The role of glutamine metabolism for host defense against Mycobacterium tuberculosis infection

Background: Rewiring cellular metabolism is important for activation of immune cells during host defense against Mycobacterium tuberculosis. Glutamine has been implicated as an immunomodulatory nutrient, but its role in response to M. tuberculosis is unknown. Methods: We assessed expression of glutamine pathway genes in M. tuberculosis infected macrophages and blood transcriptomics from individuals with latent or active tuberculosis. Subsequently, we studied the effect of blocking glutaminolysis on M. tuberculosis-induced cytokines. Finally, we examined whether polymorphisms in genes involved in the glutamine pathway influence M. tuberculosis-induced cytokines in a cohort of 500 individuals. Results: Glutamine pathway genes were differentially expressed in infected macrophages and patients with active tuberculosis. Human peripheral blood mononuclear cells stimulated with M. tuberculosis displayed decreased cytokine responses (IL-1β, IFN-γ, and IL-17) when medium was devoid of glutamine. Specific inhibitors of the glutamine pathway led to decreased cytokine responses, especially T-cell cytokines (IFN-γ, IL-17, and IL-22). Finally, genetic polymorphisms in glutamine metabolism genes (including GLS2, SLC1A5, and SLC7A5) influenced ex-vivo cytokine responses to M. tuberculosis, especially for T-cell cytokines. Conclusions: Cellular glutamine metabolism is implicated in effective host responses against M. tuberculosis. Targeting immunometabolism may represent new strategies for TB prevention and/or treatment