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Principal Investigator: ANGIE GELLI
Organization: UNIVERSITY OF CALIFORNIA AT DAVIS
Fiscal Year: 2024
Award: $50,304
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT ABSTRACT
Infections of the central nervous system (CNS) caused by fungi have the highest morbidity and
mortality when compared to other causative agents of CNS infections. Cryptococcus neoformans
(Cn), Candida albicans, Aspergillus spp., Mucor, Coccidioides spp., and Histoplasma capsulatum
are the most common cause of fungal brain infections resulting in a chronic instead of an acute
or subacute meningoencephalitis. The long-term goal will investigate the spatio-temporal
organization and molecular basis of Cn trafficking across the BBB and investigate a cross-talk
between a transcellular mechanism and the opening of a paracellular path in response to Cn
infection. Given our preliminary data and published studies, we propose that Cn represents an
excellent model pathogen with which to determine the mechanisms that pathogenic fungi use to
breach the BBB and enter the CNS. In our efforts to understand the molecular basis mediating
the Cn-brain endothelium interactions, we identified a tyrosine kinase receptor (EphA2-TKR) as
the central player. The central hypothesis states that fungal cells penetrate the BBB by engaging
EphA2-TKR in order to access a binary path into the CNS. To test our hypothesis, we will
investigate the interplay between fungal cells, EphA2-TRK and its downstream signaling
components in mediating the translocation of Cn from blood-to-brain. The following specific aims
will test the hypothesis: SA1 will investigate a Cn-induced CD44-mediated transactivation of
EphA2-TKR activity and the interactome of EphA2-TKR. SA2 will examine the role of EphA2-TKR
in upregulating vesicular traffic of Cn and resolve whether Cn-induced activity of EphA2-TKR
promotes a co-regulation of a transcellular and paracellular pathway. SA3 will resolve the
contribution of EphA2-TKR activity to the translocation of Cn from blood-to-brain in vivo and
examine the molecular basis of changes in the permeability of the BBB when challenged by Cn.
The proposed research is innovative because it will for the first time, detail the key players that
promote the internalization and trafficking of fungi across the BBB. The innovation extends to our
published studies that identified EphA2-TKR in the brain endothelium as a central element in
mediating the migration Cn from blood-to-brain. This along with the notion that crossing of the
BBB is initiated by a fungal-induced CD44-transactivation of EphA2-TKR to trigger a pathological
use of endocytosis (and possibly a secondary paracellular path) in brain endothelial cells is a
paradigm shift from our current understanding. We have proposed experiments that will use
multiple complementary approaches to tease apart the molecular interaction between Cn, EphA2-
TKR and CD44 while also using proximity-dependent labeling to identify the interactome of
EphA2-TKR. The knowledge gained from our studies will make a significant contribution to fungal
pathogenesis of the CNS, because it remains significantly understudied, and this work will
spearhead the development of molecules that could block fungal entry and thus serve as pre-
emptive or prophylactic therapy in patients at risk for developing fungal meningoencephalitis.
Terms: <AIDS><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immunodeficiency Syndrome><Acquired brain injury><Acute><Area><Aspergillus><Autopsy><BBB crossing><BBB penetration><BBB permeabilization><BBB permeable><Binding><Blood><Blood Reticuloendothelial System><Brain><Brain Injuries><Brain Nervous System><C albicans><C neoformans><C. albicans><C. neoformans><C.albicans><CD44><CD44 gene><CNS Nervous System><CNS agent><CNS infection><Candida albicans><Cause of Death><Cell Body><Cell Communication and Signaling><Cell Locomotion><Cell Migration><Cell Movement><Cell Signaling><Cells><Cellular Matrix><Cellular Migration><Cellular Motility><Central Nervous System><Central Nervous System Agents><Central Nervous System Drugs><Central Nervous System Fungal Infections><Central Nervous System Infections><Central Nervous System Infectious Disease><Central Nervous System Infectious Disorder><Central Nervous System Mycoses><Cerebral endothelium><Cerebromeningitis><Cessation of life><Chronic><Coccidioides><Columbidae><Complex><Cryptococcus><Cryptococcus neoformans><Cryptococcus neoformans infection><Cystic Lesion><Cytoskeletal System><Cytoskeleton><Data><Death><Development><Disease><Disorder><Doves><Drops><Drugs><Elements><Encephalomeningitis><Encephalon><Endocytosis><Environment><EphA2 Protein><EphA2 Receptor><EphA2 Receptor Tyrosine Kinase><EphA2-Tyrosine Kinase><Epithelial Cell Kinase Protein><Fungal Spores><Goals><H capsulatum><H. capsulatum><Health><Histoplasma capsulatum><Hospital Admission><Hospitalization><Human><In Vitro><Infection><Inhalation><Inhaling><Intracellular Communication and Signaling><Invaded><Knock-out><Knockout><Knowledge><Label><Lung Parenchyma><Lung Tissue><MDU3><Mammary-Derived Tyrosine Kinase 2><Mediating><Medication><Meningoencephalitis><Mission><Modeling><Modern Man><Molecular><Molecular Interaction><Morbidity><Morbidity - disease rate><Movement><Mucor><NIH><National Institutes of Health><Nature><Neuraxis><PTK Receptors><Pathogenesis><Pathologic><Pathway interactions><Patients><Permeability><Pgp1><Pharmaceutical Preparations><Pigeons><Process><Proliferating><Publishing><Receptor Protein-Tyrosine Kinases><Receptor Tyrosine Kinase Gene><Reporting><Reproduction spores><Research><Risk><Role><Route><Series><Signal Transduction><Signal Transduction Systems><Signaling><Soil><Spores><Structure of parenchyma of lung><Technology><Testing><Time><Torula><Transactivation><Transmembrane Receptor Protein Tyrosine Kinase><Trees><Tyrosine Kinase Linked Receptors><Tyrosine Kinase Receptors><United States National Institutes of Health><Work><aerosolized><biological signal transduction><blood-brain barrier crossing><blood-brain barrier penetration><blood-brain barrier permeabilization><blood-brain barrier permeable><bloodbrain barrier crossing><bloodbrain barrier penetration><bloodbrain barrier permeabilization><bloodbrain barrier permeable><body movement><brain damage><brain endothelial cell><brain endothelium><brain microvascular endothelial cell><brain vascular endothelial cell><brain-injured><c neoformans infection><c. neoformans infection><cell motility><centrally acting drug><cerebral endothelial cell><cerebral microvascular endothelial cell><cerebral vascular endothelial cell><cortical endothelium><design><designing><developmental><drug/agent><experiment><experimental research><experimental study><experiments><fungal pathogen><fungi pathogen><fungus><improved><in vivo><innovate><innovation><innovative><intracellular skeleton><migration><mortality><mouse model><murine model><necropsy><neurotropic><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutics><novel therapy><pathogen><pathogenic fungus><pathway><postmortem><prevent><preventing><prophylactic><recruit><response><social role><spatiotemporal><spheroids><trafficking><trans-activation>