LOSoligosaccharide modification enhances dendritic cell responses to meningococcal native outer membrane vesicles expressing a non‐toxic lipidA

Abstract

SummaryOuter membrane vesicles (OMV) are released by many bacteria, and contain immunogenic antigens in addition to harmful inflammatory factors, like lipopolysaccharides. Chemically detoxified OMV have been used in vaccines against Neisseria meningitidis (Nm); however, little is known about their interaction with antigen presenting cells. In this study, we investigated the interaction of Nm OMV with human dendritic cells (DC) to gain further understanding of their biological activity. We engineered a novel serogroup B Nm that is unencapsulated (siaD), expresses pentacylated lipid A (lpxL1), hence conferring reduced toxicity, and expresses an lgtB oligosaccharide structure designed to target OMV to DC via DC-SIGN. We show that the lgtB moiety is critical for internalization of NOMV by DC. Furthermore, the lgtB moiety significantly enhances DC maturation, IL-10 and IL-23 production in the presence of a pentacylated lipid A. While different DC phenotypes were observed for each NOMV, this had little effect on Th1 and Th2 cell differentiation; however, lgtB significantly increased Th17 cell expansion in the presence of pentacylated lipid A. We believe that lpxL1/lgtB NOMV should be considered further as a vaccine vector, particularly considering the importance of lgtB in antigen uptake and further human studies on antigen-specific responses should be considered.

Characterization and Vaccine Potential of Outer Membrane Vesicles Produced by Haemophilus parasuis

“…Interestingly, production of the anti-inflammatory cytokine IL-10 by AMac was not significantly increased in comparison to live bacteria for any of the Nagasaki vesicles tested (liquid, plate or sonicate). This finding is in contrast to results previously seen by other researchers stimulating host dendritic cells with OMV isolated from Neisseria meningitidis , in which significant production of IL-10 was observed [ 68 ]. This may indicate that cell types are differentially effected by OMV (alveolar macrophages versus dendritic cells), that the observed level of stimulation is the maximum for the concentration of OMV used, or alternatively, that the live bacteria are somehow able to stimulate an IL-10 response [ 69 ], but OMV does not (lowering the immune response).…”

Lipopolysaccharide Engineering in Neisseria meningitidis

“…It has been shown that lgtB oligosaccharide truncation can significantly increase internalization of OMVs by human dendritic cells as compared with wild-type or galE truncated oligosaccharides (37). Moreover, the presence of lgtB truncated oligosaccharide in OMVs improved human DC maturation, IL-10, and interleukin-23 production by human DC and increased Th17 cell expansion (37).…”

Outer membrane vesicle vaccines

“…In E. coli, Shigella and Salmonella these enzymes are encoded by msbB (lpxM), htrB (lpxL) and pagP, which respectively add a myristoyl, lauroyl or palmitoyl group to the lipid A [51][52][53][54]. In Neisseria meningitidis, secondary acylation of lipid A is performed by lpxL1 and lpxL2 [55][56][57][58][59][60][61].…”