REVIEW ARTICLE published: 3 May 2011 doi: 10.3389/fmicb.2011.00123 Experimental gonococcal infection in male volunteers: cumulative experience with Neisseria gonorrhoeae strains FA1090 and MS11mkC Marcia M. Hobbs 1,2 *, P. Frederick Sparling 1,2 , Myron S. Cohen 1,2 , William M. Shafer 3,4 , Carolyn D. Deal 5 and Ann E. Jerse 6 1 Departments of Medicine, University of North Carolina, Chapel Hill, NC, USA 2 Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA 3 Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA 4 Laboratories of Bacterial Pathogenesis,Veterans Affairs Medical Center (Atlanta), Decatur, GA, USA 5 National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA 6 Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA Edited by: Cynthia N. Cornelissen, Virginia Commonwealth University School of Medicine, USA Reviewed by: Stanley Spinola, Indiana University–Purdue University at Indianapolis, USA Catherine Ann Ison, Health Protection Agency, UK *Correspondence: Marcia M. Hobbs, Department of Medicine, University of North Carolina, CB# 7031, Chapel Hill, NC 27599, USA. e-mail: mmhobbs@med.unc.edu Experimental infection of male volunteers with Neisseria gonorrhoeae is safe and repro- duces 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 ure- thral 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, pathogenesis, infection, urethritis INTRODUCTION In nature, gonococcal infection is strictly limited to the human host. Uncomplicated infection can be asymptomatic or mani- fest as urethritis in men and cervicitis in women. Complications resulting from tissue invasion include orchitis, epididymitis and pelvic inflammatory disease, and systemic dissemination can lead to arthritis, tenosynovitis, or dermatitis. Like other inflamma- tory mucosal infections, gonorrhea also facilitates HIV transmis- sion and acquisition. Treatment options for gonococcal infection are dwindling as worldwide, Neisseria gonorrhoeae is becoming increasing resistant to currently available antibiotics (Lewis, 2010). Experimental human urethral infection offers the potential to bet- ter understand the contributions of microbial factors and host immune responses to infection that may eventually translate into the development of an effective gonococcal vaccine and provides an appropriate model for vaccine testing. The use of live N. gonorrhoeae to cause experimental infection has a long and sometimes sordid history dating back to the late eighteenth century when British surgeon John Hunter repeatedly inoculated patients with “venereal matter” to test whether venereal disease was infectious (Hunter, 1835). Recent reports of experi- mental gonorrhea studies conducted during the 1940s in vulner- able populations who were often deceived and infected without informed consent highlight the ethical issues that surround clini- cal research with human subjects (Frieden and Collins, 2010); the issues are particularly sensitive for experimental human infections with sexually transmitted pathogens. All of the studies described herein were subject to rigorous safety and ethical review by appro- priate Institutional Review Boards. Written informed consent was obtained from all subjects in accordance with the ethical principles set forth in the Declaration of Helsinki and the US Code of Federal Regulations for the Protection of Human Subjects. Several hun- dred subjects have participated in experimental infection studies without reported complications or adverse events. EXPERIMENTAL MODEL Experimental gonorrhea is restricted to male subjects; women cannot safely be included due to potential complications from ascendant gonococcal infection. Inoculation is accomplished by the instillation of 0.2–0.3 mL of a gonococcal suspension through a pediatric catheter inserted approximately 5 cm into the ure- thra. There are slight variations in the preparation and delivery of experimental inocula used in previously published work detailed by Cohen and Cannon (1999), Cohen et al. (1994), and Schmidt et al. (2001). Following inoculation, infection can be monitored by bacterial recovery from urogenital specimens including urine, urethral swabs and semen. Gonococcal urethritis is defined by the development of urethral discharge containing gram negative diplococci or recovery of gonococci from a urethral swab culture. Host responses can be monitored by enumeration of white blood cells in urine and urethral exudates and measurement of soluble immune mediators including antibodies and cytokines in urine www.frontiersin.org May 2011 |Volume 2 | Article 123 | 1 1