TY - JOUR T1 - Mycobacterium tuberculosis modulates mitochondrial function in human macrophages JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.congress-2021.PA3689 VL - 58 IS - suppl 65 SP - PA3689 AU - Claudio Bussi AU - Mariana Silva Dos Santos AU - Elliott M. Bernard AU - Pierre B. Santucci AU - James I. Macrae AU - Maximiliano G. Gutierrez Y1 - 2021/09/05 UR - http://erj.ersjournals.com/content/58/suppl_65/PA3689.abstract N2 - Mitochondrial dynamics and metabolism in immune cells are closely associated. However, if these interactions play a role in the human macrophage response to Mycobacterium tuberculosis (Mtb) remains largely unknown.We used human induced-pluripotent stem cell-derived macrophages together with high-content live-cell imaging, extracellular flux analysis and labelled metabolomics to investigate mitochondrial dynamics, Mtb intracellular replication and mitochondrial metabolism.Mitochondrial tracking at the single-cell level revealed extensive mitochondrial morphology heterogeneity. Mtb did not induce significant changes in mitochondrial area, length or width during the first 48h of infection. However, infection with Mtb WT but not with an attenuated strain lacking the region of difference 1 (Mtb ΔRD1) induced a decrease in the mitochondrial membrane potential and protein turnover rate, as visualised by MitoTracker Red and the ratiometric reporter MitoTimer, respectively. Notably, these changes correlated with a selective degradation of mitochondrial proteins and downregulated mitochondrial transcripts.The metabolic profile of infected macrophages showed an increase in oxygen consumption and extracellular acidification rate after 48h of infection. The inhibition of glycolysis with 2-Deoxy-d-glucose promoted Mtb replication, whereas oxamate (lactate dehydrogenase inhibitor) impaired Mtb intracellular replication.Collectively, our results show that macrophage metabolic reprogramming is required for the control of Mtb replication. Unlike other intracellular pathogens, changes in host cell metabolism induced by Mtb might correlate with disruption of mitochondrial function rather than morphology.FootnotesCite this article as: European Respiratory Journal 2021; 58: Suppl. 65, PA3689.This abstract was presented at the 2021 ERS International Congress, in session “Prediction of exacerbations in patients with COPD”.This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only). ER -