title: Mycobacterial Acid Tolerance Enables Phagolysosomal Survival and Establishment of Tuberculous Infection In Vivo.
abstract: The blockade of phagolysosomal fusion is considered a critical mycobacterial strategy to survive in macrophages. However, viable mycobacteria have been observed in phagolysosomes during infection of cultured macrophages, and mycobacteria have the virulence determinant MarP, which confers acid resistance in vitro. Here we show in mice and zebrafish that innate macrophages overcome mycobacterial lysosomal avoidance strategies to rapidly deliver a substantial proportion of infecting bacteria to phagolysosomes. Exploiting the optical transparency of the zebrafish, we tracked the fates of individual mycobacteria delivered to phagosomes versus phagolysosomes and discovered that bacteria survive and grow in phagolysosomes, though growth is slower. MarP is required specifically for phagolysosomal survival, making it an important determinant for the establishment of mycobacterial infection in their hosts. Our work suggests that if pathogenic mycobacteria fail to prevent lysosomal trafficking, they tolerate the resulting acidic environment of the phagolysosome to establish infection.
authors: Molecular Immunity Unit, Department of Medicine, University of Cambridge, MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK; Molecular and Cellular Biology Graduate Program and Medical Scientist Training Program, University of Washington, Seattle, USA.
authors: Steven
authors: S
authors: Levitte
authors: Center for Infectious Disease Research, Seattle, WA 98195, USA; Department of Pediatrics, University of Washington, Seattle, WA 98109, USA.
authors: Kristin N
authors: KN
authors: Adams
authors: Molecular and Cellular Biology Graduate Program and Medical Scientist Training Program, University of Washington, Seattle, USA.
authors: Russell D
authors: RD
authors: Berg
authors: Department of Microbiology, University of Washington, Seattle, WA 98109, USA.
authors: Christine L
authors: CL
authors: Cosma
authors: Center for Infectious Disease Research, Seattle, WA 98195, USA; Department of Immunology, University of Washington, Seattle, WA 98109, USA.
authors: Kevin B
authors: KB
authors: Urdahl
authors: Molecular Immunity Unit, Department of Medicine, University of Cambridge, MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK. Electronic address: lr404@cam.ac.uk.
authors: Lalita
authors: L
authors: Ramakrishnan
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002264:Carboxylic Acids / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D054884:Host-Pathogen Interactions; D008247:Lysosomes / Q000382:microbiology*; D008264:Macrophages / Q000382:microbiology*; D008810:Mice, Inbred C57BL; D050296:Microbial Viability / Q000187:drug effects*; D009165:Mycobacterium Infections, Nontuberculous / Q000382:microbiology; D019910:Mycobacterium marinum / Q000187:drug effects / Q000254:growth & development / Q000502:physiology*; D013312:Stress, Physiological; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002264:Carboxylic Acids; D037521:Virulence Factors