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Principal Investigator: Kelly S Doran
Organization: UNIVERSITY OF COLORADO DENVER
Fiscal Year: 2024
Award: $347,074
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY
Bacterial meningitis is the most common serious infection of the central nervous system (CNS) and a major
cause of death and disability worldwide, especially in children. Although antibiotic therapy has changed
bacterial meningitis from a uniformly fatal disease to an often curable one, the overall outcome remains
unfavorable, with mortality of 5 to 10% and permanent neurologic sequelae occurring in 5 to 40% of survivors,
depending on patient age and pathogen. Disruption and dysfunction of the blood-brain barrier (BBB) is a
hallmark event in the pathophysiology of bacterial meningitis. Little is known, however, about the very first and
crucial interaction between a bacterial pathogen with the BBB that initiates this chain of events, and may
ultimately determine a poor or favorable neurological outcome in meningitis patients. This proposal seeks to
elucidate the molecular mechanisms of BBB disruption during bacterial infection, and why it fails as a
neuroprotective barrier during bacterial meningitis. We have shown that bacterial infection induces an epithelial
to mesenchymal transition (EMT) program in endothelial cells (EndoMT), disrupting tight junctions in BBB
endothelium through the upregulation of host transcription factor Snail1, a global repressor of tight junctions.
Further, we have discovered that a bacterial adhesin interacts directly with vimentin, an intermediate filament
protein that is induced during EMT/EndoMT. I hypothesize that BBB disruption may be due to the combined
effect of bacterial entry and modulation of host signaling pathways that results in compromised barrier function.
Further that bacterial pathogens associated with CNS disease possess the unique ability to penetrate brain
endothelium, which ultimately leads to BBB dysfunction. These hypotheses will be addressed with both in vitro
and in vivo models of BBB penetration using Group B streptococcus (GBS) as a model human pathogen
associated with meningitis. AIM 1: Characterize the bacterial determinant(s) that initiate Snail1 activation and
the contribution of Snail1 to BBB breakdown during GBS meningitis; AIM 2: Characterize the host factors that
contribute to Snail1 activation during GBS infection; AIM 3: Determine the contribution of GBS-vimentin
interaction to BBB penetration and the development of meningitis. These studies should increase our
understanding of the bacterial and host factors involved in the interaction with brain endothelium that leads to
barrier disruption, pathogen transit into the brain, and disease progression.
Terms: <0-11 years old><0-4 weeks old><21+ years old><Address><Adult><Adult Human><Age><Antibiotic Therapy><Antibiotic Treatment><BBB disruption><BBB penetration><BBB permeabilization><BBB permeable><Bacterial Adhesins><Bacterial Infections><Bacterial Meningitis><Basal Transcription Factor><Basal transcription factor genes><Biochemical><Biologic Models><Biological Models><Blocking Antibodies><Blood><Blood - brain barrier anatomy><Blood Reticuloendothelial System><Blood brain barrier dysfunction><Blood-Brain Barrier><Body Tissues><Brain><Brain Edema><Brain Nervous System><Brain Swelling><Brain Vascular><CNS Diseases><CNS Nervous System><CNS disorder><CNS infection><Cause of Death><Cell Adhesion><Cell Communication and Signaling><Cell Function><Cell Line><Cell Membrane Lipid Rafts><Cell Physiology><Cell Process><Cell Signaling><Cell Surface Receptors><CellLine><Cellular Adhesion><Cellular Function><Cellular Matrix><Cellular Physiology><Cellular Process><Central Nervous System><Central Nervous System Diseases><Central Nervous System Disorders><Central Nervous System Infections><Central Nervous System Infectious Disease><Central Nervous System Infectious Disorder><Ceramides><Cerebral endothelium><Child><Child Youth><Children (0-21)><Clinical><Cytoskeletal