The ZNF148-ZEB1-AS1-IGF2BP2-NOD2 Axis Drives Microglial Antipneumococcal Immunity in Bacterial Meningitis

Streptococcus pneumoniae (Spn) meningitis remains a lethal central nervous system (CNS) infection with limited therapies. This study identifies the lncRNA ZEB1-AS1 as a central coordinator of microglial immunity against Spn through a multi-tiered regulatory cascade. Transcriptomic analysis revealed Spn-induced ZEB1-AS1 upregulation in human microglia, driven by ZNF148, which directly binds its promoter. Functional interrogation demonstrated that ZEB1-AS1 knockdown impairs bacterial clearance and pro-inflammatory cytokine production (IL-1β, IL-6, TNF-α, p < 0.01), while its overexpression amplifies these responses. Crucially, ZEB1-AS1 recruits the m6A reader IGF2BP2 to stabilize NOD2 mRNA in cytoplasmic complexes, extending transcript stability. This molecular scaffolding enables NOD2-dependent antimicrobial functions, as evidenced by rescue experiments in which IGF2BP2 overexpression reversed ZEB1-AS1 deficiency phenotypes. In vivo, microglial manipulation of the murine homolog Zeb1-os1 regulated cerebral Spn burdens, NOD2 expression, and infection-induced cognitive outcomes in both directions. The tripartite ZEB1-AS1/IGF2BP2/NOD2 interaction was validated by RNA pulldown and co-immunoprecipitation, establishing a linear pathway from ZNF148-mediated transcriptional activation to IGF2BP2-dependent mRNA stabilization. Collectively, this ZNF148 to ZEB1-AS1 to IGF2BP2 to NOD2 axis bridges the gap between transcriptional and post-transcriptional immune regulation, proposing IGF2BP2's RNA-binding domain as a therapeutic target against drug-resistant Spn meningitis.