Host Susceptibility toBrucella abortusInfection Is More Pronounced in IFN-γknockout than IL-12/β2-Microglobulin Double-Deficient Mice

Abstract

Brucella abortus is a facultative intracellular bacterial pathogen that causes abortion in domestic animals and undulant fever in humans. IFN-γ, IL-12, and CD8+ T lymphocytes are important components of host immune responses against B. abortus. Herein, IFN-γ and IL-12/β2-microglobulin (β2-m) knockout mice were used to determine whether CD8+ T cells and IL-12-dependent IFN-γ deficiency would be more critical to control B. abortus infection compared to the lack of endogenous IFN-γ. At 1 week after infection, IFN-γ KO and IL-12/β2-m KO mice showed increased numbers of bacterial load in spleens; however, at 3 weeks postinfection (p.i.), only IFN-γ KO succumbed to Brucella. All IFN-γ KO had died at 16 days p.i. whereas death within the IL-12/β2-m KO group was delayed and occurred at 32 days until 47 days postinfection. Susceptibility of IL-12/β2-m KO animals to Brucella was associated to undetectable levels of IFN-γ in mouse splenocytes and inability of these cells to lyse Brucella-infected macrophages. However, the lack of endogenous IFN-γ was found to be more important to control brucellosis than CD8+ T cells and IL-12-dependent IFN-γ deficiencies.

Identification of Immune Effectors Essential to the Control of Primary and Secondary Intranasal Infection with Brucella melitensis in Mice

“…+ T cells in the primary control of Brucella infection (16,35,(41)(42)(43). We confirmed this key role in our i.n.…”

“…infectious model, the absence of IFN-gR was associated with a drastic alteration in the granuloma composition, which appeared to primarily contain neutrophils, and a lack of tissue confinement of Brucella, as demonstrated by the high levels of bacteria observed in the blood of IFN-gR 2/2 mice during chronic infection but not during the early phases of infection. In summary, our results strongly suggest that the protective role of IFN-g against Brucella infection is primarily limited to the chronic phase of infection and may even have been overestimated based on the exceptional mortality associated with IFN-g deficiency (41,43). IFN-g is clearly crucial to late Brucella control in all organs, but is not sufficient, because we observed, in an i.p.…”

Mutant Brucella abortus Membrane Fusogenic Protein Induces Protection against Challenge Infection in Mice

“…abortus ⌬mfp induces IFN-␥ production similar to that of the vaccine strains S19 and RB51. IFN-␥ is required for the bactericidal activity of macrophages and is a key cytokine in immunity against Brucella (24,25). Therefore, we investigated the IFN-␥ production of splenocytes in mice previously immunized with the ⌬mfp::kan or ⌬omp19::kan strain in response to challenge with the B. abortus wild-type strain.…”

“…A Th1 cell-dominant response is required for protection against Brucella infection (25,30). Therefore, the induction of a Th1 profile can be used as an indicator of potential Brucella vaccine efficacy in the preliminary screenings of potential candidates (12).…”

Development of an interferon-γ release assay (IGRA) for detection of Brucella abortus and clinical diagnosis of brucellosis

“…This IFN-γ priming effect has been increasingly implicated in the immune response to several infectious diseases, including viral, bacterial, and parasitic diseases [12][13][14]. For brucellosis, the crucial role of IFN-γ was recognized, as it was shown that IFN-γ knockout mice died due to B. abortus infection and IFN-γ producing CD4+ T-cells from infected donors were able to protect the recipient mice against challenge with B. abortus [15]. IFN-γ was induced by reactive nitrogen intermediates and reactive oxygen intermediates after mouse macrophages were activated [16].…”