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. Kvß2 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.