Association of Neisseria gonorrhoeae OpaCEA with Dendritic Cells Suppresses Their Ability to Elicit an HIV-1-Specific T Cell Memory Response

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.

Invasive Salmonella exploits divergent immune evasion strategies in infected and bystander dendritic cell subsets

“…The defective T cell costimulatory capacity of CD83 -/low STM-D23580-infected MoDCs is consistent with the observation that specific siRNA-mediated knockdown of CD83 has a marked effect on the capacity of MoDCs to stimulate T cell responses 46 . MoDCs infected with the Opa CEA -expressing strain of Neisseria gonorrhoeae did not display any surface expression of CD83 and showed a reduced capacity to stimulate an allogeneic T cell proliferative response 52 . Other pathogens that establish latency, such as herpes simplex virus type 1 (HSV-1), human cytomegalovirus (HCMV) and vaccinia virus, adopt different strategies to interfere with CD83 expression on the surface of infected MoDCs.…”

Specific Binding to Differentially Expressed Human Carcinoembryonic Antigen-Related Cell Adhesion Molecules Determines the Outcome of Neisseria gonorrhoeae Infections along the Female Reproductive Tract

“…Additionally, Opa binding to CEACAM1, CEACAM5, or CEACAM6 can trigger intracellular signaling cascades that stimulate integrin-mediated focal adhesions in epithelial cells, which prevents normal shedding of infected mucosal cells (20,24). Furthermore, CEACAM1 has also been reported to depress the proinflammatory response of infected epithelia (25) and suppress the leukocytic activities necessary for the induction of an adaptive immune response (16,(26)(27)(28)(29), which would presumably provide a means for the infection to go undetected. Given these important functions, CEACAMs are generally considered to be important for facilitating mucosal colonization by N. gonorrhoeae.…”

Selection for a CEACAM Receptor-Specific Binding Phenotype during Neisseria gonorrhoeae Infection of the Human Genital Tract

“…In the female genital tract, squamous epithelia express CEACAM5, whereas CEACAM1 is expressed on columnar epithelia of the endocervix and uterus (27), allowing each to be accessible for direct docking by the gonococci. Moreover, CEACAM1 is widely expressed on lymphocytes, and CEACAM1-induced signaling can influence immune cell activation (28)(29)(30)(31)(32)(33)(34)(35), potentially providing a mechanism for immune evasion by N. gonorrhoeae. While no study to date has looked at CEACAM expression within the male urethra, a transgenic mouse line expressing human CEACAMs in a manner that closely reflects the spatiotemporal expression pattern in humans expresses CEACAM5 on the urethral mucosal surface (36).…”