ABSTRACT

Neisseria meningitidis (meningococcus) is a common bacterial colonizer of the human nasopharynx but can occasionally cause very severe systemic infections with rapid onset. Meningococci are able to degrade IgA encountered during colonization of mucosal membranes using their IgA1-specific serine protease. During systemic infection, specific IgG can induce complement-mediated lysis of the bacterium. However, meningococcal immune evasion mechanisms in thwarting IgG remain undescribed. In this study, we report for the first time that the meningococcal IgA1-specific serine protease is able to degrade IgG3 in addition to IgA. The IgG3 heavy chain is specifically cleaved in the lower hinge region thereby separating the antigen binding part from its effector binding part. Through molecular characterization, we demonstrate that meningococcal IgA1-specific serine protease of cleavage type 1 degrades both IgG3 and IgA, whereas cleavage type 2 only degrades IgA. Epidemiological analysis of 7581 clinical meningococcal isolates shows a significant higher proportion of cleavage type 1 among isolates from invasive cases compared to carrier cases, regardless of serogroup. Notably, serogroup W cc11 which is an increasing cause of invasive meningococcal disease globally harbors almost exclusively cleavage type 1 protease. Our study also shows an increasing prevalence of meningococcal isolates encoding IgA1P cleavage type 1 compared to cleavage type 2 during the observed decade (2010–2019). Altogether, our work describes a novel mechanism of IgG3 degradation by meningococci and its association to invasive meningococcal disease.

摘要

脑膜炎奈瑟菌脑膜炎双球菌是人鼻咽部常见的细菌定居者，但偶尔会引起非常严重的全身感染，起病迅速。脑膜炎球菌能够使用其IgA1特异性丝氨酸蛋白酶降解在粘膜定植过程中遇到的IgA。在全身感染期间，特异性IgG可以诱导补体介导的细菌裂解。然而，阻止IgG的脑膜炎球菌免疫逃逸机制仍未描述。在这项研究中，我们首次报告脑膜炎球菌IgA1特异性丝氨酸蛋白酶除IgA之外还能降解IgG3。IgG3重链在下部铰链区被特异性切割，从而将抗原结合部分与其效应子结合部分分开。通过分子表征 我们证明裂解型1的脑膜炎球菌IgA1特异性丝氨酸蛋白酶降解IgG3和IgA，而裂解型2仅降解IgA。对7581例临床脑膜炎球菌分离株的流行病学分析表明，与血清型携带者相比，侵入性分离株中1型卵裂的比例要高得多，而与血清群无关。值得注意的是，W cc11血清群是侵入性脑膜炎球菌疾病的一个日益增加的原因，在全球范围内几乎只具有裂解1型蛋白酶的能力。我们的研究还显示，在观察到的十年中（2010-2019年），编码IgA1P裂解类型1的脑膜炎球菌分离株与裂解类型2的流行率呈上升趋势。总之，我们的工作描述了脑膜炎球菌降解IgG3的新机制及其与侵袭性脑膜炎球菌的相关性。