title: The Cell Wall Lipid PDIM Contributes to Phagosomal Escape and Host Cell Exit ofMycobacterium tuberculosis.
abstract: The cell wall ofMycobacterium tuberculosisis composed of unique lipids that are important for pathogenesis. Indeed, the first-ever genetic screen inM. tuberculosisidentified genes involved in the biosynthesis and transport of the cell wall lipid PDIM (phthioceroldimycocerosates) as crucial for the survival ofM. tuberculosisin mice. Here we show evidence for a novel molecular mechanism of the PDIM-mediated virulence inM. tuberculosisWe characterized the DNA interaction and the regulon of Rv3167c, a transcriptional repressor that is involved in virulence regulation ofM. tuberculosis, and discovered that it controls the PDIM operon. A loss-of-function genetic approach showed that PDIM levels directly correlate with the capacity ofM. tuberculosisto escape the phagosome and induce host cell necrosis and macroautophagy. In conclusion, our study attributes a novel role of the cell wall lipid PDIM in intracellular host cell modulation, which is important for host cell exit and dissemination ofM. tuberculosisIMPORTANCEMycobacterium tuberculosisis a major human pathogen that has coevolved with its host for thousands of years. The complex and unique cell wall ofM. tuberculosiscontains the lipid PDIM (phthioceroldimycocerosates), which is crucial for virulence of the bacterium, but its function is not well understood. Here we show that PDIM expression byM. tuberculosisis negatively regulated by a novel transcriptional repressor, Rv3167c. In addition, we discovered that the escape ofM. tuberculosisfrom its intracellular vacuole was greatly augmented by the presence of PDIM. The increased release ofM. tuberculosisinto the cytosol led to increased host cell necrosis. The discovery of a link between the cell wall lipid PDIM and a major pathogenesis pathway ofM. tuberculosisprovides important insights into the molecular mechanisms of host cell manipulation byM. tuberculosis.
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Quigley
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.|Center for Bioinformatics and Computational Biology, University of Maryland-College Park, Maryland, USA.
authors.forename: V Keith
authors.initials: VK
authors.lastname: Hughitt
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.|W. M. Keck Laboratory for Structural Biology, University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, Maryland, USA.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Velikovsky
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.|W. M. Keck Laboratory for Structural Biology, University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, Maryland, USA.
authors.forename: Roy A
authors.initials: RA
authors.lastname: Mariuzza
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.|Center for Bioinformatics and Computational Biology, University of Maryland-College Park, Maryland, USA.
authors.forename: Najib M
authors.identifier: 0000-0001-7970-3312
authors.initials: NM
authors.lastname: El-Sayed
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA vbriken@umd.edu.
authors.forename: Volker
authors.initials: V
authors.lastname: Briken
mesh_terms: D001343:Autophagy; D016923:Cell Death; D002460:Cell Line; D002473:Cell Wall / Q000737:chemistry*; D005089:Exocytosis; D017353:Gene Deletion; D006017:Glycolipids / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D008264:Macrophages / Q000382:microbiology / Q000502:physiology; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D009876:Operon; D010588:Phagosomes / Q000382:microbiology*; D012097:Repressor Proteins / Q000235:genetics; D014158:Transcription, Genetic; D014774:Virulence; D037521:Virulence Factors / Q000378:metabolism*
chemical_list: D006017:Glycolipids; D012097:Repressor Proteins; D037521:Virulence Factors