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Published on: August 15, 2017
Gene expression in cortex and hippocampus during acute pneumococcal meningitis
Roney S Coimbra1, Veronique Voisin, Antoine B de Saizieu
1Institute for Infectious Diseases, University of Bern, Friedbühlstrasse 51, CH-3010, Bern, Switzerland. roney.s.coimbra@gsk.com
Background:
Pneumococcal meningitis is associated with high mortality (approximately 30%) and morbidity. Up to 50% of survivors are affected by neurological sequelae due to a wide spectrum of brain injury mainly affecting the cortex and hippocampus. Despite this significant disease burden, the genetic program that regulates the host response leading to brain damage as a consequence of bacterial meningitis is largely unknown. We used an infant rat model of pneumococcal meningitis to assess gene expression profiles in cortex and hippocampus at 22 and 44 hours after infection and in controls at 22 h after mock-infection with saline. To analyze the biological significance of the data generated by Affymetrix DNA microarrays, a bioinformatics pipeline was used combining (i) a literature-profiling algorithm to cluster genes based on the vocabulary of abstracts indexed in MEDLINE (NCBI) and (ii) the self-organizing map (SOM), a clustering technique based on covariance in gene expression kinetics.
Results:
Among 598 genes differentially regulated (change factor > or = 1.5; p < or = 0.05), 77% were automatically assigned to one of 11 functional groups with 94% accuracy. SOM disclosed six patterns of expression kinetics. Genes associated with growth control/neuroplasticity, signal transduction, cell death/survival, cytoskeleton, and immunity were generally upregulated. In contrast, genes related to neurotransmission and lipid metabolism were transiently downregulated on the whole. The majority of the genes associated with ionic homeostasis, neurotransmission, signal transduction and lipid metabolism were differentially regulated specifically in the hippocampus. Of the cell death/survival genes found to be continuously upregulated only in hippocampus, the majority are pro-apoptotic, while those continuously upregulated only in cortex are anti-apoptotic.
Conclusion:
Temporal and spatial analysis of gene expression in experimental pneumococcal meningitis identified potential targets for therapy.
Insights
Pneumococcal meningitis causes brain damage. This study identified specific gene expression patterns in the infant rat brain, revealing potential therapeutic targets for neurological sequelae.
Area of Science:
- Neuroscience
- Genomics
- Infectious Disease
Background:
- Pneumococcal meningitis has high mortality and causes significant neurological damage in survivors, particularly affecting the cortex and hippocampus.
- The genetic basis of host response leading to brain injury in bacterial meningitis remains largely unknown.
- Current understanding of the host's genetic response to pneumococcal meningitis is limited.
Purpose of the Study:
- To investigate the gene expression profiles in the infant rat brain during pneumococcal meningitis.
- To identify the genetic programs regulating host response and brain damage.
- To uncover potential therapeutic targets for neurological sequelae.
Main Methods:
- Utilized an infant rat model of pneumococcal meningitis.
- Assessed gene expression in cortex and hippocampus using Affymetrix DNA microarrays at 22 and 44 hours post-infection.
- Employed a bioinformatics pipeline combining literature profiling and self-organizing maps (SOM) for data analysis.
Main Results:
- Identified 598 differentially regulated genes, with 77% assigned to functional groups.
- Disclosed six distinct patterns of gene expression kinetics.
- Observed upregulation of genes related to growth, neuroplasticity, signal transduction, cell death/survival, cytoskeleton, and immunity.
- Noted transient downregulation of genes involved in neurotransmission and lipid metabolism.
- Found differential regulation of ionic homeostasis, neurotransmission, signal transduction, and lipid metabolism genes predominantly in the hippocampus.
- Observed contrasting regulation of cell death/survival genes: pro-apoptotic in hippocampus and anti-apoptotic in cortex.
Conclusions:
- Temporal and spatial gene expression analysis in experimental pneumococcal meningitis provides insights into the host's response.
- Identified specific genes and pathways that are differentially regulated in the brain.
- These findings highlight potential therapeutic targets for mitigating brain damage and neurological sequelae associated with pneumococcal meningitis.
