Variation of Neisseria gonorrhoeae Lipooligosaccharide Directs Dendritic Cell–Induced T Helper Responses

Abstract

Gonorrhea is one of the most prevalent sexually transmitted diseases in the world. A naturally occurring variation of the terminal carbohydrates on the lipooligosaccharide (LOS) molecule correlates with altered disease states. Here, we investigated the interaction of different stable gonoccocal LOS phenotypes with human dendritic cells and demonstrate that each variant targets a different set of receptors on the dendritic cell, including the C-type lectins MGL and DC-SIGN. Neisseria gonorrhoeae LOS phenotype C constitutes the first bacterial ligand to be described for the human C-type lectin receptor MGL. Both MGL and DC-SIGN are locally expressed at the male and female genital area, the primary site of N. gonorrhoeae infection. We show that targeting of different C-type lectins with the N. gonorrhoeae LOS variants results in alterations in dendritic cell cytokine secretion profiles and the induction of distinct adaptive CD4+ T helper responses. Whereas N. gonorrhoeae variant A with a terminal N-acetylglucosamine on its LOS was recognized by DC-SIGN and induced significantly more IL-10 production, phenotype C, carrying a terminal N-acetylgalactosamine, primarily interacted with MGL and skewed immunity towards the T helper 2 lineage. Together, our results indicate that N. gonorrhoeae LOS variation allows for selective manipulation of dendritic cell function, thereby shifting subsequent immune responses in favor of bacterial survival.

Sialic acid-modified antigens impose tolerance via inhibition of T-cell proliferation and de novo induction of regulatory T cells

“…Although uptake of Sia-antigen by DCs in vitro did not result in expression of surface markers associated with "classic" tolerogenic DCs, DCs are clearly tolerogenic in function upon internalization of sialylated antigens. We previously observed a similar absence of clear effects on the phenotype of human monocyte-derived DCs after incubation with the highly sialylated pathogen Neisseria gonorrhea, although T-cell polarizing capacity was affected (16,27). Despite producing lower amounts of the proinflammatory cytokines IL-6 and TNF, we did not observe significant differences in the quantity of IL-10 or TGF-β produced by Sia-OVA-loaded DCs compared with OVA-loaded DCs.…”

Targeting of macrophage galactose‐type C‐type lectin (MGL) induces DC signaling and activation

“…hMGL is equipped with a partial dileucine zipper and with YENF internalization motifs [11]. This receptor is involved in the recognition of a large plethora of pathogens by DCs [12][13][14][15] and in the maintenance of T-cell homeostasis [16]. Moreover, in vivo, MGL appears to play a crucial role in close proximity of the endothelial structures of lymph nodes and thymus, where iDCs are hampered in their migration activity until maturation [6].…”

Development of Electrochemical Microbiochip for the Biological Diagnosis of Neisseria gonorrhoeae

“…31 For identification of N.G., we chose the porA pseudogene, based on previous studies; the amplified DNA region was 285 -384 nt (nucleotide number) in the porA pseudogene sequence. The specific probe for N.G.…”

“…32 PCR experiment was followed by conditions; pre-denaturation 95 C (300 s), 40 cycles (94 C, 20 s; 55 C, 30 s; 72 C, 60 s), and final synthesis 72 C (300 s). 31 A DNA microarray for identification of N.G.…”