RIG-I as a therapeutic target for bacterial CNS infection: A pilot study

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Project Summary Bacterial meningitis and meningoencephalitis are serious clinical conditions that result in permanent disabilities and can even cause death within hours. It is now appreciated that resident glia, such as microglia and astrocytes, play an important role in both protective and detrimental immune responses, and such responses to bacterial infection of the central nervous system (CNS) are initiated via pattern recognition receptor (PRR)-dependent identification of pathogen motifs. Therefore, defining the mechanisms underlying glial bacterial recognition has the potential to identify novel therapeutic targets. We, and others, have shown that glial cells use a combination of cell surface and cytosolic PRRs to identify pathogen motifs. Intriguingly, while retinoic acid-inducible gene-I (RIG-I), is known to recognize viral nucleic acids, recent evidence suggests that this cytosolic PRR may play a novel role in the identification of bacterial nucleic acids. In contrast to the potentially devastating inflammatory responses that can be initiated by surface PRRs, RIG-I activation stimulates interferon production that shapes protective innate and adaptive immune responses to infection. To date, the ability of RIG-I to identify bacterial nucleic acids in glial cells thereby promoting antibacterial responses has not been explored. Our recently published data indicates RIG-I expression is upregulated in microglia following exposure to disparate clinically relevant bacterial pathogens of the CNS, and such challenge can initiate potentially protective interferon production. In this pilot R03 study, we will investigate the hypothesis that bacterial recognition via RIG-I promotes protective glial responses. Results from these pilot studies will expand our knowledge of RIG-I function and regulation in glia during bacterial challenge, and begin to evaluate the in vitro protective effects of a novel synthetic nucleic acid nanoparticle RIG-I agonist. Collectively, these pilot studies will provide a solid rationale for a future comprehensive analysis of the relative importance of RIG-I-mediated glial responses in bacterial infections of the CNS, and an in vivo examination of the therapeutic potential of novel synthetic RIG-I agonists.