Alum is the only adjuvant approved for routine use in human vaccination although the basis for its adjuvanticity remains poorly understood. We have recently demonstrated that Alum activates caspase-1 and induces secretion of mature Interleukin-12 (IL-12) and IL-18. Our preliminary results also show that caspase-1 activation and stimulation of IL-12 secretion by Alum is dependent on the protein ASC, an adaptor molecule used by several Nod-Like receptors (NLR), suggesting that members of this family may mediate Alum's immunostimulatory effects. NLR are pattern recognition receptors that recognize microbial products situated in the cytoplasm. Several NLR are part of a multiproteins complex called inflammasome that also contains the adaptor ASC and caspase-1, the protease required for processing and secretion of IL-12 and IL-18. Numerous studies documented the adjuvant activities of IL-12 and IL-18 and in particular their ability to encourage Th2 differentiation. Alum is notoriously a poor inducer of Th1 responses while it successfully sustains Th2 responses suggesting that Alum's adjuvanticity may be related to its ability to induce IL-12 and IL-18 secretion. The involvement of IL-12 and IL-18 in Alum adjuvanticity has been previously analyzed but with contradictory or inconclusive results. In light of our recent results a re-examination of this issue is needed. The present grant proposal will elucidate at the molecular level the mechanism of action of Alum by addressing the following specific aims: 1. Test the hypothesis that members of the NLR family mediate caspase-1 activation and IL-12/IL-18 secretion by Alum: 2. Test the hypothesis that caspase-1 activation and release of IL-12/IL-18 mediate the adjuvant activity of Alum. Vaccination remains the most promising strategy to fight infectious diseases in both industrialized and developing countries. Alum is the only adjuvant approved for routine use in human vaccination although the basis for its immunostimulatory activity remains poorly understood. The studies described in this grant proposal will increase our understanding of the mechanism of action of Alum. A deeper understanding of the mechanisms that determine the immunostimulatory properties of adjuvants is a prerequisite for the rational design of more sophisticated vaccines. ? ? ?
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