M cell–targeting strategy enhances systemic and mucosal immune responses induced by oral administration of nuclease-producing L. lactis
Efficient delivery of antigens to the gut-associated lymphoid tissue (GALT) is the most critical step for the induction of mucosal immunity by oral vaccines. As M cells are the main portal for luminal antigens into the GALT, the M cell-targeting of antigens affords a promising strategy toward the development of effective oral vaccines. Lactococcus lactis is a fascinating recombinant host for oral vaccines, as they survive and produce antigens in the gut and have a particularly safe profile for human use. In this study, we developed and evaluated an M cell–targeting oral immunization system using recombinant L. lactis strains. For the purpose, we generated an L. lactis strain that secretes a model antigen fused with the OmpH β1α1 domain of Yersinia enterocolitica, which has been shown to bind to a complement C5a receptor on the M cell surface. As the model antigen, Staphylococcus aureus nuclease was used for fusion, resulting in L. lactis–expressing Nuc-OmpH (LL/Nuc-OmpH). Ex vivo intestinal loop assays showed that the amount of Nuc-OmpH taken up into Peyer’s patches was more than that of the unfused nuclease (Nuc). In addition, oral administration of the recombinant L. lactis strains to mice demonstrated that LL/Nuc-OmpH-induced nuclease-specific fecal IgA and serum IgG titers were significantly higher than those induced by LL/Nuc. These results indicate that OmpH works as an M cell–targeting molecule when fused with antigens secreted from L. lactis and that the M cell–targeting strategy affords a promising platform for L. lactis–based mucosal immunization.
KeywordsLactococcus lactis Oral immunization OmpH M cell Peyer’s patch NICE system
This study was supported by a Grant-in-Aid for Young Scientists B (JP 16K19127) from the Japan Society for the Promotion of Science to KT and by a scholarship fund from the Lactic Acid Bacteria Foundation to NI.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All animal experiments were approved by the institutional Animal Care and Use Committee (approval number for ligated intestinal loop assay: 2017-236, and for immunization of mice: 2017-242).
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