1074/jbc.m114.602847
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发表时间：
2014-11-14
期刊：
影响因子：
--
通讯作者：
Cole JN
中科院分区：
文献类型：
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作者：
Henningham A;Yamaguchi M;Aziz RK;Kuipers K;Buffalo CZ;Dahesh S;Choudhury B;Van Vleet J;Yamaguchi Y;Seymour LM;Ben Zakour NL;He L;Smith HV;Grimwood K;Beatson SA;Ghosh P;Walker MJ;Nizet V;Cole JN
背景：血清型M4 A组链球菌缺乏透明质酸（HA）包膜，但能够引起人类疾病。结果：在不存在HA降解酶透明质酸裂解酶（HylA）的情况下，通过引入hasABC胶囊合成操纵子实现了胶囊化。结论：荚膜表达不会增强M4 GAS的毒力。意义：我们证明了GAS胶囊和HylA表达之间的相互排斥作用。最近对澳大利亚A组链球菌（GAS）侵袭性感染的分析显示，M4 GAS占优势，这是一种最近报道缺乏抗吞噬透明质酸（HA）胶囊的血清型。在这里，我们使用分子遗传学和生物信息学技术来表征17个临床M4分离株与侵袭性疾病的儿童在最近的流行病学。所有M4分离株缺乏HA包膜，两个分离株的全基因组序列分析显示完全不存在hasABC包膜生物合成操纵子。相反，M4分离株具有功能性HA降解透明质酸裂解酶（HylA），通过点突变使其在其他GAS中无功能。用表达hasABC的质粒转化恢复了野生型（WT）M4 GAS中的部分包封，以及缺乏HylA的同基因M4突变体中的完全包封。然而，部分包封减少了与人补体调节蛋白C4BP的结合，没有提高在人全血中的存活率，并且没有增加WT M4 GAS在全身感染小鼠模型中的毒力。生物信息学分析发现，在密切相关的物种中没有hasABC同源物，这表明该操纵子是最近获得的。这些数据显示了HA胶囊和活性HylA在这种主要人类病原体的菌株中的相互排斥的相互作用。
Background: Serotype M4 group A Streptococcus lack hyaluronic acid (HA) capsule, but are capable of causing human disease. Results: Encapsulation was achieved by introducing the hasABC capsule synthesis operon in the absence of HA-degrading enzyme hyaluronate lyase (HylA). Conclusion: Capsule expression does not enhance M4 GAS virulence. Significance: We demonstrate a mutually exclusive interaction between GAS capsule and HylA expression. A recent analysis of group A Streptococcus (GAS) invasive infections in Australia has shown a predominance of M4 GAS, a serotype recently reported to lack the antiphagocytic hyaluronic acid (HA) capsule. Here, we use molecular genetics and bioinformatics techniques to characterize 17 clinical M4 isolates associated with invasive disease in children during this recent epidemiology. All M4 isolates lacked HA capsule, and whole genome sequence analysis of two isolates revealed the complete absence of the hasABC capsule biosynthesis operon. Conversely, M4 isolates possess a functional HA-degrading hyaluronate lyase (HylA) enzyme that is rendered nonfunctional in other GAS through a point mutation. Transformation with a plasmid expressing hasABC restored partial encapsulation in wild-type (WT) M4 GAS, and full encapsulation in an isogenic M4 mutant lacking HylA. However, partial encapsulation reduced binding to human complement regulatory protein C4BP, did not enhance survival in whole human blood, and did not increase virulence of WT M4 GAS in a mouse model of systemic infection. Bioinformatics analysis found no hasABC homologs in closely related species, suggesting that this operon was a recent acquisition. These data showcase a mutually exclusive interaction of HA capsule and active HylA among strains of this leading human pathogen.