Pseudaminic Acid on Campylobacter jejuni Flagella Modulates Dendritic Cell IL-10 Expression via Siglec-10 Receptor: A Novel Flagellin-Host Interaction

Abstract

Introduction. Campylobacter jejuni is a leading cause of bacterial gastroenteritis worldwide. At present the identity of host-pathogen interactions that promote successful bacterial colonisation remain ill defined. Herein, we aimed to investigate C. jejuni-mediated effects on dendritic cell (DC) immunity.Results. We found C. jejuni to be a potent inducer of human and murine DC interleukin 10 (IL-10) in vitro, a cellular event that was MyD88- and p38 MAPK-signalling dependent. Utilizing a series of C. jejuni isogenic mutants we found the major flagellin protein, FlaA, modulated IL-10 expression, an intriguing observation as C. jejuni FlaA is not a TLR5 agonist. Further analysis revealed pseudaminic acid residues on the flagella contributed to DC IL-10 expression. We identified the ability of both viable C. jejuni and purified flagellum to bind to Siglec-10, an immune-modulatory receptor. In vitro infection of Siglec-10 overexpressing cells resulted in increased IL-10 expression in a p38-dependent manner. Detection of Siglec-10 on intestinal CD11c+ CD103+ DCs added further credence to the notion that this novel interaction may contribute to immune outcome during human infection.Conclusions. We propose that unlike the Salmonella Typhimurium flagella-TLR5 driven pro-inflammatory axis, C. jejuni flagella instead promote an anti-inflammatory axis via glycan-Siglec-10 engagement.

Siglec-mediated regulation of immune cell function in disease

“…Besides expressing Siglec ligands on lipo-oligosaccharides, the flagella of C. jejuni display pseudaminic acid, a sugar highly related to sialic acid. A recent study demonstrated that Siglec-10 expressed on human DCs interacted with this sugar and triggered IL-10 production via unknown mechanisms 43 (Fig. 2f).…”

Siglecs at the Host–Pathogen Interface

“…These observations suggest that targeting distinct DC-expressed Siglecs may represent a potential strategy for manipulating Th cell differentiation programs and forestalling autoimmune disease post C. jejuni infection. In addition to modulating host DC functions via its sialylated LOS, C. jejuni triggers IL-10 production of DCs via engaging Siglec-10 through the pseudaminic acid residues on its flagella (Stephenson et al 2014). These abundant Sia and Sia-like C. jejuni surface structures (e.g.…”

Campylobacter jejuni Motility Is Required for Infection of the Flagellotropic Bacteriophage F341

“…Based on this criterion, we tested if phage F341 was able to form plaques on lawns of C. jejuni NCTC11168 cj1295, cj1316c, and cj1324 mutants that still are motile but lack specific flagellar glycans. The cj1295 mutant lacks the di-O-methyl glyceric acid derivative of Pse5Ac7Ac, and the cj1316c mutant flagellum lacks Pse5Ac7Am, while the cj1324 mutant lacks the derivatives Leg5Am7Ac, Leg5AmNMe7Ac, and Pse5Ac7Am (25,(63)(64)(65). Interestingly, we found that phage F341 could infect these mutants as efficiently as the wild-type strain (Table 3), hence showing that binding of phage F341 to C. jejuni is not dependent on Leg5Am7Ac, Leg5AmNMe7Ac, Pse5Ac7Am, or the di-O-methyl glyceric acid derivative of Pse5Ac7Ac.…”