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Principal Investigator: Lee Erik Korshoj
Organization: UNIVERSITY OF NEBRASKA MEDICAL CENTER
Fiscal Year: 2024
Award: $22,724
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY
A craniotomy allows neurosurgeons to access the brain for procedures that include tumor resection, localization
and resection of epileptogenic foci, and aneurysm clipping via the removal and intraoperative replacement of a
skull fragment (bone flap). Infection following craniotomy occurs at rates of approximately 1-3%, although some
reports indicate rates exceeding 10%. Nearly half of craniotomy infections are caused by Staphylococcus aureus
(S. aureus) forming a biofilm on the bone flap. As biofilms are inherently difficult to eradicate due to antibiotic
tolerance and virulence factors allowing immune evasion, craniotomy infections carry significant morbidity since
a second surgery is required for treatment. When craniotomies are complicated by infection, resident immune
cells and infiltrating leukocytes throughout the brain, subcutaneous galea, and bone flap tissues are exposed to
both damage- and pathogen-associated molecular patterns (DAMPs and PAMPs) originating from the surgical
procedure and bacteria, respectively. Triggering receptor expressed on myeloid cells-2 (TREM2) is a major
pathology-induced signaling receptor involved in immune remodeling during many neurological conditions. An
important feature of TREM2 is its reported ability to bind an array of anionic ligands including DAMPs (DNA,
lipoproteins, glycolipids, and phospholipids) and PAMPs (lipoteichoic acid, peptidoglycan, and
lipopolysaccharide). This proposal will test the hypothesis that TREM2 plays a critical role in promoting
S. aureus craniotomy infection by eliciting an anti-inflammatory response through combined DAMP and
PAMP signaling. In support of this hypothesis, my preliminary studies showed increased TREM2 expression
and shifts toward an anti-inflammatory metabolic state in microglia after exposure to S. aureus. This proposed
work will seek to uncover mechanisms behind TREM2 signaling during craniotomy infection. In Specific Aim 1, I
will utilize a mouse model of S. aureus craniotomy infection with TREM2 KO animals to determine the relative
contribution of DAMP vs. PAMP signaling, temporal aspects of TREM2 activation post-surgery, the comparative
roles of membrane-associated vs. soluble TREM2, and the extent of TREM2 signaling involved in metabolic
reprogramming of microglia and individual leukocyte populations. In Specific Aim 2, a novel bacterial scRNA-
seq approach will used to identify S. aureus TREM2-targeted virulence factors that are leveraged for immune
evasion. I will be the first to use this sequencing technique to study biofilm on a single-cell level and elucidate
how bacterial pathogens, specifically biofilm, can hijack host immunity to persist. Results from this work will
provide insights into previously unstudied topics on TREM2 signaling in the context of dual DAMP and PAMP
exposure during craniotomy infection and elucidate targets for future therapeutic intervention.
Terms: <AD dementia><Abscission><Agreement><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimers Dementia><Aneurysm><Animals><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Attenuated><Bacteria><Binding><Blood leukocyte><Body Tissues><Brain><Brain Nervous System><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Chronic><Clip><Co-culture><Cocultivation><Coculture><Coculture Techniques><Craniotomy><DNA><Deoxyribonucleic Acid><Development><Disease><Disorder><Encephalon><Environment><Epilepsy><Epileptic Seizures><Epileptics><Excision><Exposure to><Extirpation><Future><Gene Expression><Generalized Growth><Genes><Genetic Alteration><Genetic Change><Genetic defect><Glycolipids><Growth><Heterogeneity><Hortega cell><Immune><Immune Evasion><Immune system><Immunes><Immunity><In Vitro><Individual><Infection><Inflammation><Inflammatory Response><Intermediary Metabolism><Intracellular Communication and Signaling><Invaded><KO mice><Knock-out Mice><Knockout Mice><Laboratories><Leucocytic infiltrate><Leukocytes><Leukocytes Reticuloendothelial System><Ligand Binding><Ligands><Lipopolysaccharides><Lipoproteins><Marrow leukocyte><Mediating><Membrane><Metabolic><Metabolic Processes><Metabolism><Mice><Mice Mammals><Microbial Biofilms><Microglia><Miscellaneous Antibiotic><Modeling><Molecular><Molecular Interaction><Morbidity><Morbidity - disease rate><Murein><Murine><Mus><Mutation><Nervous System Diseases><Nervous System Disorder><Neurologic><Neurologic Disorders><Neurological><Neurological Disorders><Neurosurgeon><Null Mouse><Operative Procedures><Operative Surgical Procedures><Paralysis Agitans><Parkinson><Parkinson Disease><Pathogenicity Factors><Pathology><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pattern><Pattern recognition receptor><Peptidoglycan><Phagocytosis><Phosphatides><Phospholipids><Play><Population><Primary Parkinsonism><Primary Senile Degenerative Dementia><Procedures><Production><Proliferating><Prosthesis><Prosthetic device><Prosthetics><Receptor Protein><Receptor Signaling><Regulation><Removal><Reporting><Research><Risk Factors><Role><S aureus><S. aureus><S. aureus infection><Seizure Disorder><Signal Induction><Signal Transduction><Signal Transduction Systems><Signaling><Skull><Staph aureus><Staph aureus infection><Staphylococcus aureus><Staphylococcus aureus infection><Sterility><Surgical><Surgical Injuries><Surgical Interventions><Surgical Procedure><Surgical Removal><TLR protein><TREM2><TREM2 gene><Techniques><Testing><Therapeutic Intervention><Tissue Growth><Tissues><Toll-Like Receptor Family Gene><Toll-like receptors><Triggering Receptor Expressed in Myeloid Cells 2><Triggering Receptor Expressed on Myeloid Cells 2><Up-Regulation><Upregulation><Virulence Factors><White Blood Cells><White Cell><Work><Wound Repair><antibiotic tolerance><attenuate><attenuates><bacteria pathogen><bacterial pathogen><biofilm><biological signal transduction><bone><cell type><comparative><cranium><cytokine><developmental><epilepsia><epileptogenic><experiment><experimental research><experimental study><experiments><genome mutation><gitter cell><human disease><immune clearance><immune elimination><immune evasive><improved><in vivo><infected with S. aureus><infected with Staph aureus><infected with Staphylococcus aureus><insight><intervention therapy><lipo-teichoic acid><lipoteichoic acid><membrane structure><mesoglia><microglial cell><microgliocyte><mouse model><murine model><mutant><neuro-surgeon><neurological disease><neurosurgery><novel><ontogeny><pathogen><pathogenic bacteria><patient oriented outcomes><perivascular glial cell><primary degenerative dementia><receptor><recruit><resection><response><scRNA-seq><senile dementia of the Alzheimer type><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><skull incision><social role><sterile><subcutaneous><subdermal><surgery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><tolerance to antibiotics><tolerate antibiotics><transcriptomics><tumor><white blood cell><white blood corpuscle><wound healing><wound recovery><wound resolution>