title: Lack of IL-1 Receptor-Associated Kinase-4 Leads to Defective Th1 Cell Responses and Renders Mice Susceptible to Mycobacterial Infection.
abstract: The Toll-like and IL-1 family receptors play critical roles in innate and adaptive immunity against intracellular pathogens. Although previous data demonstrated the importance of TLRs and IL-1R signaling events for the establishment of an effective immune response to mycobacteria, the possible function of the adaptor molecule IL-1R-associated kinase (IRAK)-4 against this pathogen has not been addressed. In this study, we determined the role of IRAK-4 in signaling pathways responsible for controlling mycobacterial infections. This kinase is important for the production of IL-12 and TNF-α by macrophages and dendritic cells exposed to mycobacteria. Moreover, Mycobacterium bovis-infected IRAK-4-knockout macrophages displayed impaired MAPK and NF-κB activation. IL-1β secretion and caspase-1 activation were also dependent on IRAK-4 signaling. Mice lacking IRAK-4 showed increased M. bovis burden in spleen, liver, and lungs and smaller liver granulomas during 60 d of infection compared with wild-type mice. Furthermore, 80% of IRAK-4(-/-) mice succumbed to virulent M. tuberculosis within 100 d following low-dose infection. This increased susceptibility to mycobacteria correlated with reduced IFN-γ/TNF-α recall responses by splenocytes, as well as fewer IL-12p70-producing APCs. Additionally, we observed that IRAK-4 is also important for the production of IFN-γ by CD4(+) T cells from infected mice. Finally, THP-1 cells treated with an IRAK-4 inhibitor and exposed to M. bovis showed reduced TNF-α and IL-12, suggesting that the results found in mice can be extended to humans. In summary, these data demonstrate that IRAK-4 is essential for innate and adaptive immunity and necessary for efficient control of mycobacterial infections.
authors.affiliation: Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil;
authors.forename: Fábio V
authors.identifier: 0000-0001-6885-3438
authors.initials: FV
authors.lastname: Marinho
authors.affiliation: Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil;
authors.forename: Júlia S
authors.initials: JS
authors.lastname: Fahel
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; and.
authors.forename: Charles A
authors.identifier: 0000-0003-3654-5603
authors.initials: CA
authors.lastname: Scanga
authors.affiliation: Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil;
authors.forename: Marco Tulio R
authors.identifier: 0000-0002-7892-1200
authors.initials: MT
authors.lastname: Gomes
authors.affiliation: Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil;
authors.forename: Gabriela
authors.initials: G
authors.lastname: Guimarães
authors.affiliation: Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil;
authors.forename: Gabrielle R M
authors.initials: GR
authors.lastname: Carvalho
authors.affiliation: Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina 88040900, Brazil.
authors.forename: Stefanny V
authors.initials: SV
authors.lastname: Morales
authors.affiliation: Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina 88040900, Brazil.
authors.forename: André
authors.identifier: 0000-0002-5148-600X
authors.initials: A
authors.lastname: Báfica
authors.affiliation: Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil; scozeus@icb.ufmg.br.
authors.forename: Sergio Costa
authors.initials: SC
authors.lastname: Oliveira
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D058491:Bacterial Load; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology / Q000382:microbiology; D006801:Humans; D007113:Immunity, Innate; D053592:Interleukin-1 Receptor-Associated Kinases / Q000172:deficiency* / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008099:Liver / Q000382:microbiology / Q000473:pathology; D008168:Lung / Q000382:microbiology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology* / Q000473:pathology; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000382:microbiology; D009163:Mycobacterium bovis / Q000254:growth & development / Q000276:immunology / Q000472:pathogenicity; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000382:microbiology; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology*; D014373:Tuberculin / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D016328:NF-kappa B; D014373:Tuberculin; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D053592:Interleukin-1 Receptor-Associated Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D020170:Caspase 1