Neisseria gonorrhoeae co-opts C4b-binding protein to enhance complement-independent survival from neutrophils

Neisseria gonorrhoeae (Gc) is a human-specific pathogen that causes the sexually transmitted infection gonorrhea. Gc survives in neutrophil-rich gonorrheal secretions, and recovered bacteria predominantly express phase-variable, surface-expressed opacity-associated (Opa) proteins (Opa+). However, expression of Opa proteins like OpaD decreases Gc survival when exposed to human neutrophils ex vivo. Here, we made the unexpected observation that incubation with normal human serum, which is found in inflamed mucosal secretions, enhances survival of Opa+ Gc from primary human neutrophils. We directly linked this phenomenon to a novel complement-independent function for C4b-binding protein (C4BP). When bound to the bacteria, C4BP was necessary and sufficient to suppress Gc-induced neutrophil reactive oxygen species production and prevent neutrophil phagocytosis of Opa+ Gc. This research identifies for the first time a complement-independent role for C4BP in enhancing the survival of a pathogenic bacterium from phagocytes, thereby revealing how Gc exploits inflammatory conditions to persist at human mucosal surfaces. Author Summary Gonorrhea is considered an urgent threat to public health with an estimated 98 million cases occurring annually worldwide, growing antimicrobial resistance, and the absence of a gonococcal vaccine. Currently, we do not understand how N. gonorrhoeae expressing opacity (Opa) proteins survive neutrophil defenses and are recovered viable from infected patients. Here, we investigated how soluble elements of gonorrhea infection, present in human serum, contribute to N. gonorrhoeae survival from neutrophils. We found that the serum component C4b-binding protein (C4BP) protects N. gonorrhoeae from neutrophil killing and suppresses neutrophil activation. C4BP limited neutrophil phagocytosis of N. gonorrhoeae that expressed Opa proteins that bound to neutrophil receptors of the CEACAM family. This work provides novel insight into the interplay between the noncellular and cellular aspects of the innate immune response to N. gonorrhoeae.