Neisseria gonorrhoeae (Ng) causes the sexually transmitted disease gonorrhoea, which has significant impact on global health, infecting >100 million people each year. The emergence of almost untreatable multi-drug resistance strains of Ng is on the rise, prompting calls for urgent development of new treatment options and a vaccine. Human cells are covered in a glycocalyx, a rich surface layer of glycans and glycoproteins, that provides an external barrier between the cell and the environment, mediates cell-cell interactions and recognition, as well as signalling and cell proliferation. Many microbes have evolved to exploit these interactions to promote colonisation and disease. In our approach to discover new drug and vaccine targets for Ng, we characterised its interactions with human cell glycans.
Using glycan arrays we have shown that Ng binds >260 mammalian glycans, including fucosylated, sialylated, mannosylated and glycosaminoglycan structures. Concurrently, we investigated glycans on the surface of human cervical and urethral epithelial cells (main niche for gonococcus). Our analysis has shown than mannose containing glycans are highly abundant on the surface of cervical and urethral epithelial cells allowing us to focus on this particular interaction. By studying the kinetics of these interactions we showed that Ng binds mannoses with high affinity. To determine the role of these interactions during infection, we performed gonococcal adherence blocking assays with cultured human cervical and urethral epithelial cells pre-treated mannose-binding lectin (ConA) or in presence of a mannoside (α-methyl D-mannoside). Gonococcal adherence was reduced 5-fold in presence of ConA, and mannoside has reduced gonococcal adherence in dose dependent manner, suggesting that mannosides and other drugs can be used to target these interactions. We are now investigating a panel of mannosides and testing these potentially novel treatment options for gonorrhoeae in mice. We also identified ten gonococcal proteins that interact with mannose and may be responsible for adherence to epithelial cells. These putative mannose-binding proteins could be used as vaccine antigens and are currently being investigated.