Neisseria gonorrhoeae Suppresses Dendritic Cell-Induced, Antigen-Dependent CD4 T Cell Proliferation

Abstract

Neisseria gonorrhoeae is the second most common sexually transmitted bacterial pathogen worldwide. Diseases associated with N. gonorrhoeae cause localized inflammation of the urethra and cervix. Despite this inflammatory response, infected individuals do not develop protective adaptive immune responses to N. gonorrhoeae . N. gonorrhoeae is a highly adapted pathogen that has acquired multiple mechanisms to evade its host's immune system, including the ability to manipulate multiple immune signaling pathways. N. gonorrhoeae has previously been shown to engage immunosuppressive signaling pathways in B and T lymphocytes. We have now found that N. gonorrhoeae also suppresses adaptive immune responses through effects on antigen presenting cells. Using primary, murine bone marrow-derived dendritic cells and lymphocytes, we show that N. gonorrhoeae -exposed dendritic cells fail to elicit antigen-induced CD4+ T lymphocyte proliferation. N. gonorrhoeae exposure leads to upregulation of a number of secreted and dendritic cell surface proteins with immunosuppressive properties, particularly Interleukin 10 (IL-10) and Programmed Death Ligand 1 (PD-L1). We also show that N. gonorrhoeae is able to inhibit dendritic cell- induced proliferation of human T-cells and that human dendritic cells upregulate similar immunosuppressive molecules. Our data suggest that, in addition to being able to directly influence host lymphocytes, N. gonorrhoeae also suppresses development of adaptive immune responses through interactions with host antigen presenting cells. These findings suggest that gonococcal factors involved in host immune suppression may be useful targets in developing vaccines that induce protective adaptive immune responses to this pathogen.

Mutation of the Conserved Calcium-Binding Motif in Neisseria gonorrhoeae PilC1 Impacts Adhesion but Not Piliation

“…In addition, this pathogen manipulates the host's immune defenses by evading the adaptive immune response and recruiting neutrophils to serve as a protective niche for further colonization (4)(5)(6)(7). One mechanism that N. gonorrhoeae uses during early colonization is adherence to human cervical epithelial cells prior to the formation of microcolonies on the cell surface (8).…”

Could Vaccination Against Neisseria Gonorrhoeae be on the Horizon?

“…The first of these, is the recent findings that N. gonorrhoeae proactively manipulates the host immune response for its own benefit, by selectively eliciting innate host defenses that it can survive while concomitantly suppressing adaptive immune responses that would eliminate it [11]. Several mechanisms have been described that contribute to this ability, including inactivation of T-helper cells [12], modulation of dendritic cells or macrophages [13,14] and upregulation of IL-10, TGF-β and type 1 regulatory T cells [15]. These findings reveal new understandings of immunity to N. gonorrhoeae and suggest that novel approaches to reverse gonococcus-induced immunosuppression might be fruitful; moreover they inform new strategies for vaccine development.…”

Animal Models of Immunity to Female Genital Tract Infections and Vaccine Development

“…A female mouse model is now available and has been useful for studying N. gonorrhoeae adaptation to the female genital tract , signaling through innate receptors Packiam et al, 2014), and the relationship between antibiotic resistance and fitness (Kunz et al, 2012;Warner et al, 2008). The mouse model has also been used to identify protective and immunosuppressive pathways Liu et al, , 2013Packiam et al, 2014, Zhu et al, 2012 and to accelerate the development of therapeutic and prophylactic products against gonorrhea (Gulati et al, 2013;Plante et al, 2000;Spencer et al, 2004;Zeitlin et al, 2001;Zhu et al, 2011). Known host restrictions that limit the capacity of female mice to mimic gonorrhea in humans include the absence of human-specific receptors for adherence and invasion pathways, human transferrin and lactoferrin glycoproteins, soluble regulators of the complement cascade (factor H, C4b-binding protein), and IgA1, the substrate of gonococcal IgA1 protease (extensively reviewed in Jerse et al (2011)).…”

“…Activation of NLRP3 inflammasomes in human monocytic cells or DCs also results in the production of the inflammatory cytokines IL-1β and IL-18 (Zhu et al, 2012;Duncan et al, 2009). TLR4 was shown to control colonization as evidenced by significantly fewer gonococci recovered from wild-type BALB/c (TLR4lps n ) mice versus BALB/c mice with the defective TLR4lps d allele.…”

“…Several mechanisms have been identified by which N. gonorrhoeae may evade specific antibodies, including antigenic variation of surface antigens, expression of blocking antigens, production of IgA1 protease, molecular mimicry, retreat into epithelial cells, and blebbing of membranes to create a decoy (Cohen and Sparling, 1992). However, because the humoral immune response to infection is transient and the titer of specific antibody in serum and genital secretions is undetectable or not remarkable (Hedges et al, 1999;Ison et al, 1986;Kearns et al, 1973;McMillan et al, 1979;O'Reilly et al, 1973), investigations of the immunological basis by which N. gonorrhoeae suppresses the adaptive response have been undertaken more recently (Boulton and Gray-Owen, 2002;Duncan et al, 2009;Zhu et al, 2012;Pantelic et al, 2005;Normark et al, 2002). Several mechanisms of immunosuppression have been identified in cell culture systems, including induction of apoptosis in APCs through the NLRP3 inflammasome pathway ) and inhibition of DC-induced proliferation of T cells (Zhu et al, 2012) (Figure 2).…”