Uncovering the neuroprotective effect of vitamin B12 in pneumococcal meningitis: insights into its pleiotropic mode of action at the transcriptional level

Frontiers in Immunology

Immunology

Cláudia Martins Carneiro¹  Karina Barbosa de Queiroz²  Marina da Silva Oliveira²  Alice Muglia Thomaz da Silva Amancio²  Roney Santos Coimbra²  Larissa Marcely Gomes Cassiano³  Gabriel da Rocha Fernandes⁴  Anna Christina de Matos Salim⁵ 

[1] Laboratório de Imunopatologia, Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, Ouro Preto, MG, Brazil;Neurogenômica, Imunopatologia, Instituto René Rachou (IRR), Fiocruz, Belo Horizonte, MG, Brazil;Neurogenômica, Imunopatologia, Instituto René Rachou (IRR), Fiocruz, Belo Horizonte, MG, Brazil;Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil;Plataforma Tecnológica de Bioinformática, Instituto René Rachou (IRR), Fiocruz, Belo Horizonte, MG, Brazil;Plataforma Tecnológica de Sequenciamento NGS (Next Generation Sequencing), Instituto René Rachou (IRR), Fiocruz, Belo Horizonte, MG, Brazil;

关键词: pneumococcal meningitis;    vitamin B12;    epidrugs;    neuroinflammation;    histone methylation;    neuroprotection;   

DOI  :  10.3389/fimmu.2023.1250055

 received in 2023-06-29, accepted in 2023-09-22,  发布年份 2023

来源: Frontiers

【 摘 要 】

BackgroundThe interplay between bacterial virulence factors and the host innate immune response in pneumococcal meningitis (PM) can result in uncontrolled neuroinflammation, which is known to induce apoptotic death of progenitor cells and post-mitotic neurons in the hippocampal dentate gyrus, resulting in cognitive impairment. Vitamin B12 attenuates hippocampal damage and reduces the expression of some key inflammatory genes in PM, by acting as an epidrug that promotes DNA methylation, with increased production of S-adenosyl-methionine, the universal donor of methyl.Material and methodsEleven-day-old rats were infected with S. pneumoniae via intracisternal injection and then administered either vitamin B12 or a placebo. After 24 hours of infection, the animals were euthanized, and apoptosis in the hippocampal dentate gyrus, microglia activation, and the inflammatory infiltrate were quantified in one brain hemisphere. The other hemisphere was used for RNA-Seq and RT-qPCR analysis.ResultsIn this study, adjuvant therapy with B12 was found to modulate the hippocampal transcriptional signature induced by PM in infant rats, mitigating the effects of the disease in canonical pathways related to the recognition of pathogens by immune cells, signaling via NF-kB, production of pro-inflammatory cytokines, migration of peripheral leukocytes into the central nervous system, and production of reactive species. Phenotypic analysis revealed that B12 effectively inhibited microglia activation in the hippocampus and reduced the inflammatory infiltrate in the central nervous system of the infected animals. These pleiotropic transcriptional effects of B12 that lead to neuroprotection are partly regulated by alterations in histone methylation markings. No adverse effects of B12 were predicted or observed, reinforcing the well-established safety profile of this epidrug.ConclusionB12 effectively mitigates the impact of PM on pivotal neuroinflammatory pathways. This leads to reduced microglia activation and inflammatory infiltrate within the central nervous system, resulting in the attenuation of hippocampal damage. The anti-inflammatory and neuroprotective effects of B12 involve the modulation of histone markings in hippocampal neural cells.

【 授权许可】

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Copyright © 2023 Cassiano, Oliveira, de Queiroz, Amancio, Salim, Fernandes, Carneiro and Coimbra