Serum-resistant strains down-regulate complement activation on their surface by expressing PorB molecules that bind C4b-binding protein or factor H [21]. Phase

variation of glycosyltransferase genes can cause production of LOS species that are more resistant to bactericidal antibodies [22]. Survival of Gc within PMNs may prolong infection and increase dissemination and transmission and occurs by mechanisms not yet fully elucidated [23]. During acute infections, Gc induces a purulent exudate that consists of PMNs, exfoliated epithelial cells, and intracellular and extracellular Gc. The capacity of Gc to evade the inflammatory response is supported PI3K Inhibitor Library high throughput by the observation that Gc colonization levels are similar in BALB/c and C57/BL6 mice despite marked differences in vaginal PMN influx

[24]. Elevated proinflammatory cytokines and chemokines have selleck compound been detected in experimentally infected men [25], but not in naturally infected women unless coinfected with another STI pathogen [26]. In the mouse model Gc selectively induces Th17 cells, which leads to the recruitment of innate defense effectors including PMNs and results in faster clearance of infection [27]. Signaling through TLR4 is critical for Th17 responses in vitro [27] and in vivo [28], and colonization load is increased in TLR4-deficient mice [28]. Gonococcal LOS-mediated signaling through lectins such as DC SIGN induces cytokine production [29] and both PorB and the H.8 lipoprotein stimulate TLR2 leading to NF-κB activation, inflammatory cytokine production, and dendritic cell (DC) maturation [30] and [31].

Activation of NLRP3 inflammasomes in human Metalloexopeptidase monocytic cells or DCs by Gc results in the production of the inflammatory cytokines IL-1β and IL-18 and pyronecrosis of the cells [32] and [33] (Fig. 1). The adaptive response to Gc is ineffective as evidenced by the fact that repeat infections are common. The humoral response to uncomplicated Gc infections is poor. Quantitative evaluation of serum and local antibody responses in both female and male subjects presenting with uncomplicated cervicitis or urethritis showed at best only modest responses to antigens expressed by the homologous clinical isolates. Antibody responses were not sustained over the few weeks of follow-up, and there was no discernable memory arising from known prior episodes of infection [26] and [34]. These results are consistent with earlier reports by others (reviewed in [35]). Insights into the mechanisms by which Gc interferes with immune responses are being elucidated (Fig. 1). In mice, Gc suppresses the development of Th1- and Th2-driven adaptive immune responses by mechanisms dependent on TGF-β and IL-10 as well as type 1 regulatory T cells [36] and [37] (Liu et al., Mucosal Immunol, in press).