Identification and characterization of gut microbial bioactive molecules that determine predisposition to autoimmune disease and atopy

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Project Summary/Abstract SARS-CoV-2 infections are exacting a horrific burden of morbidity and mortality around the world. While we have much to learn about the virus and COVID-19, the disease it causes, the most likely way to control and possibly eliminate COVID-19 is a vaccine for SARS-CoV-2. Typically successful vaccines need adjuvants to increase the immunogenicity of their response. A strong response will be especially important for COVID-19 as the virus particle has multiple spikes (S- proteins) that are the target of the majority of vaccines under development. This project would leverage ongoing efforts to discover novel small molecule immunomodulators produced by members of the human gut microbiota to discover and develop adjuvants. The small molecule immunomodulators discovered in this project appear to have excellent prospects as adjuvants as they both boost and resolve immune responses. The two Specific Aims, which can be prosecuted simultaneously, deal with further molecular and mechanistic analysis of a promising set of lipids produced by Akkermansia muciniphila, a recently recognized member of the human gut microbiota whose abundance is highly correlated with outcomes in both type 2 diabetes (T2D), and PD-1 cancer immunotherapy. Work in Specific Aim 1 will identify the structure-activity relations for the lipids where activity is release of inflammatory cytokines like TNFα and IL-6. The lipids signal through TLR2, and we would establish whether heterodimerization with TLR-1 or TLR-6 is required for activity and the need for adaptor proteins like MAL/TIRAP and MyD88. We will also assess the downstream T cell polarization following mBMDC activation. In Specific Aim 2 we will replicate the studies that led to the initial identification of the A. mucinophila lipids on other members of the human gut microbiota, especially those that correlate or anti-correlate strongly with inflammatory diseases. In sum, the project will characterize the immune signaling pathways triggered by bacterial TLR2 agonists to identify adjuvant candidates that may increase the therapeutic efficacy of soon to be developed COVID-19 vaccines.