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The metabolic regulator CodY links L isteria monocytogenes metabolism to virulence by directly activating the virulence regulatory gene prfA
Author(s) -
Lobel Lior,
Sigal Nadejda,
Borovok Ilya,
Belitsky Boris R.,
Sonenshein Abraham L.,
Herskovits Anat A.
Publication year - 2015
Publication title -
molecular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 247
eISSN - 1365-2958
pISSN - 0950-382X
DOI - 10.1111/mmi.12890
Subject(s) - virulence , biology , gene , transcription (linguistics) , pathogen , transcription factor , microbiology and biotechnology , regulator , crosstalk , transcriptional regulation , genetics , linguistics , philosophy , physics , optics
Summary Metabolic adaptations are critical to the ability of bacterial pathogens to grow within host cells and are normally preceded by sensing of host‐specific metabolic signals, which in turn can influence the pathogen's virulence state. Previously, we reported that the intracellular bacterial pathogen L isteria monocytogenes responds to low availability of branched‐chain amino acids ( BCAA s) within mammalian cells by up‐regulating both BCAA biosynthesis and virulence genes. The induction of virulence genes required the BCAA ‐responsive transcription regulator, CodY , but the molecular mechanism governing this mode of regulation was unclear. In this report, we demonstrate that CodY directly binds the coding sequence of the L . monocytogenes master virulence activator gene, prfA , 15 nt downstream of its start codon, and that this binding results in up‐regulation of prfA transcription specifically under low concentrations of BCAA . Mutating this site abolished CodY binding and reduced prfA transcription in macrophages, and attenuated bacterial virulence in mice. Notably, the mutated binding site did not alter prfA transcription or PrfA activity under other conditions that are known to activate PrfA , such as during growth in the presence of glucose‐1‐phosphate. This study highlights the tight crosstalk between L . monocytogenes metabolism and virulence, while revealing novel features of CodY ‐mediated regulation.