L-glutamine Induces Expression of Listeria monocytogenes Virulence Genes

Abstract

The high environmental adaptability of bacteria is contingent upon their ability to sense changes in their surroundings. Bacterial pathogen entry into host poses an abrupt and dramatic environmental change, during which successful pathogens gauge multiple parameters that signal host localization. The facultative human pathogen Listeria monocytogenes flourishes in soil, water and food, and in ~50 different animals, and serves as a model for intracellular infection. L. monocytogenes identifies host entry by sensing both physical (e.g., temperature) and chemical (e.g., metabolite concentrations) factors. We report here that L-glutamine, an abundant nitrogen source in host serum and cells, serves as an environmental indicator and inducer of virulence gene expression. In contrast, ammonia, which is the most abundant nitrogen source in soil and water, fully supports growth, but fails to activate virulence gene transcription. We demonstrate that induction of virulence genes only occurs when the Listerial intracellular concentration of L-glutamine crosses a certain threshold, acting as an on/off switch: off when L-glutamine concentrations are below the threshold, and fully on when the threshold is crossed. To turn on the switch, L-glutamine must be present, and the L-glutamine high affinity ABC transporter, GlnPQ, must be active. Inactivation of GlnPQ led to complete arrest of L-glutamine uptake, reduced type I interferon response in infected macrophages, dramatic reduction in expression of virulence genes, and attenuated virulence in a mouse infection model. These results may explain observations made with other pathogens correlating nitrogen metabolism and virulence, and suggest that gauging of L-glutamine as a means of ascertaining host localization may be a general mechanism.

Recent advances in understanding Listeria monocytogenes infection: the importance of subcellular and physiological context

“…L-glutamine, abundant within host blood plasma and host cell cytosol, has recently been reported as another major cytosolic cue for the upregulation of virulence genes in Lm 16 . It is currently unknown whether L-glutamine, similarly to glutathione, affects PrfA activity at the post-translational level.…”

Selective substrate uptake: The role of ATP-binding cassette (ABC) importers in pathogenesis

“…In Group B streptococci, a ΔglnQ strain shows decreased fibronectin adherence, lower invasion of human adenocarcinoma epithelial A549 cells in vitro , and decreased virulence in neonatal rats [76]. Inactivation of L. monocytogenes glnPQ abolished glutamine uptake, lowered the response of type I interferon in infected bone marrow-derived macrophages, and down-regulated transcription of virulence factors, such as, hly , plcA , plcB , and actA [77]. Liver and spleen colonization of C57BL/6 mice intravenously injected with the ΔglnPQ strain was reduced compared to the wildtype strain, leading to a 30-fold and a 10-fold decrease in bacterial load of the liver and spleen, respectively [77].…”

ATP binding and hydrolysis disrupt the high-affinity interaction between the heme ABC transporter HmuUV and its cognate substrate-binding protein

“…They are involved in many important physiological processes such as nutrient import, cellular detoxification, lipid homeostasis, signal transduction, antiviral defense, and antigen presentation (5)(6)(7)(8)(9)(10)(11). From a clinical perspective, ABC transporters are of great interest as they are directly involved in tumor resistance to multiple chemotherapeutics, bacterial multidrug resistance, and bacterial virulence and pathogenesis (12)(13)(14)(15)(16)(17)(18)(19). All ABC transporters share a basic architecture, minimally composed of two intracellular nucleotide-binding domains (NBDs), and two trans-membrane domains (TMDs).…”