The Mucosal Cytokine Landscape of Acute Gonorrhea Using a Controlled Human Infection Model

The host response to <i>Neisseria gonorrhoeae</i> is variable, and understanding its systemic and local components is critical to understanding anti-gonococcal immunity for vaccine development. We used a controlled human infection model of male gonococcal urethritis in naïve volunteers in combination with multiplex cytokine analyte analysis of blood and urine specimens taken before infection, at the time of acute symptoms, and after curative treatment of <i>N. gonorrhoeae</i> to study responses to early infection. (This study utilized data and specimens from all 11 participants assigned to control arms of two previous randomized clinical trials). All 11 participants developed urethritis between 2 and 5 days post inoculation with <i>N. gonorrhoeae</i> strain FA1090, with a majority having visible discharge by day 3. In urine, we found increases in IL-1RA, G-CSF, and chemokines CXCL10, CCL4, CCL11, GROα/β/γ, and IL-8/CXCL8, with IL-1RA and CCL4 showing direct correlation with the degree of pyuria at the time of infection. Contrary to a prior study using the human challenge model and <i>N. gonorrhoeae</i> strain MS11mkC, we did not see similar increases in urine IL-6, TNF-α, or IL-1β, although differences in IL-6, TNF-α were observed in participants with later development of infection. Additionally, plasma cytokine levels were unchanged in this cohort over the course of their infection, suggesting these infections were confined to the urethra. We propose that differences in strain virulence or the threshold to define a clinical case may be responsible for this discrepancy, meriting further study and continued use of non-invasive inflammatory markers to study local effects in addition to systemic effects of gonococcal infection.