Abstract Gonorrhea, caused by the bacterium Neisseria gonorrhoeae (Gc), is characterized by the influx of neutrophils to sites of infection. Gc has many nonredundant mechanisms to manipulate neutrophil activation and resist killing by neutrophil antimicrobial components. In neutrophil-rich male urethral exudates, the oligosaccharide of Gc lipooligosaccharide (LOS) becomes modified by sialic acid in a process known as sialylation. Gc incorporates host derived sialic acid into LOS using the surface-exposed enzyme LOS sialyltransferase (Lst). While sialylation by Lst has been shown to protect Gc from complement-mediated killing and enhances Gc infectivity in in vitro and animal models of infection, how it affects the ability of Gc to survive in association with neutrophils is unclear. My preliminary results show that sialylated Gc significantly reduces the oxidative burst of primary human neutrophils, suggesting modulation of neutrophil anti-gonococcal properties. In this proposal, I will test the hypothesis that LOS sialylation protects Gc from killing by primary human neutrophils, with potential mechanisms including increased resistance to neutrophil antimicrobial components and limiting the production and/or release of these components by neutrophils. I will simultaneously test the hypothesis that neutrophils modify the sialylation state of Gc by providing sialic acid as substrate and through their sialyltransferase and sialidase activities. To address these hypotheses, I have created isogenic Gc strains that produce single, physiologically relevant OS chemotypes and express or are deficient for Lst. My collaborators and I have also developed a method to monitor the sialylation state of Gc during infection using click chemistry, the first time sialylation on Gc can be directly monitored in real-time. Results from this project will show how modification by sialylation drives the ability of Gc to evade killing by neutrophils and persist in its obligate human host, and will provide me with the scientific and professional training for my PhD to ultimately be a leader in the host-pathogen interactions field.