Introduction
Gonorrhoea caused by Neisseria gonorrhoeae remains a major global public health challenge due to rising antimicrobial resistance and the absence of a licensed vaccine. Clinical presentation differs markedly between sexes, with women frequently experiencing asymptomatic infection and long-term reproductive complications. To investigate whether host sex influences gonococcal population structure and immune responses during natural infection, we analysed isolates and matched sera collected during a clinical trial.
Methods
Whole-genome sequencing and phylogenetic analysis were performed on 367 clinical gonococcal isolates. Population structure was assessed in relation to patient metadata and sexual network. An exploratory bacterial genome-wide association study (GWAS) was undertaken to identify loci associated with cervical infection. Humoral immune responses were investigated using a protein microarray containing 91 gonococcal outer membrane proteins and matched sera from 123 infected patients. Functional antibody activity was assessed using serum bactericidal assays (SBA) with matched patient isolates and sera (n = 78 analysed to date).
Results
Phylogenetic analysis demonstrated marked sexual-network-associated clustering, with 65.3% of female-derived isolates grouping within a single lineage. Male-derived isolates within this lineage were predominantly from men who have sex with women, whereas isolates from men who have sex with men were phylogenetically dispersed. Other patient metadata did not correlate with population structure. GWAS identified 15 significant genes associated with cervical infection, including 11 mapping to the gonococcal genetic island encoding a Type IV secretion system, suggesting a role in cervical niche adaptation. Protein microarray analysis revealed distinct sex-associated antibody recognition profiles, with women displaying antibody-binding patterns clearly separated from men, even when infected with genetically similar isolates. Functional analysis demonstrated significantly greater complement-mediated killing by sera from women compared with men.
Conclusion
These findings demonstrate that gonococcal population structure, bacterial genetic determinants and humoral immune responses differ according to host sex and sexual network. Collectively, the data support the hypothesis that gonococci adapt to sex-specific genital niches and that host sex is a key determinant of immune outcome during natural infection.