Uncovering the neuroprotective effect of vitamin B12 in pneumococcal meningitis: insights into its pleiotropic mode of action at the transcriptional level
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, result...
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Frontiers Media S.A.
2023-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1250055/full |
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| author | Larissa Marcely Gomes Cassiano Larissa Marcely Gomes Cassiano Marina da Silva Oliveira Karina Barbosa de Queiroz Alice Muglia Thomaz da Silva Amancio Anna Christina de Matos Salim Gabriel da Rocha Fernandes Cláudia Martins Carneiro Roney Santos Coimbra |
| author_facet | Larissa Marcely Gomes Cassiano Larissa Marcely Gomes Cassiano Marina da Silva Oliveira Karina Barbosa de Queiroz Alice Muglia Thomaz da Silva Amancio Anna Christina de Matos Salim Gabriel da Rocha Fernandes Cláudia Martins Carneiro Roney Santos Coimbra |
| author_sort | Larissa Marcely Gomes Cassiano |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T20:19:25Z |
| format | Article |
| id | doaj.art-670980ff1c90412eb2a5051f411ebf72 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-11T20:19:25Z |
| publishDate | 2023-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-670980ff1c90412eb2a5051f411ebf722023-10-03T08:14:32ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-10-011410.3389/fimmu.2023.12500551250055Uncovering the neuroprotective effect of vitamin B12 in pneumococcal meningitis: insights into its pleiotropic mode of action at the transcriptional levelLarissa Marcely Gomes Cassiano0Larissa Marcely Gomes Cassiano1Marina da Silva Oliveira2Karina Barbosa de Queiroz3Alice Muglia Thomaz da Silva Amancio4Anna Christina de Matos Salim5Gabriel da Rocha Fernandes6Cláudia Martins Carneiro7Roney Santos Coimbra8Neurogenômica, Imunopatologia, Instituto René Rachou (IRR), Fiocruz, Belo Horizonte, MG, BrazilDepartamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, BrazilNeurogenômica, Imunopatologia, Instituto René Rachou (IRR), Fiocruz, Belo Horizonte, MG, BrazilNeurogenômica, Imunopatologia, Instituto René Rachou (IRR), Fiocruz, Belo Horizonte, MG, BrazilNeurogenômica, Imunopatologia, Instituto René Rachou (IRR), Fiocruz, Belo Horizonte, MG, BrazilPlataforma Tecnológica de Sequenciamento NGS (Next Generation Sequencing), Instituto René Rachou (IRR), Fiocruz, Belo Horizonte, MG, BrazilPlataforma Tecnológica de Bioinformática, Instituto René Rachou (IRR), Fiocruz, Belo Horizonte, MG, BrazilLaboratório de Imunopatologia, Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, Ouro Preto, MG, BrazilNeurogenômica, Imunopatologia, Instituto René Rachou (IRR), Fiocruz, Belo Horizonte, MG, BrazilBackgroundThe 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.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1250055/fullpneumococcal meningitisvitamin B12epidrugsneuroinflammationhistone methylationneuroprotection |
| spellingShingle | Larissa Marcely Gomes Cassiano Larissa Marcely Gomes Cassiano Marina da Silva Oliveira Karina Barbosa de Queiroz Alice Muglia Thomaz da Silva Amancio Anna Christina de Matos Salim Gabriel da Rocha Fernandes Cláudia Martins Carneiro Roney Santos Coimbra Uncovering the neuroprotective effect of vitamin B12 in pneumococcal meningitis: insights into its pleiotropic mode of action at the transcriptional level Frontiers in Immunology pneumococcal meningitis vitamin B12 epidrugs neuroinflammation histone methylation neuroprotection |
| title | Uncovering the neuroprotective effect of vitamin B12 in pneumococcal meningitis: insights into its pleiotropic mode of action at the transcriptional level |
| title_full | Uncovering the neuroprotective effect of vitamin B12 in pneumococcal meningitis: insights into its pleiotropic mode of action at the transcriptional level |
| title_fullStr | Uncovering the neuroprotective effect of vitamin B12 in pneumococcal meningitis: insights into its pleiotropic mode of action at the transcriptional level |
| title_full_unstemmed | Uncovering the neuroprotective effect of vitamin B12 in pneumococcal meningitis: insights into its pleiotropic mode of action at the transcriptional level |
| title_short | Uncovering the neuroprotective effect of vitamin B12 in pneumococcal meningitis: insights into its pleiotropic mode of action at the transcriptional level |
| title_sort | uncovering the neuroprotective effect of vitamin b12 in pneumococcal meningitis insights into its pleiotropic mode of action at the transcriptional level |
| topic | pneumococcal meningitis vitamin B12 epidrugs neuroinflammation histone methylation neuroprotection |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1250055/full |
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