Abstract
Vaccine delivery is an essential element for the development of mucosal vaccine, but it remains to be investigated how physical barriers such as mucus and cilia affect vaccine delivery efficacy. Previously, we reported that C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE) targeted claudin-4, which is expressed by the epithelium associated with nasopharynx-associated lymphoid tissue (NALT), and could be effective as a nasal vaccine delivery. Mice lacking tubulin tyrosine ligase-like family, member 1 (Ttll1-KO mice) showed mucus accumulation in nasal cavity due to the impaired motility of respiratory cilia. Ttll1-KO mice nasally immunized with C-CPE fused to pneumococcal surface protein A (PspA-C-CPE) showed reduced PspA-specific nasal IgA responses, impaired germinal center formation, and decreased germinal center B-cells and follicular helper T cells in the NALT. Although there was no change in the expression of claudin-4 in the NALT epithelium in Ttll1-KO mice, the epithelium was covered by a dense mucus that prevented the binding of PspA-C-CPE to NALT. However, administration of expectorant N-acetylcysteine removed the mucus and rescued the PspA-specific nasal IgA response. These results show that the accumulation of mucus caused by impaired respiratory cilia function is an interfering factor in the C-CPE-based claudin-4-targeting nasal vaccine.
Highlights
Mucosal vaccines are used clinically to induce antigen-specific immune responses in mucosal tissue as the first line of defense against pathogens[1,2]
We found that nasally administered pneumococcal surface protein A (PspA), a surface protein expressed by Streptococcus pneumoniae, fused to C-terminus of Clostridium perfringens enterotoxin (CPE) (C-CPE) (PspA-C-CPE) preferentially bound to nasopharynx-associated lymphoid tissue (NALT), including to M cells, and induced PspA-specific immune responses in the systemic and respiratory compartments[11]
To examine whether airway mucociliary function affected the efficacy of the claudin-4-targeting nasal vaccine, we nasally immunized Ttll[1] mice with PspA-C-CPE once a week for three weeks
Summary
Antigen-specific nasal IgA response was decreased in Ttll1-KO mice nasally immunized with PspA-C-CPE. The percentages of GC B cells and Tfh cells were comparable between Ttll1-He and -KO mice with N-acetylcysteine treatment (Fig. 4c,d) These results indicate that the dense mucus produced by the Ttll1-KO mice impaired the nasal immune responses induced by PspA-C-CPE, and that the removal of the mucus by administration of an expectorant rescued the impaired nasal immune response. We elucidated the immunological role of airway mucociliary function with respect to delivery of a claudin-4-targeting nasal vaccine in Ttll1-KO mice, which possess straight rather than normal curved airway mucocilia due to impaired tubulin glutamylation, resulting in the loss of beating asymmetry and accumulation of a dense nasal mucus[14] This dense nasal mucus prevented the binding of PspA-C-CPE to NALT epithelium, leading to reduced PspA-specific nasal IgA responses together with impaired GC formation in the NALT. The present findings indicate that nasal mucus acts as a barrier against the delivery of nasal vaccines, and, that removal of nasal mucus is one approach to improve the efficacy of nasal vaccines
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