A Novel Cleavage Pattern of Complement C5 Induced by Chlamydia trachomatis Infection via the Chlamydial Protease CPAF.

Lei Cui,Hong Xu,Lingli Tang,Xiao‐Tong Su ,Zihao Hu,Hongbo Zhang,Jianlin Chen,Xiaojing Feng,Shanshan Liu,Yujie Zhao,Liang Peng,Yutao Fang ,Fuyan Wang,Jingping Gao

doi:10.3389/fcimb.2021.732163

Abstract

Urogenital Chlamydia trachomatis infection is one of the most common bacterial sexually transmitted diseases globally. Untreated C. trachomatis 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 C. trachomatis 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 C. trachomatis-HeLa229 cell lysates were analyzed, and a novel cleavage pattern of C5 activation induced by C. trachomatis infection was identified. C5 was cleaved efficiently at the previously unidentified site K970, but was cleaved poorly at site R751. C5b was modified to C5bCt, which later formed C5bCt-9, which had enhanced lytic ability compared with C5b-9. The chlamydial serine protease CPAF contributed to C3-independent C5 activation during C. trachomatis 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.

Highlights

Rapid growth of sexually transmitted diseases (STDs) worldwide in the 21st century has caused many serious public health problems (Levy et al, 2019)
To explore the mechanism of C3-independent C5 activation induced by C. trachomatis infection, a co-incubation system containing purified human C5 (400 nM) and C. trachomatisHeLa229 cell lysates (MOI=1) or mock infected HeLa229 cell lysates or phosphate-buffed saline (PBS) (C5 control) was established
The results propose a novel cleavage pattern of C5 induced by C. trachomatis infection that is different from the traditional cleavage pattern of C5 in the complement system

Summary

Introduction

Rapid growth of sexually transmitted diseases (STDs) worldwide in the 21st century has caused many serious public health problems (Levy et al, 2019). Urogenital Chlamydia trachomatis infection is one of the most common STDs globally, with approximately 127.2 million new cases each year (Sieving et al, 2019), and its symptoms are relatively insidious. Untreated C. trachomatis infections can ascend to the upper genital tract and establish a chronic infection, potentially leading to serious complications including ectopic pregnancy, pelvic inflammation disease, and tubal factor infertility (den Heijer et al, 2019; Hoenderboom et al, 2019; Reekie et al, 2019). Fibrosis and occlusion of the fallopian tube, as the pathological basis of tubal factor infertility, are the final stage of the pathological progression induced by C. trachomatis infection in the female upper reproductive tract (Growe et al, 2013). The development of tubal fibrosis induced by chlamydial infection is multifactorial; there is no complete theory to fully elaborate the pathological mechanism

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Conclusion