L-glutamine Induces Expression of Listeria monocytogenes Virulence Genes.

Adi Haber,Nadejda Sigal,Anat A Herskovits,Nurit Livnat-Levanon,Lior Lobel,Tamar Burg-Golani,Jessica Rose,Oded Lewinson,Sivan Friedman,Marcel A Behr

doi:10.1371/journal.ppat.1006161

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.

Highlights

Listeria monocytogenes is a Gram-positive facultative intracellular bacterial pathogen and the causative agent of listeriosis in humans, a disease with deleterious impacts, such as increased risk of meningitis and miscarriage [1]
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 thrive in the human body and cause disease, bacterial pathogens rely on the expression of a battery of genes, termed virulence genes

Summary

Introduction

Listeria monocytogenes is a Gram-positive facultative intracellular bacterial pathogen and the causative agent of listeriosis in humans, a disease with deleterious impacts, such as increased risk of meningitis and miscarriage [1]. The metabolism and virulence of L. monocytogenes are intimately linked via the combined regulation of PrfA and the global metabolism regulator CodY [12], [13] The latter, among other things, senses low concentrations of branched-chain amino acids (BCAAs—isoleucine, leucine, and valine), as encountered within mammalian cells, and as a result affects transcription of prfA [14]. Host derived glutathione was shown to serve as yet another intracellular signal that activates PrfA via allosteric binding [15], [16]. Together, these and other signals reflect the metabolic conditions within the mammalian cell and assist the bacteria in apprising the required metabolic and virulence adaptations

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Results

Conclusion