title: The impact of ISGylation during Mycobacterium tuberculosis infection in mice.
abstract: Mycobacterium tuberculosis infection results in 1.5 million deaths annually. Type I interferon (IFN) signaling through its receptor IFNAR correlates with increased severity of disease, although how this increases susceptibility to M. tuberculosis remains uncertain. ISG15 is one of the most highly induced interferon stimulated genes (ISGs) during M. tuberculosis infection. ISG15 functions by conjugation to target proteins (ISGylation), by noncovalent association with intracellular proteins, and by release from the cell. Recent studies indicated that ISG15 can function via conjugation-independent mechanisms to suppress the type I IFN response. These data raised the question of whether ISG15 may have diverse and sometimes opposing functions during M. tuberculosis infection. To address this, we analyzed ISGylation during M. tuberculosis infection and show that ISGylated proteins accumulate following infection in an IFNAR-dependent manner. Type I IFN and ISG15 both play transient roles in promoting bacterial replication. However, as the disease progresses, ISGylation deviates from the overall effect of type I IFN and, ultimately, mice deficient in ISGylation are significantly more susceptible than IFNAR mice. Our data demonstrate that ISGs can both protect against and promote disease and are the first to report a role for ISGylation during M. tuberculosis infection.
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Kimmey
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Campbell
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Weiss
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Kristen J
authors.initials: KJ
authors.lastname: Monte
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Lenschow
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO, USA. Electronic address: stallings@wusm.wustl.edu.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Stallings
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics*; D007370:Interferon Type I / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D053633:Receptor, Interferon alpha-beta / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D014397:Tuberculosis, Pulmonary / Q000382:microbiology / Q000473:pathology*; D014452:Ubiquitins / Q000235:genetics
chemical_list: D016207:Cytokines; C489550:G1p2 protein, mouse; C508032:Ifnar1 protein, mouse; D007370:Interferon Type I; D014452:Ubiquitins; D053633:Receptor, Interferon alpha-beta
keywords: ISG15; Immune response; Infection; Interferon; Mycobacteria; Pathogenesis