title: Interleukin-1 receptor-associated kinase 4 is essential for initial host control of Brucella abortus infection.
abstract: Brucella abortus is a facultative intracellular bacterial pathogen that causes abortion in domestic animals and undulant fever in humans. Recent studies have revealed that Toll-like receptor (TLR)-initiated immune response to Brucella spp. depends on myeloid differentiation factor 88 (MyD88) signaling. Therefore, we decided to study the role of the interleukin-1 receptor-associated kinase 4 (IRAK-4) in host innate immune response against B. abortus. After Brucella infection, it was shown that the number of CFU in IRAK-4(-/-) mice was high compared to that in IRAK-4(+/-) animals only at 1 week postinfection. At 3 and 6 weeks postinfection, IRAK-4(-/-) mice were able to control the infection similarly to heterozygous animals. Furthermore, the type 1 cytokine profile was evaluated. IRAK-4(-/-) mice showed lower production of systemic interleukin-12 (IL-12) and gamma interferon (IFN-γ). Additionally, a reduced percentage of CD4(+) and CD8(+) T cells expressing IFN-γ was observed compared to IRAK-4(+/-). Further, the production of IL-12 and tumor necrosis factor alpha (TNF-α) by macrophages and dendritic cells from IRAK-4(-/-) mice was abolished at 24 h after stimulation with B. abortus. To investigate the role of IRAK-4 in mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways, macrophages were stimulated with B. abortus, and the signaling components were analyzed by protein phosphorylation. Extracellular signal-regulated kinase 1 (ERK1) and ERK2 and p38 as well as p65 NF-κB phosphorylation was profoundly impaired in IRAK-4(-/-) and MyD88(-/-) macrophages activated by Brucella. In summary, the results shown in this study demonstrated that IRAK-4 is critical to trigger the initial immune response against B. abortus but not at later phases of infection.
authors.affiliation: Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Fernanda S
authors.initials: FS
authors.lastname: Oliveira
authors.forename: Natália B
authors.initials: NB
authors.lastname: Carvalho
authors.forename: Ana Paula M S
authors.initials: AP
authors.lastname: Brandão
authors.forename: Marco Túlio R
authors.initials: MT
authors.lastname: Gomes
authors.forename: Leonardo A
authors.initials: LA
authors.lastname: de Almeida
authors.forename: Sérgio C
authors.initials: SC
authors.lastname: Oliveira
mesh_terms: D000818:Animals; D002003:Brucella abortus; D002006:Brucellosis / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D054884:Host-Pathogen Interactions; D007249:Inflammation / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout
chemical_list: D016207:Cytokines; D053592:Interleukin-1 Receptor-Associated Kinases; C507774:Irak4 protein, mouse