Interleukin-1 Receptor-Associated Kinase 4 Is Essential for Initial Host Control of Brucella abortus Infection
ABSTRACTBrucella abortusis 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 toBrucellaspp. 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 againstB. abortus. AfterBrucellainfection, 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 withB. abortus. To investigate the role of IRAK-4 in mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways, macrophages were stimulated withB. 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 byBrucella. In summary, the results shown in this study demonstrated that IRAK-4 is critical to trigger the initial immune response againstB. abortusbut not at later phases of infection.