PROJECT SUMMARY C-di-GMP, c-di-AMP, and 3′3′-cGAMP, among others, are bacterial second messengers that regulate a variety aspects of bacterial physiology and pathogen-associated molecular patterns (PAMPs) that elicit host immune responses during infection. These CDNs are widely produced by bacteria, and more importantly, crucial for the pathogenesis of human pathogens including Group B Streptococcus, Mycobacterium tuberculosis, Staphylococcus aureus, Chlamydia trachomatis and Listeria monocytogenes. CDNs also have significant potential as vaccine adjuvants for infectious diseases due to their capability to boost type I IFN and adaptive immune responses. Pattern recognition receptors (PRRs) that recognize PAMPs are the first line defense for bacterial infection. Identification and characterization of CDN PRRs are therefore critical to the study of pathogenesis of infectious diseases and the application of CDNs as vaccine adjuvants. Here, we identified Kvb2, the cytosolic b subunit of voltage-dependent potassium channel Kv1, as a c-di-AMP-interacting protein through c-di-AMP affinity pull-down assay. Kvb2 is a functional aldo-keto reductase (AKR) which modulates the cellular excitability depending on the oxidative and redox status of its NADPH cofactor. Kvβ2 is widely expressed in human brain, heart and lymphoid organs. However, the dominating consequence of Kvb2 dysfunction is causing neurological impairments that leads to memory impairments and seizures. We hypothesize that Kvb2 is an innate immune guard in the neuroimmune system that senses bacterial infection by detecting CDNs and potential oxidative stresses. We aim to (i) characterize the specificity and dynamics of Kvb2 for CDN binding, as well as the mechanisms of Kv channel modulation by Kvb2 response to CDN binding; (ii) investigate the role of Kvb2 in restricting bacterial growth and modulating innate immune responses using a microglia cell line and L. monocytogenes meningitis mouse model. Our studies will couple the excitability of cells with detection of bacterial infection, which will broaden our understanding of CDN-mediated antibacterial immunity in the central nervous system.