Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Department of Pharmacology and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA, USA.
Virulence. 2021 Dec;12(1):2633-2647. doi: 10.1080/21505594.2021.1982501.
(group A , GAS) is a strict human pathogen causing a broad spectrum of diseases and a variety of autoimmune sequelae. The pathogenesis of GAS infection mostly relies on the production of an extensive network of cell wall-associated and secreted virulence proteins, such as adhesins, toxins, and exoenzymes. PrsA, the only extracellular parvulin-type peptidyl-prolyl isomerase expressed ubiquitously in Gram-positive bacteria, has been suggested to assist the folding and maturation of newly exported proteins to acquire their native conformation and activity. Two PrsA proteins, PrsA1 and PrsA2, have been identified in GAS, but the respective contribution of each PrsA in GAS pathogenesis remains largely unknown. By combining comparative proteomic and phenotypic analysis approaches, we demonstrate that both PrsA isoforms are required to maintain GAS proteome homeostasis and virulence-associated traits in a unique and overlapping manner. The inactivation of both PrsA in GAS caused remarkable impairment in biofilm formation, host adherence, infection-induced cytotoxicity, and virulence in a murine soft tissue infection model. The concordance of proteomic and phenotypic data clearly features the essential role of PrsA in GAS full virulence.
(group A, GAS) 是一种严格的人类病原体，可引起广泛的疾病和多种自身免疫后遗症。GAS 感染的发病机制主要依赖于广泛的细胞壁相关和分泌的毒力蛋白的产生，如黏附素、毒素和外切酶。PrsA 是唯一在革兰氏阳性菌中广泛表达的细胞外小泛肽型肽基脯氨酰顺反异构酶，它被认为有助于新分泌蛋白的折叠和成熟，以获得其天然构象和活性。在 GAS 中已经鉴定出两种 PrsA 蛋白，PrsA1 和 PrsA2，但每种 PrsA 在 GAS 发病机制中的各自贡献在很大程度上仍然未知。通过结合比较蛋白质组学和表型分析方法，我们证明两种 PrsA 同工酶以独特且重叠的方式维持 GAS 蛋白质组平衡和与毒力相关的特征。在 GAS 中同时失活两种 PrsA 会导致生物膜形成、宿主黏附、感染诱导的细胞毒性和在小鼠软组织感染模型中的毒力显著受损。蛋白质组学和表型数据的一致性清楚地表明了 PrsA 在 GAS 完全毒力中的重要作用。
