Neisseria gonorrhoeae (gonococci, GC) cause gonorrhea and pelvic inflammatory disease (PID). Studies show that gonorrhea can facilitate infection of both HIV and Chlamydia trachomatis (CT). The infection results from the ability of the pathogens to adhere to and penetrate host cells. However, little is known about whether the host immune responses play a role in GC infection. To establish infection, bacteria must interact with receptors on host cells. The opacity (Opa) proteins of GC mediate adherence and phagocytosis in epithelial cells and neutrophils in part through interaction with members of the carcinoembryonic antigen family (CEA, CEACAM, or CD66), CEACAM3 (CD66d) and CEACAM1 (CD66a). CEACAM1 is an inhibitory receptor, which mediates negative signals in DT40 B cells. The biological functions of inhibitory receptors are the inhibition of phagocytic ability of cells and proliferation as well as antibody production in B cells. Neutrophils and lymphocytes play a critical role in protection against infectious bacteria. Consistent with our ? preliminary data that GC inhibits the production of antibodies in human B cells in vitro, local and systemic anti-GC antibody levels in gonorrhea patients with a history of prior infection are low, suggesting that GC might inhibit local host immune responses. In the proposed research, we hypothesize that local immune inhibition mediated by GC infection may be achieved through the following two events: 1). GC binds to neutrophils and inhibits their ability to phagocytose microorganisms. 2). GC enters the host and binds to CEACAM1 on B cells to activate inhibitory pathways, and consequently inhibits lymphocyte proliferation and antibody production. We expect that signal transduction is involved in these events. Therefore, we propose these specific aims to: 1. Determine whether GC inhibits the phagocytic ability of neutrophils. 2. Elucidate how the interaction of CEACAM1 with GC inhibits antibody production. 3. Identify CEACAM3 and CEACAMl-mediated signal transduction pathways following infection with GC. The proposed research will begin to unveil the potential mechanisms of antibody suppression, which consequently play a role in the GC induced immuno-suppression during infection. We believe that these studies will uncover some mechanisms of GC infection and will help us to understand how microbial pathogens exploit host cells. This ? knowledge will allow us to develop novel strategies to combat other infectious diseases. ? ?
| Pantelic, Milica; Kim, Young-June; Bolland, Silvia et al. (2005) Neisseria gonorrhoeae kills carcinoembryonic antigen-related cellular adhesion molecule 1 (CD66a)-expressing human B cells and inhibits antibody production. Infect Immun 73:4171-9 |
