MucoVac · Unravelling the mode of action of mucosal adjuvants
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2016-09-01 → 2018-08-31
- EU contribution
- €185,076
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Unravelling the mode of action of mucosal adjuvants
Background: Flagellin, a TLR5 agonist, is a leading candidate that is being developed as a potent adjuvant in mucosal vaccines. Interestingly, the mechanism that drive the adjuvant activity of flagellin is influenced by the route of administration. Recent results have suggested that cross talk between epithelial cells and mucosal dendritic cells drives flagellin's adjuvant activity. The present project aims at identifying (i) signals from flagellin-stimulated epithelial cells that are of paramount importance in the transactivation of dendritic cells, (ii) how these dendritic cells condition T lymphocytes to produce specific mucosal immune responses. Results: In this study, we sought to investigate how the lung epithelial cells regulate the mucosal adjuvanticity of flagellin. The data suggests that the lung epithelial cells sense recombinant S. typhimurium flagellin to trigger the release of GM-CSF, in a TLR5 dependent fashion. Furthermore, the flagellin driven release of GM-CSF, in the lung, enhance the recruitment of activated type 2 conventional dendritic cells (cDC2s) to the lung draining lymph node. In addition, neutralizing GM-CSF modulates the functions of lung cDC2 that result in diminished antigen specific CD4+ T cell driven antibody response thus effecting flagellin’s mucosal adjuvanticity. Conclusion: Our data indicate that the lung epithelial cell derived GM-CSF orchestrates the cross talk between cDC2 and CD4+ T cells to drive the mucosal adjuvant effect of flagellin. This study provides new insight into the role of epithelial cells in activating dendritic cells to promote adjuvant effect of flagellin and opens up new avenues in the development of better, safer adjuvants. ***The manuscript is in preparation for submission to the journal ''Mucosal Immunology''
Data: CORDIS, © European Union
Project objective
The development of new vaccines against infectious diseases is a major worldwide public health objective. Despite the availability of antimicrobial therapies, vaccines still constitute the most effective means of controlling infections. Adjuvants are crucial for increasing the onset, magnitude, diversity and memory of immune responses to vaccines. Whereas a range of adjuvants is available for conventional vaccination routes, there are currently no mucosal adjuvants for promoting the neutralization of respiratory, gastrointestinal or urogenital infections at the pathogens' port of entry. This proposal will focus on (i) performing innovative research on mucosal adjuvants' mode of action and (ii) catalysing the mid-term development of novel, safe, efficient vaccines for nasal or oral administration.Adjuvants that specifically target Toll-like receptors are efficacious in mucosal vaccination because they trigger mucosal immunity (including secretory antibodies). The host laboratory has a longstanding research programme on the mucosal adjuvant activity of a Toll-like receptor 5 agonist (namely flagellin). Recent results have suggested that cross talk between epithelial cells and mucosal dendritic cells drives flagellin's adjuvant activity. The present project aims at identifying (i) signals from flagellin-stimulated epithelial cells that are of paramount importance in the transactivation of dendritic cells, (ii) dendritic cell factors that condition T and B lymphocytes to produce specific mucosal immune responses, and (iii) unique features of memory responses in the mucosa. This proposal will provide unprecedented opportunities for characterizing mucosal adjuvants. Moreover, better knowledge of the mechanism underlying flagellin's action would not only shed light on the latter's properties but also aid the development of better, safer adjuvants. The overall objective is to generate significant new insights into the field of adjuvants and vaccines.
Original text from CORDIS.
Participants
- UNIVERSITE DE LILLE · LilleCoordinatorFrance
Links
Data: CORDIS, © European Union