Metabolic Responses of Primary and Transformed Cells to Intracellular Listeria monocytogenes

Abstract

The metabolic response of host cells, in particular of primary mammalian cells, to bacterial infections is poorly understood. Here, we compare the carbon metabolism of primary mouse macrophages and of established J774A.1 cells upon Listeria monocytogenes infection using 13C-labelled glucose or glutamine as carbon tracers. The 13C-profiles of protein-derived amino acids from labelled host cells and intracellular L. monocytogenes identified active metabolic pathways in the different cell types. In the primary cells, infection with live L. monocytogenes increased glycolytic activity and enhanced flux of pyruvate into the TCA cycle via pyruvate dehydrogenase and pyruvate carboxylase, while in J774A.1 cells the already high glycolytic and glutaminolytic activities hardly changed upon infection. The carbon metabolism of intracellular L. monocytogenes was similar in both host cells. Taken together, the data suggest that efficient listerial replication in the cytosol of the host cells mainly depends on the glycolytic activity of the hosts.

Metabolic host responses to infection by intracellular bacterial pathogens

“…This result may be in part the consequence of the incomplete gene array used in this study, but—more likely—is again due to the already upregulated metabolism of the used THP-1 cells (even in the uninfected state—see above). This assumption is supported by recent 13 C-isotopologue studies, carried out with primary murine bone marrow-derived macrophages (BMM) and the murine macrophage-like J774A.1 cells infected with L. monocytogenes (Gillmaier et al, 2012). When the two cell types are fed with uniformly 13 C-labeled glucose or 13 C-labeled glutamine, high induction of glucose uptake and GL is observed in BMM upon infection with L. monocytogenes , but not in the J774A.1 cells (which already show up-regulated GL and glutaminolysis in the un-infected state).…”

“…More recently, metabolomics analyzing qualitatively and quantitatively small metabolites in cells or tissue samples of the infected host by MS or NMR have been also applied to determine changes in the metabolite patterns (Han et al, 2008; de Carvalho et al, 2010; Antunes et al, 2011). Other techniques which may provide valuable information on the dynamics of metabolic changes in infected host cells include 13 C-isotopologue profiling, Raman spectroscopy, nano SIMS, and fluorescence lifetime imaging (FLIM) (Wagner, 2009; Szaszák et al, 2011; Gillmaier et al, 2012; Musat et al, 2012). Each of these methods has, however, specific drawbacks and only the integration of these techniques may provide a satisfactory solution to this complex problem (Zhang et al, 2010).…”

Regulating the Intersection of Metabolism and Pathogenesis in Gram-positive Bacteria

“…The reliance on glycerol and G6P rather than glucose intracellularly likely reflects the metabolic adaptation of infected host cells to L. monocytogenes . A marked increase in glycolysis and glutaminolysis accompanies infection of primary macrophages with the bacterium, which could lead to the intracellular accumulation of glycerol and G6P (241). While the regulatory pathways that control this host response are still unknown, HIF-1α induction of glycolysis may play an as-of-yet uncharacterized role.…”

Central metabolic interactions of immune cells and microbes: prospects for defeating infections

“…Immunometabolic shifts cause increased concentrations of glucose and lactate in host cells that could promote intracellular survival of Listeria monocytogenes, Legionella pneumophila, Brucella abortus and M. tuberculosis [74][75][76][77]111]. heightened glycolysis, disruptions to the TCA cycle and changes to mitochondrial respiration, drive antimicrobial inflammation and the production of direct antimicrobial effectors, such as itaconate and ROS.…”