T4 Pili Promote Colonization and Immune Evasion Phenotypes of Nonencapsulated M4 Streptococcus pyogenes
T4 Pili Promote Colonization and Immune Evasion Phenotypes of Nonencapsulated M4 Streptococcus pyogenes
复制标题
DOI：
10.1128/mbio.01580-20
复制
发表时间：
2020-07-01
期刊：
影响因子：
6.4
通讯作者：
Chang, Yung-Chi
中科院分区：
文献类型：
--
作者：
Chen, Yi-Hsuan;Li, Shao-Hui;Chang, Yung-Chi
化脓性链球菌（A组链球菌[GAS]）是一种重要的人类病原体，可引起广泛的疾病，并与全球显著的发病率和死亡率相关。几乎所有的GAS分离株都表达表面透明质酸胶囊，这是一种有助于宿主定植并阻碍吞噬细胞杀伤的毒力决定因素。然而，最近的流行病学监测报告了持续增加的粘膜和侵袭性感染引起的非囊化GAS，质疑透明质酸胶囊在GAS发病机制中不可或缺的作用。在这项研究中，我们发现M4 GAS的菌毛不仅显著促进生物膜形成、粘附和对人上呼吸道上皮细胞和角质形成细胞的细胞毒性，而且还促进人全血中的存活和侵袭性感染小鼠模型中的毒力增加。T4抗原是M4 GAS的菌毛骨架蛋白，结合细菌表面上的触珠蛋白，触珠蛋白是一种在感染和炎症时上调的丰富的人类急性期蛋白。结合珠蛋白隔离降低了未包封的M4 GAS对活化的中性粒细胞和血小板释放的抗菌肽的敏感性。我们的研究结果揭示了一个以前不受重视的毒性促进作用的M4气体皮利，部分介导的增选的生物学的触珠蛋白，以减轻主机antimicrobial defenses.IMPORTANCE组链球菌（GAS）是一个严格的人类病原体造成超过700万感染全球每年。大多数致病的GAS都被包裹起来，这极大地保证了宿主的存活和传播。在最近的流行病学监测中出现的荚膜阴性GAS，如M4 GAS，警告了阐明这些病原体的毒力决定因素的必要性。在此，我们发现M4皮利在促进M4 GAS对人咽上皮细胞和角质形成细胞的粘附和细胞毒性中起重要作用。相同的分子还显著增强了M4 GAS在人全血和实验鼠感染中的存活和复制。构成M4皮利骨架的T4抗原能够螯合非常丰富的血清蛋白结合珠蛋白，以进一步赋予M4 GAS对中性粒细胞和血小板释放的抗菌物质的抗性。
Streptococcus pyogenes (group A Streptococcus [GAS]) is an important human pathogen causing a broad spectrum of diseases and associated with significant global morbidity and mortality. Almost all GAS isolates express a surface hyaluronic acid capsule, a virulence determinant that facilitates host colonization and impedes phagocyte killing. However, recent epidemiologic surveillance has reported a sustained increase in both mucosal and invasive infections caused by nonencapsulated GAS, which questions the indispensable role of hyaluronic acid capsule in GAS pathogenesis. In this study, we found that pilus of M4 GAS not only significantly promotes biofilm formation, adherence, and cytotoxicity to human upper respiratory tract epithelial cells and keratinocytes, but also promotes survival in human whole blood and increased virulence in murine models of invasive infection. T4 antigen, the pilus backbone protein of M4 GAS, binds haptoglobin, an abundant human acute-phase protein upregulated upon infection and inflammation, on the bacterial surface. Haptoglobin sequestration reduces the susceptibility of nonencapsulated M4 GAS to antimicrobial peptides released from activated neutrophils and platelets. Our results reveal a previously unappreciated virulence-promoting role of M4 GAS pili, in part mediated by co-opting the biology of haptoglobin to mitigate host antimicrobial defenses.IMPORTANCE Group A Streptococcus (GAS) is a strict human pathogen causing more than 700 million infections globally each year. The majority of the disease-causing GAS are encapsulated, which greatly guarantees survival and dissemination in the host. Emergence of the capsule-negative GAS, such as M4 GAS, in recent epidemiologic surveillance alarms the necessity to elucidate the virulence determinants of these pathogens. Here, we found that M4 pili play an important role in promoting M4 GAS adherence and cytotoxicity to human pharyngeal epithelial cells and keratinocytes. The same molecule also significantly enhanced M4 GAS survival and replication in human whole blood and experimental murine infection. T4 antigen, which composes the backbone of M4 pili, was able to sequester the very abundant serum protein haptoglobin to further confer M4 GAS resistance to antibacterial substances released by neutrophils and platelets.