title: Interferon regulatory factor 8-deficiency determines massive neutrophil recruitment but T cell defect in fast growing granulomas during tuberculosis.
abstract: Following Mycobacterium tuberculosis (Mtb) infection, immune cell recruitment in lungs is pivotal in establishing protective immunity through granuloma formation and neogenesis of lymphoid structures (LS). Interferon regulatory factor-8 (IRF-8) plays an important role in host defense against Mtb, although the mechanisms driving anti-mycobacterial immunity remain unclear. In this study, IRF-8 deficient mice (IRF-8⁻/⁻) were aerogenously infected with a low-dose Mtb Erdman virulent strain and the course of infection was compared with that induced in wild-type (WT-B6) counterparts. Tuberculosis (TB) progression was examined in both groups using pathological, microbiological and immunological parameters. Following Mtb exposure, the bacterial load in lungs and spleens progressed comparably in the two groups for two weeks, after which IRF-8⁻/⁻ mice developed a fatal acute TB whereas in WT-B6 the disease reached a chronic stage. In lungs of IRF-8⁻/⁻, uncontrolled growth of pulmonary granulomas and impaired development of LS were observed, associated with unbalanced homeostatic chemokines, progressive loss of infiltrating T lymphocytes and massive prevalence of neutrophils at late infection stages. Our data define IRF-8 as an essential factor for the maintenance of proper immune cell recruitment in granulomas and LS required to restrain Mtb infection. Moreover, IRF-8⁻/⁻ mice, relying on a common human and mouse genetic mutation linked to susceptibility/severity of mycobacterial diseases, represent a valuable model of acute TB for comparative studies with chronically-infected congenic WT-B6 for dissecting protective and pathological immune reactions.
authors.affiliation: Department of Veterinary Medicine, University of Sassari, Sassari, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Rocca
authors.forename: Giovanna
authors.initials: G
authors.lastname: Schiavoni
authors.forename: Michela
authors.initials: M
authors.lastname: Sali
authors.forename: Antonio Giovanni
authors.initials: AG
authors.lastname: Anfossi
authors.forename: Laura
authors.initials: L
authors.lastname: Abalsamo
authors.forename: Ivana
authors.initials: I
authors.lastname: Palucci
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Mattei
authors.forename: Massimo
authors.initials: M
authors.lastname: Sanchez
authors.forename: Anna
authors.initials: A
authors.lastname: Giagu
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Antuofermo
authors.forename: Giovanni
authors.initials: G
authors.lastname: Fadda
authors.forename: Filippo
authors.initials: F
authors.lastname: Belardelli
authors.forename: Giovanni
authors.initials: G
authors.lastname: Delogu
authors.forename: Lucia
authors.initials: L
authors.lastname: Gabriele
mesh_terms: D000818:Animals; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D015769:Granuloma, Respiratory Tract / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D006801:Humans; D050835:Interferon Regulatory Factors / Q000172:deficiency* / Q000235:genetics; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008221:Lymphoid Tissue / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D020556:Neutrophil Infiltration; D013601:T-Lymphocytes / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000473:pathology; D000099185:Interferon Regulatory Factor-8
chemical_list: D050835:Interferon Regulatory Factors; D000099185:Interferon Regulatory Factor-8