Modelling enhanced phagocytosis of activated macrophage by outer membrane vesicles from Neisseria gonorrhoeae

Background: Gonorrhoea, caused by Neisseria gonorrhoeae, remains a significant health concern. N. gonorrhoeae produces outer membrane vesicles (NOMVs) that modulate the host immune system by delivering virulence factors. Macrophages are crucial for eliminating foreign material through phagocytosis; dysfunction in this process can lead to infections. Mathematical models offer insights into bacteria-phagocyte interactions, where infection size can exhibit bistable effects. It's unclear if naïve or NOMV-activated macrophages induce bistable bacterial kinetics, which is critical for understanding if activated macrophages can alter infection outcomes, potentially aiding interventions without antimicrobials. Methods: We activated macrophages with NOMVs and used live cell imaging (LCI) assay to monitor activated cell survival during N. gonorrhoeae and E. coli infection. We developed a family of mathematical models to quantify bacterial kinetics, considering macrophage concentration, inoculum size, natural macrophage death, phagocytosis efficiency, and comparing antibacterial capabilities of trained and naïve macrophages. Results: LCI data showed NOMV activation doesn't increase macrophage natural death. Phagocytosis efficiency increases and saturates with higher macrophage and bacteria concentrations. Activation notably enhances phagocytosis efficiency, demonstrating strain-specific effects and reducing phagocytosis-associated macrophage death. Both activated and naïve macrophages induced bistable bacterial kinetics for E. coli and N. gonorrhoeae: high inoculum sizes persisted, while low inoculum sizes were inhibited. Significantly, the antibacterial capability of activated macrophages was 14.2 times stronger for E. coli and 12.4 times for N. gonorrhoeae than that of naïve macrophages, aligning with observed 10- to 20-fold increases. Conclusions: Our findings highlight the critical role of NOMV activation in enhancing macrophage antibacterial capability, offering a potential mechanistic explanation for developing N. gonorrhoeae OMV vaccines.