The influence of glutamine transporters and global regulators on metabolism, colonization and virulence of Streptococcus pneumoniae

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Streptococcus pneumoniae (pneumococci) are versatile human pathogenic bacteria. Besides viru-lence factors, the maintenance of pneumococcal fitness during adaptation to different host milieus is also of central importance in causing local infections and invasive pneumococcal diseases (IPD) in humans. The regulation of amino acid uptake systems including glutamine transporters or sugar uptake systems is likely crucial for the fitness of pneumococci in the nasopharynx or during IPD. As bacterial fitness and virulence are tightly linked we will investigate the role of metabolic regula-tors such as ArgR, GlnR, or Rex, of the enzymes of the arginine deiminase system (ADS), and of the enzyme Zwf for pneumococcal fitness and virulence. Mice infection experiments and phagocy-tosis studies using macrophages and pneumococcal mutants deficient for the transcriptional regu-lators, ADS, and Zwf will be conducted to assess the impact of these bacterial factors on S. pneumoniae virulence and intracellular survival. The individual role of the regulators or metabol-ic enzymes on pneumococcal metabolism will be studied by applying isotopolomics and metabo-lomics. We will further decipher and compare the metabolism between pneumococci cultured un-der in vitro conditions in a synthetic medium and under in vivo conditions, i.e. when pneumococci were taken up by macrophages. This will be done by analysing the isotopologue profiles and moni-toring the extracellular and intracellular bacterial metabolites of phagocytosed pneumococci.