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Inducing Meningococcal Meningitis Serogroup C in Mice via Intracisternal Delivery
Published on: November 5, 2019
The ZNF148-ZEB1-AS1-IGF2BP2-NOD2 Axis Drives Microglial Antipneumococcal Immunity in Bacterial Meningitis
Xiufu Hu1, Fang Jiang1, Xinjie Liu2
1Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, Shandong, China.
Abstract:
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.
Insights
This study reveals ZEB1-AS1 as a key regulator of microglial immune response to Streptococcus pneumoniae meningitis. It highlights the ZEB1-AS1/IGF2BP2/NOD2 pathway, offering a potential therapeutic target for this infection.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Streptococcus pneumoniae meningitis is a severe CNS infection with limited treatment options.
- Microglia play a crucial role in the brain's immune response to infection.
- Long non-coding RNAs (lncRNAs) are increasingly recognized for their regulatory roles in immunity.
Purpose of the Study:
- To identify key molecular regulators of microglial immunity against Streptococcus pneumoniae.
- To elucidate the regulatory mechanisms governing microglial responses during Spn meningitis.
- To explore potential therapeutic targets for Spn meningitis.
Main Methods:
- Transcriptomic analysis of human microglia infected with Spn.
- Functional studies involving knockdown and overexpression of ZEB1-AS1.
- RNA immunoprecipitation, co-immunoprecipitation, and rescue experiments.
- In vivo studies using murine models of Spn meningitis.
Main Results:
- Spn infection upregulates lncRNA ZEB1-AS1 in microglia, driven by ZNF148.
- ZEB1-AS1 knockdown impairs bacterial clearance and pro-inflammatory cytokine production.
- ZEB1-AS1 recruits IGF2BP2 to stabilize NOD2 mRNA, enhancing antimicrobial functions.
- Manipulation of Zeb1-os1 in vivo affects Spn burden and cognitive outcomes.
Conclusions:
- The ZNF148-ZEB1-AS1-IGF2BP2-NOD2 axis is a critical regulator of microglial immunity against Spn.
- This pathway bridges transcriptional and post-transcriptional regulation of the immune response.
- IGF2BP2's RNA-binding domain represents a potential therapeutic target for Spn meningitis.
