Abstract
Smooth virulent Brucella abortus strain 2308 (S2308) causes zoonotic brucellosis in cattle and humans. Rough B. abortus strain RB51, derived from S2308, is a live attenuated cattle vaccine strain licensed in the USA and many other countries. Our previous report indicated that RB51, but not S2308, induces a caspase-2-dependent apoptotic and necrotic macrophage cell death. Dendritic cells (DCs) are professional antigen presenting cells critical for bridging innate and adaptive immune responses. In contrast to Brucella-infected macrophages, here we report that S2308 induced higher levels of apoptotic and necrotic cell death in wild type bone marrow-derived DCs (WT BMDCs) than RB51. The RB51 and S2308-induced BMDC cell death was regulated by caspase-2, indicated by the minimal cell death in RB51 and S2308-infected BMDCs isolated from caspase-2 knockout mice (Casp2KO BMDCs). More S2308 bacteria were taken up by Casp2KO BMDCs than wild type BMDCs. Higher levels of S2308 and RB51 cells were found in infected Casp2KO BMDCs compared to infected WT BMDCs at different time points. RB51-infected wild type BMDCs were mature and activated as shown by significantly up-regulated expression of CD40, CD80, CD86, MHC-I, and MHC-II. RB51 induced the production of cytokines TNF-α, IL-6, IFN-γ and IL12/IL23p40 in infected BMDCs. RB51-infected WT BMDCs also stimulated the proliferation of CD4+ and CD8+ T cells compared to uninfected WT BMDCs. However, the maturation, activation, and cytokine secretion are significantly impaired in Casp2KO BMDCs infected with RB51 or Salmonella (control). S2308-infected WT and Casp2KO BMDCs were not activated and could not induce cytokine production. These results demonstrated that virulent smooth strain S2308 induced more apoptotic and necrotic dendritic cell death than live attenuated rough vaccine strain RB51; however, RB51, but not its parent strain S2308, induced caspase-2-mediated DC maturation, cytokine production, antigen presentation, and T cell priming.
Highlights
Brucella is a facultative intracellular a2-proteobacterium that causes brucellosis, one of the most common zoonotic diseases, in humans and a wide variety of animals [1]
Whether caspase-2 regulates cell death of Dendritic cells (DCs) infected with any pathogens is unknown. It remains to be explored whether caspase-2 regulates protective T cell immunity against brucellosis and other infectious diseases. We report that both live attenuated vaccine strain RB51 and its parent virulent strain strain 2308 (S2308) induced caspase-2dependent apoptotic and necrotic Bone marrow-derived DCs (BMDCs) cell death, and more cell death was observed in S2308-infected wild type BMDCs
The different levels of RB51 and S2308induced BMDC cell death was observed with a multiplicity of infection (MOI) of 20 for 4 h or a MOI of 5 for 24 h
Summary
Brucella is a facultative intracellular a2-proteobacterium that causes brucellosis, one of the most common zoonotic diseases, in humans and a wide variety of animals [1]. Brucella pathogenicity resides mainly in its ability to survive and replicate intracellularly in mononuclear phagocytes and to control host immune responses. Virulent smooth Brucella survive and replicate within these professional phagocytes. Smooth Brucella strains contain intact lipopolysaccharide (LPS) O-antigen (e.g., S2308). While smooth Brucella strains prevent macrophage cell death, rough attenuated Brucella strains cannot survive inside macrophages and often induce programmed macrophage cell death [3,4,5,6]. There is no licensed human Brucella vaccine. Rough B. abortus strain RB51, derived from virulent smooth strain 2308 (S2308), is a live attenuated cattle vaccine strain licensed in the USA and many other countries [7]. Brucella-specific T helper type 1 (Th1) response and cytotoxic T lymphocyte (CTL) activities are critical for RB51-induced protective immunity [8]
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