CONICET | Buscador de Institutos y Recursos Humanos

Inhalation of infected aerosols is one of the most frequent routes for acquiring Brucella spp. infection. The role of IL-1beta and inflammasome activation in the initial control of this infection has not been studied. To determine whether pulmonary IL-1beta contributes to the control of airborne B. abortus infection, IL-1 receptor knock-out mice (IL-1R KO) and wild type (WT) controls (C57BL/6 mice) were infected by the intra-tracheal route, and lung CFU were measured at 2 and 7 days p.i. While no significant difference was found at 2 days p.i., CFU counts were significantly higher in IL-1R KO mice at 7 days p.i. as compared to WT (mean, 3.15 x 107 vs. 1.12 x 106 CFU). Pulmonary levels of KC (neutrophils chemoattractant) were significantly lower in IL-1R KO mice at 7 days p.i. (88.3 vs. 146.2 pg/ml). To determine whether inflammasomes contribute to the control of airborne B. abortus infection, KO mice for caspase-1 (Casp-1), NRLP3 or AIM2 were infected by the intra-tracheal route, and lung CFU and cytokines were measured at different p.i. times. CFU counts were higher in Casp-1, NLRP3 and AIM2 KO mice (8.01 x 106, 1.18 x 107, and 5.43 x 106 CFU/ml, respectively) as compared to WT (0.81 x 106 CFU/ml), although differences only reached statistical significance for NLRP3. In addition, at 2 days p.i. levels of IL-1beta were lower in Casp-1 KO mice than in WT (213 vs. 465 pg/ml), and the same was true for KC (96 vs. 157 pg/ml), IL-12 (73 vs. 295 pg/ml) and TNF-alpha (130 vs. 260 pg/ml). To determine the role of different lung cells in these responses, alveolar macrophages and pneumocytes were obtained from WT mice and were infected in vitro in the presence or absence of a Casp-1 inhibitor (Z-WEHD-FMK). For both cell types, IL-1beta levels were significantly lower in the presence of the inhibitor. These results show that inflammasomes play an important role in the initial control of Brucella infection acquired through the airways.