Inhibition of Neisseria gonorrhoeae complement-mediated killing during acute gonorrhea is dependent upon the IgG2:IgG3 antibody ratio

TL;DR

This study shows that Neisseria gonorrhoeae can resist immune attack by causing the body to produce more IgG2 antibodies, which block the protective IgG3 antibodies.

Contribution

The study identifies a novel mechanism of serum resistance in N. gonorrhoeae involving the IgG2:IgG3 antibody ratio.

Findings

Blocking of complement-mediated killing was observed in 3% of autologous sera from participants.

An increased IgG2:IgG3 ratio on the bacterial surface correlates with resistance to complement-mediated killing.

Blocking antibodies prevent IgG3 from initiating bactericidal activity against N. gonorrhoeae.

Abstract

Excessive binding of antibodies to the bacterial cell surface can paradoxically increase resistance of some Gram-negative pathogens to complement-mediated killing (CMK). We examined the CMK of 336 Neisseria gonorrhoeae isolates from 283 participants recruited to a clinical trial. Serum bactericidal assays revealed 3% (9/283) of the autologous participant sera blocked CMK. Gonococci isolated from these participants were resistant to the autologous host serum, but sensitive to pooled healthy control sera (HCS) and protected by autologous host serum in a 1:1 mixture with HCS. Analysis of clinical metadata showed that there was a significantly higher proportion of blocking sera found in participants with urethral infection and from men within the transmission network of men who have sex with women, when compared to the whole cohort. Following antibody purification from participants with blocking sera (5/9), total IgG protected autologous isolates from HCS-mediated killing. A closer examination of IgG subclasses using whole gonococcal cell ELISAs revealed a significant correlation between increased IgG2 binding and decreased IgG3 binding to the cell surface of isolates that were resistant to CMK. This indicates that IgG2 prevents bactericidal IgG3 from initiating CMK, with an increased IgG2:IgG3 ratio blocking CMK of gonococci. We therefore reveal a previously unrecognized mechanism by which blocking antibodies prevent CMK of N. gonorrhoeae.

The antigenic variation of Neisseria gonorrhoeae and a limited mechanistic understanding of immune responses to this bacterium have presented multiple challenges to generating a protective vaccine. Here, we use a collection of N. gonorrhoeae clinical isolates (n = 336) for a robust analysis of the host immune response to infection. We reveal a mechanism for serum resistance in which some isolates of N. gonorrhoeae drive the production of inhibitory IgG2 antibodies, which block the activity of IgG3 bactericidal antibodies. Importantly, an increased ratio of IgG2:IgG3 bound to the bacterium promotes serum resistance. Recently, there has been increased interest in developing a vaccine against N. gonorrhoeae given the observation that the licensed outer membrane vesicle-based vaccine against Neisseria meningitidis (MeNZB) generated some cross-protection against N. gonorrhoeae. Thus, the mechanism described here should guide the development of a vaccine that simultaneously prevents serum resistance and promotes serum killing of the gonococcus.

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