Neisseria meningitidis IgA1-specific serine protease exhibits novel cleavage activity against IgG3

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.

An Introduction to Bacterial Biofilms and Their Proteases, and Their Roles in Host Infection and Immune Evasion

“…Another Gram-negative bacterium capable of modulating the immunoglobulin response is Neisseria meningitidis , a bacterial colonizer of the human nasopharynx in approximately 10% of human adults. However, when leaving its commensal environment, Neisseria harnesses its IgA1-specific serine peptidase IgA1P, which is also capable of degrading IgG3 [ 106 ], and an IdeS-like peptidase capable of cleaving the IgA hinge region [ 107 ], to evade the immune system, thereby causing blood sepsis and bacterial meningitis [ 108 ].…”

Rabbit IgA Hinges That Resist IgA1 Protease Action Provide Options for Improved IgA-Based Therapeutic Agents

“…Similarly, type 2 IgA proteases were shown to cut hinges that do not have any Pro-Thr sites (30). Moreover, Neisseria meningitidis cleavage type 1 IgA1 protease has been demonstrated to cleave specifically human IgG3, despite all IgG subtypes have the identified Pro-Ala cleavage motif in the lower hinge region in common (31). Therefore, it remains difficult to predict where these IgA proteases cleave the hinge region purely based on their amino acid sequence.…”

The Host-Pathogen Interactions and Epicellular Lifestyle of Neisseria meningitidis

“…Nme IgA1 proteases can be divided into two classes (type 1 and type 2) based on their cleavage specificities (Mulks et al, 1980). IgA1 protease cleavage type 1 has the additional capacity to degrade IgG3, which are typically bactericidal antibodies that activate opsonophagocytosis (Spoerry et al, 2021). Interestingly, cc11 isolates exclusively encode cleavage type I IgA1 proteases (Spoerry et al, 2021).…”

“…IgA1 protease cleavage type 1 has the additional capacity to degrade IgG3, which are typically bactericidal antibodies that activate opsonophagocytosis (Spoerry et al, 2021). Interestingly, cc11 isolates exclusively encode cleavage type I IgA1 proteases (Spoerry et al, 2021). CAMPs are a class of short peptides secreted by the host cells which bind negatively charged bacterial surfaces, disrupting membrane integrity and leading to bacterial lysis (McCormick and Weinberg, 2010).…”