Glutamine metabolism in tuberculosis

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Abstract Mycobacterium tuberculosis (Mtb) remains the most successful human pathogen, causing 1.5 million deaths in 2018. Accumulating evidence suggests that Mtb’s ability to survive, persist and cause disease is largely due to its ability to subvert the host immune and antimicrobial response to infection. Recent advances in immunometabolism studies have shown that a metabolic shift to glycolysis, aka the Warburg effect, is critical for the activation and effector functions of immune cells to control the infection. However, there are limited studies on how the change of metabolic state of infected macrophages affects the activation and function of innate and adaptive immunity in TB. Our laboratory and others have characterized the immunometabolic changes in multiple model of TB and found that the metabolic remodeling to the HIF-1-mediated Warburg effect is a general response to Mtb infection. Through detailed analysis of immunometabolic properties of Mtb-infected macrophages using transcriptomics, metabolomics and therapeutic compound treatment, we discovered novel evidence that M1 polarization at initial stage of macrophage infection is accompanied by increased glutamine uptake and metabolism. Given the pleiotropic roles of glutamine metabolism, including anaplerotic reactions from the TCA cycle, redox homeostasis, and synthesis of nucleotides and NADPH, findings from our studies suggest that glutamine uptake and metabolism constitute an integral component of metabolic remodeling program of M1 macrophages. Based on these observations, we hypothesize that glutamine functions as important carbon and nitrogen source for immune cells and that its availability and metabolism are essential for the activation and function of host innate and adaptive immunity against Mtb infection. To test our hypothesis, we propose two Specific Aims. In Aim 1, we will define the role of glutamine in mediating the metabolism and physiology of M1 macrophages. We will also decipher the metabolic footprints of glutamine as carbon and nitrogen source during M1 polarization using stable isotope tracing metabolomics with 13C (1-13C and 5-13C) glutamine and 15N (a-N, and g-N) glutamine. In Aim 2, we will characterize the role of glutamine metabolism in mediating the activation and functions of innate and adaptive immune cells using therapeutically validated small molecule inhibitor for glutaminolysis pathway. We will also evaluate whether supplementation of glutamine to Mtb-infected animals can serve as a viable strategy of adjunct host directed therapies (HDTs) to boost antimicrobial response of host immune cells against Mtb infection in a mouse model of TB. By elucidating the effects of glutamine metabolism on the functional property of host immune cells, this study will establish a novel immunometabolic aspect of TB research. Outcomes of this study will open new avenues for the development of new adjunct HDTs by targeting glutamine metabolism to treat TB worldwide.