System><Cytoskeleton><Data><Development><Disease><Disease Progression><Disorder><Dysfunction><EGF Receptor><EGFR><ERBB Protein><Elevated Intracranial Pressure><Encephalon><Endothelial Cells><Endothelium><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Event><Extracellular Signal-Regulated Kinase Gene><Failure><Fibroblast Intermediate Filament Proteins><Functional disorder><General Transcription Factor Gene><General Transcription Factors><HER1><Hemato-Encephalic Barrier><Host Factor><Host Factor Protein><Human><Immune signaling><In Vitro><Infection><Initiation Factors><Innate Immunity><Integration Host Factors><Intermediate Filament Proteins><Intracellular Communication and Signaling><Intracranial Edema><Intracranial Hypertension><Intracranial Pressure Elevation><Intracranial Pressure Increase><Invaded><KO mice><Knock-out Mice><Knockout Mice><Life><Lipids><MAP Kinase Gene><MAP kinase><MAPK><Mediating><Membrane Microdomains><Meningitis><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mitogen-Activated Protein Kinase Gene><Mitogen-Activated Protein Kinases><Model System><Modern Man><Molecular><Native Immunity><Natural Immunity><Neoplasm Metastasis><Neuraxis><Neurologic><Neurologic outcome><Neurological><Neurological outcome><Newborn Infant><Newborns><Non-Specific Immunity><Nonspecific Immunity><Null Mouse><Nutrient><Occluding Junctions><Outcome><PTK Receptors><Pathogenesis><Pathway interactions><Patients><Penetration><Peptide Initiation Factors><Physiopathology><Process><Publishing><Receptor Protein-Tyrosine Kinases><Receptor Signaling><Receptor Tyrosine Kinase Gene><Research Proposals><Role><S agalactiae><S. agalactiae><Secondary Neoplasm><Secondary Tumor><Seizures><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Snails><Sphingolipid Microdomains><Sphingolipid-Cholesterol Rafts><Strains Cell Lines><Strep pyogenes adhesin><Streptococcal Infections><Streptococcus Group B><Streptococcus adhesin><Streptococcus agalactiae><Streptococcus infection><Subcellular Process><Survivors><TGF-alpha Receptor><Tight Junctions><Tissues><Transcription Factor Proto-Oncogene><Transcription Repressor><Transcription factor genes><Transcriptional Repressor><Transforming Growth Factor alpha Receptor><Translation Initiation Factor><Translational Initiation Factor><Transmembrane Receptor Protein Tyrosine Kinase><Tyrosine Kinase Linked Receptors><Tyrosine Kinase Receptors><Up-Regulation><Upregulation><Urogastrone Receptor><Vimentin><Work><Zinc Finger Domain><Zinc Finger Motifs><Zinc Fingers><Zonula Occludens><adhesin><adulthood><ages><bacteria infection><bacteria pathogen><bacterial disease><bacterial disease treatment><bacterial infectious disease treatment><bacterial pathogen><biological signal transduction><blood-brain barrier disruption><blood-brain barrier penetration><blood-brain barrier permeabilization><blood-brain barrier permeable><bloodbrain barrier><bloodbrain barrier disruption><bloodbrain barrier penetration><bloodbrain barrier permeabilization><bloodbrain barrier permeable><brain endothelial cell><brain endothelium><brain microvascular endothelial cell><brain vascular endothelial cell><c-erbB-1><c-erbB-1 Protein><cancer metastasis><cerebral endothelial cell><cerebral microvascular endothelial cell><cerebral vascular><cerebral vascular endothelial cell><cerebral vein><cerebral venous><cerebro-vascular><cerebrovascular><cortical endothelium><cultured cell line><developmental><disability><epithelial to mesenchymal transition><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><genetic repressor><human model><human pathogen><in vivo><in vivo Model><inhibitor><intracellular skeleton><kids><knock-down><knockdown><lipid raft><model of human><model organism><mortality><neuropathologic><neuropathological><neuropathology><neuroprotection><neuroprotective><newborn child><newborn children><novel><overexpress><overexpression><pathogen><pathogenic bacteria><pathophysiology><pathway><programs><proto-oncogene protein c-erbB-1><raised ICP><raised intracranial pressure><social role><transcription factor><tumor cell metastasis><wet brain><youngster>