title: Macrophage Epithelial Reprogramming Underlies Mycobacterial Granuloma Formation and Promotes Infection.
abstract: Mycobacterium tuberculosis infection in humans triggers formation of granulomas, which are tightly organized immune cell aggregates that are the central structure of tuberculosis. Infected and uninfected macrophages interdigitate, assuming an altered, flattened appearance. Although pathologists have described these changes for over a century, the molecular and cellular programs underlying this transition are unclear. Here, using the zebrafish-Mycobacterium marinum model, we found that mycobacterial granuloma formation is accompanied by macrophage induction of canonical epithelial molecules and structures. We identified fundamental macrophage reprogramming events that parallel E-cadherin-dependent mesenchymal-epithelial transitions. Macrophage-specific disruption of E-cadherin function resulted in disordered granuloma formation, enhanced immune cell access, decreased bacterial burden, and increased host survival, suggesting that the granuloma can also serve a bacteria-protective role. Granuloma macrophages in humans with tuberculosis were similarly transformed. Thus, during mycobacterial infection, granuloma macrophages are broadly reprogrammed by epithelial modules, and this reprogramming alters the trajectory of infection and the associated immune response.
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Cronan
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Rebecca W
authors.initials: RW
authors.lastname: Beerman
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Allison F
authors.initials: AF
authors.lastname: Rosenberg
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Saelens
authors.affiliation: Division of Infectious Diseases, Duke University School of Medicine, Durham, NC 27710, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Johnson
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Oehlers
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Dana M
authors.initials: DM
authors.lastname: Sisk
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Jurcic Smith
authors.affiliation: Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Medvitz
authors.affiliation: Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Miller
authors.affiliation: Molecular and Computational Biology and Translational Imaging Center, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Le A
authors.initials: LA
authors.lastname: Trinh
authors.affiliation: Molecular and Computational Biology and Translational Imaging Center, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Fraser
authors.affiliation: Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Madden
authors.affiliation: Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210, USA; Center for Microbial Interface Biology, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Turner
authors.affiliation: Division of Infectious Diseases, Duke University School of Medicine, Durham, NC 27710, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Stout
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Sunhee
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Immunology, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: david.tobin@duke.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Tobin
mesh_terms: D000818:Animals; D015820:Cadherins / Q000276:immunology; D004848:Epithelium / Q000276:immunology* / Q000382:microbiology; D006099:Granuloma / Q000276:immunology / Q000382:microbiology; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D019910:Mycobacterium marinum / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000276:immunology; D015027:Zebrafish
chemical_list: D015820:Cadherins