Reproductive Medicine Center, Department of Obstetrics and Gynecology, The Second Xiangya Hospital, Central South University, Changsha, China.
Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, China.
Front Cell Infect Microbiol. 2022 Jan 11;11:732163. doi: 10.3389/fcimb.2021.732163. eCollection 2021.
Urogenital infection is one of the most common bacterial sexually transmitted diseases globally. Untreated infections can ascend to the upper genital tract and establish a series of severe complications. Previous studies using C3 and C5 mice models demonstrated that C3-independent activation of C5 occurred during infection. However, the mechanism of how chlamydial infection activates C5 in the absence of C3 has yet to be elucidated. To delineate interactions between C5 and chlamydial infection, cleavage products in a co-incubation system containing purified human C5 and -HeLa229 cell lysates were analyzed, and a novel cleavage pattern of C5 activation induced by infection was identified. C5 was cleaved efficiently at the previously unidentified site K970, but was cleaved poorly at site R751. C5b was modified to C5b, which later formed C5b-9, which had enhanced lytic ability compared with C5b-9. The chlamydial serine protease CPAF contributed to C3-independent C5 activation during infection. Nafamostat mesylate, a serine protease inhibitor with a good safety profile, had a strong inhibitory effect on C5 activation induced by chlamydial infection. These discoveries reveal the mechanism of C3-independent C5 activation induced by chlamydial infection, and furthermore provide a potential therapeutic target and drug for preventing tubal fibrosis caused by chlamydial infection.
泌尿生殖系统感染是全球最常见的细菌性性传播疾病之一。未经治疗的感染可向上生殖道蔓延，并引发一系列严重的并发症。先前使用 C3 和 C5 小鼠模型的研究表明，在感染期间会发生 C5 的 C3 非依赖性激活。然而，尚不清楚衣原体感染在缺乏 C3 的情况下如何激活 C5 的机制。为了阐明 C5 与衣原体感染之间的相互作用，在含有纯化的人 C5 和 -HeLa229 细胞裂解物的共孵育系统中分析了裂解产物，并鉴定出一种由感染诱导的新型 C5 激活的裂解模式。C5 在先前未鉴定的位点 K970 处被有效切割，但在位点 R751 处切割较差。C5b 被修饰为 C5b，随后形成 C5b-9，与 C5b-9 相比，其裂解能力增强。衣原体丝氨酸蛋白酶 CPAF 有助于衣原体感染期间 C3 非依赖性 C5 的激活。那屈肝素钙，一种具有良好安全性的丝氨酸蛋白酶抑制剂，对衣原体感染诱导的 C5 激活具有很强的抑制作用。这些发现揭示了衣原体感染诱导的 C3 非依赖性 C5 激活的机制，并为预防衣原体感染引起的输卵管纤维化提供了潜在的治疗靶点和药物。
