title: Unique role for ATG5 in neutrophil-mediated immunopathology during M. tuberculosis infection.
abstract: Mycobacterium tuberculosis, a major global health threat, replicates in macrophages in part by inhibiting phagosome-lysosome fusion, until interferon-γ (IFNγ) activates the macrophage to traffic M. tuberculosis to the lysosome. How IFNγ elicits this effect is unknown, but many studies suggest a role for macroautophagy (herein termed autophagy), a process by which cytoplasmic contents are targeted for lysosomal degradation. The involvement of autophagy has been defined based on studies in cultured cells where M. tuberculosis co-localizes with autophagy factors ATG5, ATG12, ATG16L1, p62, NDP52, BECN1 and LC3 (refs 2-6), stimulation of autophagy increases bacterial killing, and inhibition of autophagy increases bacterial survival. Notably, these studies reveal modest (~1.5-3-fold change) effects on M. tuberculosis replication. By contrast, mice lacking ATG5 in monocyte-derived cells and neutrophils (polymorponuclear cells, PMNs) succumb to M. tuberculosis within 30 days, an extremely severe phenotype similar to mice lacking IFNγ signalling. Importantly, ATG5 is the only autophagy factor that has been studied during M. tuberculosis infection in vivo and autophagy-independent functions of ATG5 have been described. For this reason, we used a genetic approach to elucidate the role for multiple autophagy-related genes and the requirement for autophagy in resistance to M. tuberculosis infection in vivo. Here we show that, contrary to expectation, autophagic capacity does not correlate with the outcome of M. tuberculosis infection. Instead, ATG5 plays a unique role in protection against M. tuberculosis by preventing PMN-mediated immunopathology. Furthermore, while Atg5 is dispensable in alveolar macrophages during M. tuberculosis infection, loss of Atg5 in PMNs can sensitize mice to M. tuberculosis. These findings shift our understanding of the role of ATG5 during M. tuberculosis infection, reveal new outcomes of ATG5 activity, and shed light on early events in innate immunity that are required to regulate disease pathology and bacterial replication.
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Kimmey
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Huynh
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Weiss
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Sunmin
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Amal
authors.initials: A
authors.lastname: Kambal
authors.affiliation: Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California 94143, USA.
authors.forename: Jayanta
authors.initials: J
authors.lastname: Debnath
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Virgin
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Stallings
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D000071187:Autophagy-Related Protein 5; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D007113:Immunity, Innate / Q000276:immunology; D007371:Interferon-gamma / Q000172:deficiency / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000502:physiology; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*
chemical_list: C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D007371:Interferon-gamma