title: Myeloid Growth Factors Promote Resistance to Mycobacterial Infection by Curtailing Granuloma Necrosis through Macrophage Replenishment.
abstract: The mycobacterial ESX-1 virulence locus accelerates macrophage recruitment to the forming tuberculous granuloma. Newly recruited macrophages phagocytose previously infected apoptotic macrophages to become new bacterial growth niches. Granuloma macrophages can then necrose, releasing mycobacteria into the extracellular milieu, which potentiates their growth even further. Using zebrafish with genetic or pharmacologically induced macrophage deficiencies, we find that global macrophage deficits increase susceptibility to mycobacterial infection by accelerating granuloma necrosis. This is because reduction in the macrophage supply below a critical threshold decreases granuloma macrophage replenishment to the point where apoptotic infected macrophages, failing to get engulfed, necrose. Reducing macrophage demand by removing bacterial ESX-1 offsets the susceptibility of macrophage deficits. Conversely, increasing macrophage supply in wild-type fish by overexpressing myeloid growth factors induces resistance by curtailing necrosis. These findings may explain the susceptibility of humans with mononuclear cytopenias to mycobacterial infections and highlight the therapeutic potential of myeloid growth factors in tuberculosis.
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge CB2 0QH, UK; Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Pagán
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Chao-Tsung
authors.initials: CT
authors.lastname: Yang
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
authors.forename: James
authors.initials: J
authors.lastname: Cameron
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Swaim
authors.affiliation: Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
authors.forename: Felix
authors.initials: F
authors.lastname: Ellett
authors.affiliation: Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Lieschke
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge CB2 0QH, UK; Department of Microbiology, University of Washington, Seattle, WA 98195, USA; Department of Immunology, University of Washington, Seattle, WA 98195, USA; Department of Medicine, University of Washington, Seattle, WA 98195, USA. Electronic address: lr404@cam.ac.uk.
authors.forename: Lalita
authors.initials: L
authors.lastname: Ramakrishnan
mesh_terms: D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D006099:Granuloma / Q000276:immunology / Q000382:microbiology / Q000473:pathology*; D054884:Host-Pathogen Interactions; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology*; D019910:Mycobacterium marinum / Q000254:growth & development* / Q000276:immunology*; D009336:Necrosis / Q000473:pathology; D010587:Phagocytosis; D015027:Zebrafish
chemical_list: D036341:Intercellular Signaling Peptides and Proteins