Role of the Nlrp3 Inflammasome in Adaptive Immunity

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DESCRIPTION (provided by applicant): Aluminum adjuvants, typically referred to as "alum", are the most commonly used adjuvants in human and animal vaccines worldwide. We recently discovered that alum activates an intracellular innate immune response system called the Nlrp3 inflammasome. However, it remains unclear how inflammasome activation regulates long-lasting adaptive immunity. We hypothesize that alum triggers Nlrp3 inflammasome activation in antigen presenting cells, resulting in the release of IL-1 family members, which provide requisite priming signals for lymphocyte activation. [Using Nlrp3, conditional caspase-1, IL-1RI and other knockout mouse lines, both in vitro and in vivo studies will test the components of this hypothesis with the following specific aims: 1) Identify the cells that control the adaptive immune response to aluminum hydroxide adjuvants via the Nlrp3 inflammasome and 2) Define the immunoregulatory products of alum-induced Nlrp3 inflammasome activation that control T and B cell priming. By understanding the way in which alum orchestrates an effective adaptive immune response through this innate pathway, we will be able to develop new generations of adjuvants to specifically target the appropriate components of the immune system, resulting in more effective vaccines.] Candidate: Stephanie Eisenbarth is an MD, PhD trained in immunology and clinical pathology/laboratory medicine and she plans to address questions regarding the mechanism of action of vaccine adjuvants with the aim of improving adjuvant design. Her long-term career goal is to obtain a tenure-track position at an academic institution with a majority of her time dedicated to basic scientific investigation, complemented with clinical involvement in a pathology department. To this end, she has chosen two mentors who have a long history of effectively training young scientists, Dr. Richard Flavell and Dr. Mark Shlomchik in the Department of Immunobiology at Yale University. The biomedical research center at Yale School of Medicine will provide ample scientific and clinical resources to pursue the research proposed above. She has also established a career advisory committee, planned on-going clinical activities in the Department of Laboratory Medicine and outlined a 5-year research project that will expand her field of expertise within immunology by tackling new lines of investigation and methodologies. Therefore this proposal will address critically important questions in our understanding of vaccine immunology and will prepare the candidate to approach additional questions that arise as an independent physician-scientist. Narrative: The development of vaccines against infectious pathogens has been and continues to be one of the most important medical interventions in global health. This proposal delineates the experiments necessary to understand how the Nlrp3 inflammasome, a component of the innate branch of the immune system, regulates immunity during vaccination with aluminum hydroxide adjuvants. Such an understanding could facilitate the development of a new generation of vaccine adjuvants.