Does the Cervicovaginal Microbiome Facilitate Transmission ofNeisseria gonorrhoeaeFrom Women to Men? Implications for Understanding Transmission of Gonorrhea and Advancing Vaccine Development

This is the authors' abstract. We don't add key points for this paper.

(See the major article by Ketterer et al on pages 1621–8.) The successful infection of the male urethra by Neisseria gonorrhoeae is dependent upon the availability of a lipooligosaccharide (LOS) structure with a free terminal galactose necessary to bind the entry receptor, the asialoglycoprotein receptor (ASGP-R). In contrast, cervical cell uptake of the gonococcus by complement receptor 3 (CR3) is independent of the LOS sialylation state of the organism. During growth in both cervical and urethral epithelial cells, the organism acquires cytidine-monophosphate-N-acetylneuraminic acid (CMP-Neu5Ac; also known as “sialic acid”), which is transferred to the terminal galactose on the LOS. To facilitate transmission from female to the male, sialidases produced by cervicovaginal flora (eg, Gardnerella vaginalis and Prevotella bivia) remove the sialic acid from the gonococcal LOS. This modification allows transfer of N. gonorrhoeae to the male partner with a free terminal galactose, resulting in engagement of and uptake by the asialoglycoprotein receptor on the urethral epithelial cell. As background, a key modification of the N. gonorrhoeae cell surface that affects bacterial invasion of host cells involves the transfer of sialic acid to the terminal galactose of the α-chain of LOS (the N-acetyllactosamine region); this LOS modification also provides N. gonorrhoeae with the ability to resist complement-dependent killing by normal human serum. Relevant to host cell invasion, sialylation of N. gonorrhoeae LOS influences sex-specific host epithelial cell invasion. Sialylation of LOS, first described by the late Sir Harry Smith and colleagues [8], occurs within both male and female epithelial cells (Figure 1). Transfer of sialic acid from cytidine-monophosphate-N-acetylneuraminic acid (hereafter, “sialic acid”) to the terminal galactose occurs through the action of the N. gonorrhoeae–encoded α2,3-sialyltransferase; N. gonorrhoeae does not have the capacity to synthesize sialic acid and relies on intracellular stores for this modification of the LOS. While a number of past studies have concentrated on the enzymatic properties of this reaction and the biologic consequences of sialylation of LOS, little is known about the importance of this modification during transmission of N. gonorrhoeae between the sexes. The work of Ketterer et al presented herein strongly suggests that, during cevicovaginal infection, bacteria in the female microbiome provide sialidases that remove sialic acid from the terminal galactose of the N. gonorrhoeae LOS N-acetyllactosamine region prior to transmission of the bacteria to a male partner. This action would render N. gonorrhoeae ready to engage urethral epithelial cells via the asialoglycoprotein receptor (Figure 1); this receptor only binds N. gonorrhoeae lacking sialic acid attached to the N-acetyllactosamine–bearing LOS. Briefly, their work, which used a combination of biochemical and immunologic assays that permitted discrimination of sialylated versus nonsialylated LOS, revealed that cervicovaginal secretions from women reporting to sexually transmitted diseases clinics contained higher levels of sialidases than samples from uninfected (control) women or urethral exudates from N. gonorrhoeae–infected male partners. Importantly, increased levels of sialidases were correlated with elevated levels of certain bacteria (Gardnerella vaginalis, Megasphaera species, or Prevotella bivia) in the microbiome associated with bacterial vaginosis (BV). Relevant to this finding, it was known from work reported >20 years ago [9] that vaginal secretions from women with BV contain sialidases and proteases. Thus, an unhealthy cervicovaginal microbiome (eg, one in which BV is present) could provide the sialidases that promote transmission of N. gonorrhoeae to a male partner. In short, the findings have a number of important ramifications that will influence our thinking of transmission of N. gonorrhoeae between the sexes and the development of a protective vaccine against gonorrhea. First, bacteria within the microbiome of patients with BV may provide a helping hand in transmitting N. gonorrhoeae to men; hence, effective BV treatment regimens may help reduce the spread of gonorrhea in the community. Second, we now have a mechanism to explain how N. gonorrhoeae can be modified within an infected female so as to maximize transmission of a population of N. gonorrhoeae that are ready to attach to the asialoglycoprotein receptor on the target male urethral epithelia (Figure 1). While desialylation of LOS may increase the susceptibility of N. gonorrhoeae to complement-mediated killing, this potential disadvantage may be counteracted by antigenic variation systems that provide resistance to serum killing [10]. Third, in addition to known processes that promote chameleon behavior of N. gonorrhoeae (see above), we can now add sialidases of the microbiome to the list. In theory, removal of the terminal sialic acid would present an LOS structure (N-acetyllactosamine) mimicking host glycosphingolipids. The concept that one microbe can modify the surface of another is not new, as evidenced by the earlier report that pneumococcal sialidases can desialylate LOS from N. meningitidis and Haemophilus influenzae [11]. Thus, while considerable effort has been invested in recent years in defining human microbiomes, it is clear that future research also be directed to understanding how bacterial species within such communities influence the biology of pathogens. Finally (and perhaps most importantly), the results presented by Ketterer et al and in earlier work [9] emphasize that the microbiome can directly influence the cell surface chemistry of coresident pathogens and influence their infectivity. This final point has significance for the renewed interests of several groups [5] directed toward developing a protective vaccine against gonorrhea. The presence of sialidases and proteases in cervicovaginal secretions could alter the vaccine targets on the surface of N. gonorrhoeae during infection. Accordingly, it is imperative that vaccine discovery and development efforts evaluate the presence and availability of candidate antigens of N. gonorrhoeae in samples cultured directly from women (and men), as they may be significantly different in sexually exchanged fluids than what is observed when N. gonorrhoeae is grown in laboratory medium, Thus, sensitive, microscale proteomic and glycomic approaches must be developed, refined, and used to critically address antigen integrity on N. gonorrhoeae in secretions from infected humans if a gonorrhea vaccine is to become a reality. In this era of emergence of N. gonorrhoeae strains resistant to frontline antibiotics [1, 2], it is imperative that such efforts are successful. Disclaimer. The contents of this article is solely the responsibility of the author and do not necessarily reflect the official views of the Department of Veterans Affairs, the National Institutes of Health, or the US government. Financial support. This work was supported by the National Institutes of Health (grants R37 AI021150, R21 AI 103270, U01 AI114378, and U19 AI113170 to W. M. S.) and the Biomedical Laboratory Research and Development Service of the Department of Veterans Affairs (VA Merit Award 510 1BX000112-07 and Senior Research Career Scientist Award to W. M. S.). Potential conflict of interest. The author: No reported conflicts. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.