Abstract
Infection with Neisseria gonorrhoeae (N. gonorrhoeae) can trigger an intense local inflammatory response at the site of infection, yet there is little specific immune response or development of immune memory. Gonococcal surface epitopes are known to undergo antigenic variation; however, this is unlikely to explain the weak immune response to infection since individuals can be re-infected by the same serotype. Previous studies have demonstrated that the colony opacity-associated (Opa) proteins on the N. gonorrhoeae surface can bind human carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1) on CD4+ T cells to suppress T cell activation and proliferation. Interesting in this regard, N. gonorrhoeae infection is associated with impaired HIV-1 (human immunodeficiency virus type 1)-specific cytotoxic T-lymphocyte (CTL) responses and with transient increases in plasma viremia in HIV-1-infected patients, suggesting that N. gonorrhoeae may also subvert immune responses to co-pathogens. Since dendritic cells (DCs) are professional antigen presenting cells (APCs) that play a key role in the induction of an adaptive immune response, we investigated the effects of N. gonorrhoeae Opa proteins on human DC activation and function. While morphological changes reminiscent of DC maturation were evident upon N. gonorrhoeae infection, we observed a marked downregulation of DC maturation marker CD83 when the gonococci expressing CEACAM1-specific OpaCEA, but not other Opa variants. Consistent with a gonococcal-induced defect in maturation, OpaCEA binding to CEACAM1 reduced the DCs’ capacity to stimulate an allogeneic T cell proliferative response. Moreover, OpaCEA-expressing N. gonorrhoeae showed the potential to impair DC-dependent development of specific adaptive immunity, since infection with OpaCEA-positive gonococci suppressed the ability of DCs to stimulate HIV-1-specific memory CTL responses. These results reveal a novel mechanism to explain why infection of N. gonorrhoeae fails to trigger an effective specific immune response or develop immune memory, and may affect the potent synergy between gonorrhea and HIV-1 infection.
Highlights
Gonorrhea, caused by the Gram-negative intracellular diplococcus Neisseria gonorrhoeae (N. gonorrhoeae), is one of the most prevalent sexually transmitted diseases (STDs) of humans, with over 88 million new cases reported globally each year
Flow cytometric analysis using monoclonal antibody (mAb) D14HD11, which detects the extracellular domain of human carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1), showed that immature MDDCs (iMDDCs) expressed low, but detectable levels of CEACAM1 on the cell surface (Fig. 1A), which is consistent with the previous observation that mouse dendritic cells (DCs) express CEACAM1 [25]
Considering that binding occurred without Opa or pilus adhesin expression, we investigated whether N. gonorrhoeae or E. coli bound to iMDDCs through the surface molecule DC-SIGN, which structurally contains a mannan-binding lectin domain [58,59]
Summary
Gonorrhea, caused by the Gram-negative intracellular diplococcus Neisseria gonorrhoeae (N. gonorrhoeae), is one of the most prevalent sexually transmitted diseases (STDs) of humans, with over 88 million new cases reported globally each year (http:// whqlibdoc.who.int/hq/2011/WHO_RHR_11.14_eng.pdf). N. gonorrhoeae infection initiates with the physical attachment of the bacterial surface appendages called pili to the apical side of the host mucosal cells [1,2]. This loose attachment is followed by a more intimate association involving integral outer membrane protein adhesins, including the colony opacity-associated (Opa) proteins on the bacterial surface [3,4]. A minority of Opa variants can bind to heparan sulfate proteoglycans (HSPG) [7,8,9], the majority of Opa proteins characterized to date target members of the carcinoembryonic antigen-related cellular adhesion molecule (CEACAM) family of receptors [10,11,12,13,14,15], which are expressed on various epithelial and endothelial tissues, and on immune cells [16,17,18]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
