Dietary regulation of inflammasome-mediated host defense by branched-chain amino acid metabolism

PROJECT SUMMARY/ABSTRACT Respiratory infectious diseases including pneumonia are an immediate public threat to the USA and global healthcare systems. We must gain a deeper understanding of the innate immune system’s response to pulmonary pathogens in order to develop host-directed therapeutic approaches that combat infections in the lung. To this end, my lab studies innate immune mechanisms of defense against the bacterial pathogen Legionella pneumophila (Lp), an important cause of community- and hospital-acquired pneumonia. Effective host defense against Lp is driven by a class of inflammasome-assembling innate immune sensor proteins, which detect bacterial motifs to trigger an inflammatory form of cell death termed pyroptosis. By driving the production of inflammatory interleukin (IL)-1 cytokines and restricting the replicative niche for intracellular bacterial pathogens, inflammasomes promote host protection against a broad array of respiratory infectious diseases. Despite this knowledge, achieving a mechanistic understanding of the specific dietary factors and metabolic signaling events that license inflammasome function to drive antimicrobial defense remains an overlooked – and yet critically important – arm of host immunity. To fill this gap in understanding, I study the branched-chain amino acids (BCAAs), a physiologically abundant and dietarily tunable (i.e., essential) class of amino acids that have important metabolic properties. In addition to catabolically supporting oxidative energy production, the BCAAs are key factors that drive cellular anabolic signaling mediated by mammalian target of rapamycin complex 1 (mTORC1) and metabolic stress adaptation orchestrated by the integrated stress response (ISR). As such, the disparate nodes of BCAA metabolism and sensing integrate to selectively shape transcriptional and translational processes in the cell. Despite this knowledge, a mechanistic understanding of the pulmonary host defense functions of the BCAAs remains unknown. This scientific question motivates my studies proposed herein. I have generated preliminary data demonstrating that the BCAAs promote IL-1 cytokine production and broadly license diverse triggers of inflammasome-mediated pyroptotic cell death in macrophages. These findings therefore provoke the conceptually novel hypothesis that the coordinated sensing of the BCAAs through mTORC1 and the ISR transcriptionally and translationally supports inflammasome-driven host defense against respiratory bacterial pathogens. In Aim 1, I will mechanistically dissect how BCAA catabolism and sensing converge to transcriptionally and translationally drive inflammasome function and IL-1 release. In Aim 2, I will determine if and how the BCAAs are required for inflammasome-driven restriction of Lp in vitro and in vivo. The major scientific goal of this fellowship is to unveil a novel role for essential nutrient sensing in functionally tuning inflammasome-mediated defense against pulmonary pathogens. Another goal is to advance my training in preparation for a career in leading my own independent research group. The strong mentorship of Dr. Sunny Shin and exceptional research environment at Penn will ensure successful completion of this fellowship.