Proteomics of Neisseria gonorrhoeae: the treasure hunt for countermeasures against an old disease

Abstract

Neisseria gonorrhoeae is an exquisitely adapted, strictly human pathogen and the causative agent of the sexually transmitted infection gonorrhea. This ancient human disease remains a serious problem, occurring at high incidence globally and having a major impact on reproductive and neonatal health. N. gonorrhoeae is rapidly evolving into a superbug and no effective vaccine exists to prevent gonococcal infections. Untreated or inadequately treated gonorrhea can lead to severe sequelae, including pelvic inflammatory disease and infertility in women, epididymitis in men, and sight-threatening conjunctivitis in infants born to infected mothers. Therefore, there is an immediate need for accelerated research toward the identification of molecular targets for development of drugs with new mechanisms of action and preventive vaccine(s). Global proteomic approaches are ideally suited to guide these studies. Recent quantitative proteomics (SILAC, iTRAQ, and ICAT) have illuminated the pathways utilized by N. gonorrhoeae to adapt to different lifestyles and micro-ecological niches within the host, while comparative 2D SDS-PAGE analysis has been used to elucidate spectinomycin resistance mechanisms. Further, high-throughput examinations of cell envelopes and naturally released membrane vesicles have unveiled the ubiquitous and differentially expressed proteins between temporally and geographically diverse N. gonorrhoeae isolates. This review will focus on these different approaches, emphasizing the role of proteomics in the search for vaccine candidates. Although our knowledge of N. gonorrhoeae has been expanded, still far less is known about this bacterium than the closely related N. meningitidis, where genomics- and proteomics-driven studies have led to the successful development of vaccines.

Antimicrobial Resistance Expressed by Neisseria gonorrhoeae : A Major Global Public Health Problem in the 21st Century

“…In parallel to ongoing research on new antimicrobials to treat gonorrhea, it is important to note that after years of relative stagnation the quest for a gonococcal vaccine that would protect humans from infection or reduce the severity of disease has been rejuvenated and target antigens are now being pursued in pre-clinical vaccine studies (162). Additionally, high-throughput genomics, metabolomics, methylomics, transcriptomics, proteomics and other novel molecular technologies and approaches will revolutionize future research aimed at improving diagnostics, antimicrobial resistance detection and vaccine development (162–165). Given the remarkable history of the evolution of antibiotic resistance displayed by gonococci, how resistance has changed treatment regimens over the past 80 years, the relative dearth of new antimicrobials in the pharmaceutical pipeline that will soon be available in the clinic and the lack of a vaccine to prevent gonorrhea, there is every reason to be concerned that this STI will continue to be a major global public health problem in the 21 st century.…”

Proteomics-driven Antigen Discovery for Development of Vaccines Against Gonorrhea

“…Gonorrhea vaccine development can therefore benefit from a comprehensive, unbiased approach for antigen discovery. The application of comparative proteomics described in this study, together with previous comprehensive analyses of the N. gonorrhoeae cell envelopes and MVs (21), as well as other global proteomic approaches are ideally suited for identifying promising N. gonorrhoeae antigens and to guide future gonorrhea vaccine development (102). These newly identified cell envelope-associated proteins can then be subjected to rigorous evaluation that includes their expression as recombinant proteins in E. coli, examination of their surface localization and conservation among temporally, geographically, and genetically diverse panels of gonococcal strains, assessment of their ability to induce antibodies that react against heterologous N. gonorrhoeae strains and are bactericidal, functional characterization, identification of protective epitopes, testing different combinations of antigens with various adjuvants and routes of immunization, as well as their protective capabilities in the gonorrhea mouse models.…”

Deciphering the Function of New Gonococcal Vaccine Antigens Using Phenotypic Microarrays

“…Critically, vaccination with FA1090-derived membrane vesicles protects from challenges with the commonly used laboratory strains MS11 and FA19, as well as recent clinical isolates GC68 and GC69 (15). Using proteomics-based reverse vaccinology (16), we have investigated the composition of N. gonorrhoeae cell envelopes and naturally released membrane vesicles across common laboratory strains, including FA1090, MS11, and FA19 (6), as well as FA1090 cell envelopes under four different host-relevant growth conditions (5) to identify vaccine candidate targets. Among the ubiquitously expressed proteins in four examined isolates were novel vaccine candidates NGO2121, NGO1985, NGO2054, NGO2111, NGO1205, and NGO1344 (5,6), with predicted functions associated with cell envelope homeostasis.…”