Avaliação do papel da proteína Cinase associada ao receptor de interleucina-1 4 (IRAK-4) na resposta imuneinata durante a infecção causada pela bactéria intracelular Brucella abortus.

Abstract

Interleukin-1 receptor associated kinase 4 (IRAK-4) is a kinase that plays an important role in immune responses as a mediator on cellular signaling in responses to IL-1 receptor and various TLR ligands. This study aimed to determine the role of the IRAK-4 in host innate immune response against Brucella abortus infection. IRAK-4 knockout mice(IRAK-4-/-) and heterozygous mice (IRAK-4+/-) were infected with Brucella abortus strain S2308. Herein, it was shown that the number of colony-forming units (CFU) in IRAK-4-/- mice spleen was higher compared to IRAK-4+/- animals only at one week post-infection. At3 and 6 weeks post-infection, knockout mice were able to control the infection as the heterozygous mice. Furthermore, it was evaluated in vivo and in vitro production of type 1 cytokines crucial for brucellosis control. IRAK-4 deficient mice (IRAK-4-/-) showed lower production of systemic IL-12, and lower production of IFN- and TNF- by spleen cellswhen compared to IRAK-4+/- mice. However, the difference in IFN- production between IRAK-4+/- and IRAK-4-/- animals was higher only at first week post-infection, in agreement with the increased susceptibility of IRAK-4-/- mice. That reduction of IFN- production by IRAK-4-/- mice was observed in CD4+, CD8+ T cells and NK1.1+CD3- cells, indicating theinvolvement of IRAK-4 in activation of those cells. Also, the production of IL-12 and TNF- by macrophages and dendritic cells from IRAK-4-/- mice was abolished at 24hrs after stimulation with B. abortus. Additionally, macrophages from IRAK-4-/- mice stimulated with B. abortus, showed a deficient phosphorylation of MAPK, ERK1/2 and p38, and p65 subunit of NF-B. Furthermore, macrophages from MyD88 deficient mice also demonstrated total absence of MAPK and NF-B activation. Therefore, the results summarized in this study suggest that the IRAK-4 molecule is critical to trigger the initial immune response against B. abortus but not to late phases of infection.