{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T15:00:40Z","timestamp":1772204440158,"version":"3.50.1"},"posted":{"date-parts":[[2026,2,25]]},"group-title":"Infectious Diseases (except HIV\/AIDS)","reference-count":39,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T00:00:00Z","timestamp":1771977600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The host response to\n                  <jats:italic>Neisseria gonorrhoeae<\/jats:italic>\n                  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 na\u00efve 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\n                  <jats:italic>N. gonorrhoeae<\/jats:italic>\n                  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\n                  <jats:italic>N. gonorrhoeae<\/jats:italic>\n                  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, GRO\u03b1\/\u03b2\/\u03b3, 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\n                  <jats:italic>N. gonorrhoeae<\/jats:italic>\n                  strain MS11mkC, we did not see similar increases in urine IL-6, TNF-\u03b1, or IL-1\u03b2, although differences in IL-6, TNF-\u03b1 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.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Author Summary<\/jats:title>\n                  <jats:p>\n                    Gonorrhea, caused by the bacterium\n                    <jats:italic>Neisseria gonorrhoeae<\/jats:italic>\n                    , remains a global public health concern, yet repeated infections are common and no vaccine is available. A key challenge for vaccine development is limited understanding of how the human immune system responds during early infection, when bacteria are confined to the urethra, vagina, or other mucosal sites. To address this gap, we studied immune responses in a controlled human infection model in which male volunteers with no prior exposure were experimentally infected with\n                    <jats:italic>N. gonorrhoeae<\/jats:italic>\n                    into their urethra. Immune signaling molecules were measured in urine and blood samples collected before infection, during symptoms, and after antibiotic treatment.\n                  <\/jats:p>\n                  <jats:p>\n                    All participants developed urethral inflammation within a few days of infection. We observed marked increases in multiple inflammatory cytokines in urine, some which correlated with the degree of neutrophils in their urine. In contrast, immune markers in the bloodstream remained largely unchanged. These findings suggest that early infection with the\n                    <jats:italic>N. gonorrhoeae<\/jats:italic>\n                    strain tested triggers a strong localized immune response without widespread systemic inflammation. Our results highlight the value of urine-based, non-invasive sampling and demonstrate the power of human challenge models for studying early immune responses that have been difficult to characterize in animal systems.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.02.22.26346846","type":"posted-content","created":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T22:30:16Z","timestamp":1772058616000},"source":"Crossref","is-referenced-by-count":0,"title":["The Mucosal Cytokine Landscape of Acute Gonorrhea Using a Controlled Human Infection Model"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4271-1375","authenticated-orcid":false,"given":"Michael P.","family":"Motley","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"},{"name":"Institute for Global Health and Infectious 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Durham, North Carolina, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4438-2018","authenticated-orcid":false,"given":"Joseph A.","family":"Duncan","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"},{"name":"Institute for Global Health and Infectious Diseases, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"},{"name":"Department of Pharmacology, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"},{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 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