title: Identification of a Transcription Factor That Regulates Host Cell Exit and Virulence of Mycobacterium tuberculosis.
abstract: The interaction of Mycobacterium tuberculosis (Mtb) with host cell death signaling pathways is characterized by an initial anti-apoptotic phase followed by a pro-necrotic phase to allow for host cell exit of the bacteria. The bacterial modulators regulating necrosis induction are poorly understood. Here we describe the identification of a transcriptional repressor, Rv3167c responsible for regulating the escape of Mtb from the phagosome. Increased cytosolic localization of MtbΔRv3167c was accompanied by elevated levels of mitochondrial reactive oxygen species and reduced activation of the protein kinase Akt, and these events were critical for the induction of host cell necrosis and macroautophagy. The increase in necrosis led to an increase in bacterial virulence as reflected in higher bacterial burden and reduced survival of mice infected with MtbΔRv3167c. The regulon of Rv3167c thus contains the bacterial mediators involved in escape from the phagosome and host cell necrosis induction, both of which are crucial steps in the intracellular lifecycle and virulence of Mtb.
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, United States of America.
authors.forename: Lalitha
authors.initials: L
authors.lastname: Srinivasan
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, United States of America.
authors.forename: Serdar A
authors.initials: SA
authors.lastname: Gurses
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, United States of America.
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Hurley
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, United States of America.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Miller
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Petros C
authors.initials: PC
authors.lastname: Karakousis
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, United States of America.
authors.forename: Volker
authors.initials: V
authors.lastname: Briken
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D006168:Guinea Pigs; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity*; D016133:Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism*; D014376:Tuberculosis / Q000378:metabolism*; D014774:Virulence / Q000502:physiology*; D037521:Virulence Factors / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D014157:Transcription Factors; D037521:Virulence Factors