RIG-I promotes protective type I interferon production by glia in response to Neisseria meningitidis and Streptococcus pneumoniae challenge 2257066

Abstract Introduction Bacterial meningitis is a rapidly progressing and often fatal infection of the central nervous system (CNS), driven by glial cell activation and potent neuroinflammatory responses. While many pattern recognition receptors are well characterized in CNS immunity, the role of cytosolic nucleic acid sensors such as retinoic acid-inducible gene I (RIG-I) remains largely undefined. Although classically associated with antiviral defense, emerging evidence indicates that RIG-I can also detect bacterial nucleic acids. Methods To investigate the role of RIG-I during bacterial meningitis, primary murine microglia, astrocytes, and human microglia were infected with Neisseria meningitidis or Streptococcus pneumoniae in the absence or presence of RIG-I-targeting siRNA, recombinant IFN-β, or RIG-I agonists. Whole-cell lysates and supernatants were analyzed for RIG-I and interferon-stimulated gene (ISG) expression by Western blot, cytokine levels (IL-6 and IFN-β) by ELISA and bacterial burden by plating viable CFU. Results We demonstrate that RIG-I is constitutively expressed in human and murine glial cells and is upregulated upon bacterial infection, with protein levels varying by pathogen. RIG-I activation enhanced IFN production and ISG induction, leading to reduced bacterial burden in an IFNAR-dependent manner. Treatment with RIG-I agonists further amplified these protective responses. Additionally, DNA-templated silver nanoclusters (DNA-AgNCs) served as a complementary antimicrobial approach, exhibiting potent bactericidal activity against N. meningitidis and S. pneumoniae in infected glia. Conclusion Together, these findings identify RIG-I as a key cytosolic sensor driving protective IFN-dependent antimicrobial responses in glial cells, while AgNCs offer a direct antimicrobial strategy. Collectively, these approaches highlight the potential for targeting both innate immune pathways and direct antimicrobial mechanisms to enhance pathogen control during bacterial meningitis. Funding Source R03 NS120047-01A1 Topic Categories Neuroimmunology (NEUR)