Abstract
Brucella has developed a stealth strategy through pathogen-associated molecular patterns reduction, modification, and hiding to ensure low stimulatory activity. This strategy allows Brucella to reach its replication niche before activating antimicrobial mechanisms by host immune responses. However, inside the host cells, Brucella releases vital molecules for the bacteria that trigger the activation of host cytosolic receptors. First, we defined that Brucella LPS is the ligand for the receptor caspase-11. Additionally, we determined that B. abortus is able to trigger pyroptosis leading to pore formation and cell death, and this process is dependent on caspase-11 and gasdermin-D (GSDMD). Mice lacking either caspase-11 or GSDMD were significantly more susceptible to infection with B. abortus than wild-type animals. Our findings suggest that caspase-11/GSDMD-dependent pyroptosis triggered by B. abortus is important to infection restriction in vivo and contributes to immune cell recruitment and activation. Besides LPS, DNA is another important bacterial ligand. Then, we determined that the cGAS/STING pathway is able to recognize bacterial genomic DNA and cyclic dinucleotides. Further, we have demonstrated that STING but not cGAS is critical for host protection against Brucella infection in macrophages and in vivo. Additionally, we revealed that STING contributes to an inflammatory M1-like macrophage profile upon Brucella abortus infection. This metabolic reprogramming is induced by STING-dependent stabilization of hypoxia-inducible factor-1 alpha (HIF-1a). HIF-1a stabilization reduces oxidative phosphorylation and increases glycolysis during infection with B. abortus and enhances nitric oxide production, inflammasome activation and IL-1b release in macrophages that are involved in reduced bacterial replication. In summary, identifying innate immune receptors and their ligands is critical to the development of new vaccines and control measures against Brucella infection. In addition, we speculate on the prospect of targeting immunometabolism in the effort to develop novel therapeutics to treat brucellosis and other bacterial infections.
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