Abstract
Abstract Lyme disease (LD) which is caused by the spirochete Borrelia burgdorferi (Bb) poses a global health threat. Bb infection induces type I IFN response that is associated with arthritis and other symptoms. However, the ligands, PAMPs, and signaling pathways associated with type I IFN production by Bb are poorly characterized. Stimulator of Interferon Genes (STING) signaling pathway is an intracellular surveillance pathway that detects c-di-nucleotides (CDNs) produced by pathogens through STING and induces type I IFN production. Bb produces CDNs and hence it has the potential to activate the STING signaling pathway. In this study, the role of c-di-AMP in the elicitation of type I IFN response to Bb infection was elucidated. The RAW cell line was infected with Bb and activation of STING signaling was measured by detecting the activation of downstream proteins (pSTING, pTBK1, pIRF3 & pNF-κB), proinflammatory cytokines (IL6, TNF-α) and Type I IFN (IFN-β) response using ELISA, western blotting, immunostaining, and Luciferase Reporter assay. Bb infection to macrophage results in c-di-AMP mediated elicitation of type I IFN response. The induction level of type I IFN response was dependent on the level of c-di-AMP as the Bb mutant strain producing higher c-di-AMP level induced higher cytokine production. Interestingly, c-di-AMP released into the BSK-II medium during the culture of Bb could also stimulate the production of type I IFN response. The induction of type I IFN by c-di-AMP was dependent on STING protein as the RAW STING KO cell line showed a reduction in the level of IFN-β. In conclusion, our results show that Bb-produced c-di-AMP is a major PAMP that triggers type I interferon production in macrophage by activation of the STING signaling pathway.
Published Version
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