Experimental Gonococcal Infection in Male Volunteers: Cumulative Experience with Neisseria gonorrhoeae Strains FA1090 and MS11mkC

Abstract

Experimental infection of male volunteers with Neisseria gonorrhoeae is safe and reproduces the clinical features of naturally acquired gonococcal urethritis. Human inoculation studies have helped define the natural history of experimental infection with two well-characterized strains of N. gonorrhoeae, FA1090 and MS11mkC. The human model has proved useful for testing the importance of putative gonococcal virulence factors for urethral infection in men. Studies with isogenic mutants have improved our understanding of the requirements for gonococcal LOS structures, pili, opacity proteins, IgA1 protease, and the ability of infecting organisms to obtain iron from human transferrin and lactoferrin during uncomplicated urethritis. The model also presents opportunities to examine innate host immune responses that may be exploited or improved in development and testing of gonococcal vaccines. Here we review results to date with human experimental gonorrhea.

Keywords: gonorrhea; infection; pathogenesis; urethritis.

Figure 1

Neisseria gonorrhoeae strain MS11mkC is more infectious than strain FA1090 in experimental infection of the male urethra. Multiple logistic regression analysis was used to generate dose response models with data from 55 men inoculated with MS11mkC (dashed line) and 43 men inoculated with FA1090 (solid line). All inocula contained predominantly piliated, Opa-negative, wild-type gonococci. The estimated ID₅₀ (indicated by the horizontal dotted line) is 1.8 × 10³ cfu for MS11mkC and 1.0 × 10⁵ cfu for FA1090.

Figure 2

Population dynamics during experimental gonococcal infections. The schematic representation depicts an inoculating population that is predominantly composed of one combination of variable traits, represented by red in the first pie chart and the red trace in the graph below. Following the eclipse period during which few gonococci are recovered, new variants, indicated by different colors, emerge. The population of infecting gonococci becomes increasingly complex over time. The colors represent different phenotypic variants that could arise by phase and/or antigenic variation of opacity and pilin proteins and are based on previously reported observations (Jerse et al., ; Seifert et al., ; Wright et al., ; Hamrick et al., 2001) but are not intended to represent specific characteristics of actual reisolates from an experimental infection.

Figure 3

Potential influence of population dynamics on outcomes of mixed experimental infections. In (A), theoretical outcomes are shown for infections initiated by a 50:50 mixture of two isogenic strains differing in expression of a predicted virulence factor, depicted as black and white, under conditions with (bottom) and without (top) a population-restricting bottleneck early after inoculation. Potential outcomes consistent with and without a competitive advantage for the black strain are indicated as four patterns of pie charts representing populations of gonococci recovered from infected subjects. In (B), actual outcomes are shown for infections initiated by a 45:55 mixture of isogenic Tf+Lf− (white) and Tf+Lf+ (black) strains of N. gonorrhoeae FA1090 (Anderson et al., 2003). In patterns 1–3, each pie chart represents the mixture of gonococcal strains recovered from infected subjects over the 1- to 5-day period after inoculation. The ⊘ symbol indicates no gonococci were recovered at early times (1–3 days in different volunteers) after inoculation of four subjects.