Listeria monocytogenes ( Lm ) is a saprophyte and intracellular pathogen. Transition to the pathogenic state relies on sensing of host-derived metabolites, yet it remains unclear how these are recognized and how they mediate virulence gene regulation. We previously found that low availability of isoleucine signals Lm to activate the virulent state. This response is dependent on CodY, a global regulator and isoleucine sensor. Isoleucine-bound CodY represses metabolic pathways including branched-chain amino acids (BCAA) biosynthesis, however under BCAA depletion, as occurs during infection, BCAA biosynthesis is upregulated and isoleucine-unbound CodY activates virulence genes. While isoleucine was revealed as an important input signal, it was not identified how internal levels are controlled during infection. Here we show that Lm regulates BCAA biosynthesis via CodY and via a riboregulator located upstream to the BCAA biosynthesis genes, named Rli60. rli60 is transcribed when BCAA levels drop, forming a ribosome-mediated attenuator that cis -regulates the downstream genes according to BCAA supply. Notably, we found that Rli60 restricts BCAA production, essentially starving Lm , a mechanism that is directly linked to virulence, as it controls the internal isoleucine pool and thereby CodY activity. This controlled BCAA auxotrophy likely evolved to enable isoleucine to serve as a host signal and virulence effector. Author summary Bacterial pathogens must adapt to their host environment to carry out a successful infection. Sensing host-derived signals precedes adaptation, and triggers switching to the virulent state. Within mammalian cells L . monocytogenes responds to branched-chain amino acids (BCAA) deficiency by inducing virulence gene expression. In this study, we provide compelling evidence that fine tuning BCAA biosynthesis in L . monocytogenes allows the bacteria to sense isoleucine as a host-specific signal. Tightly controlled BCAA production depends on Rli60, a riboregulator, which is transcribed upstream to the BCAA biosynthesis genes. Rli60 functions as a ribosome mediated attenuator that cis -regulates BCAA production under limiting conditions. This study highlights the remarkable cross-regulation of metabolism and virulence in bacterial pathogens.
【초록키워드】 Infection, metabolism, pathogen, amino acids, Control, Pathogens, Gene regulation, Bacteria, metabolites, Bacterial pathogens, adaptation, virulence, expression, mechanism, function, Evidence, Listeria monocytogenes, intracellular pathogen, regulate, metabolic pathways, Trigger, switching, triggers, isoleucine, deficiency, Regulation, metabolic pathway, transition, pathogenic, BCAA, BCAA biosynthesis, BCAA biosynthesis genes, branched-chain amino acids, CodY, downstream genes, Rli60, saprophyte, virulence genes, upstream, virulent, while, mammalian cell, Host, highlight, occur, dependent on, restrict, transcribed, upregulated, activate, conditions, respond, represse, virulence gene, branched-chain amino acid, downstream gene, L . monocytogene, Listeria monocytogene, 【제목키워드】 amino acids, Listeria monocytogenes, Listeria, Host, Controlled, branched-chain amino acid,