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Principal Investigator: Scott Benjamin Biering
Organization: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Fiscal Year: 2024
Award: $162,000
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY/ABSTRACT
Research Project: Dengue virus (DENV) is a medically important pathogen posing a major public health threat.
DENV infection can result in potentially fatal cases of severe dengue associated with vascular leak as a result
of endothelial dysfunction, but the triggers of these pathologies were unknown. We and others have defined a
direct role for the DENV non-structural protein 1 (NS1) in mediating endothelial dysfunction in vitro and vascular
leak in vivo, independently from viral infection, via direct interactions with endothelial cells. Our preliminary data
indicate that NS1 binding to endothelial cells and uptake via clathrin-mediated endocytosis are distinct steps that
are both critical for NS1-mediated endothelial dysfunction, but the NS1 receptors on endothelial cells that
mediate uptake of NS1 are unknown. My preliminary data identified a role for beta-2 adrenergic receptor (β2AR)
and epidermal growth factor receptor (EGFR) in NS1-mediated endothelial dysfunction. Further, activation of
β2AR has been reported to transactivate EGFR, triggering endocytosis. Thus, I hypothesize that β2AR and
EGFR serve as a NS1 receptor complex where NS1 functions as a β2AR agonist to trigger EGFR-
mediated endocytosis. This proposal will test this hypothesis by investigating the capacity of NS1 to activate
β2AR and EGFR signaling pathways in Aim 1. Aim 2 will investigate the capacity of β2AR and EGFR to serve
as NS1 receptors. The proposal holds the potential to characterize a fundamental and novel step in dengue virus
pathogenesis via identification of NS1 receptors which also serve as therapeutic targets for treatment of dengue.
Candidate and Career Goals: The candidate for this K22 proposal has a strong track record investigating host-
pathogen interactions from his work studying entry mechanisms of Nipah virus as an undergraduate student in
the labs of Dr. Benhur Lee and Dr. Hector Aguilar-Carreno at the University of California, Los Angeles,
investigating innate immune mechanisms by which interferons control viral infection as a graduate student in Dr.
Seungmin Hwang’s lab at the University of Chicago, and investigating flavivirus NS1-mediated pathogenesis as
a postdoctoral scholar in Dr. Eva Harris’s lab at the University of California, Berkeley. In Dr. Harris’s lab, Dr.
Biering recently identified candidate NS1 receptors on endothelial cells and will investigate their role in NS1
pathogenesis in this proposal. Dr. Biering is committed to establishing his own research group at a major
research university where he will investigate mechanisms by which viral pathogens cause disease.
Career Development Plans and Environment: Dr. Biering will work with his mentor (Dr. Eva Harris) and
mentoring committee (Dr. Britt Glaunsinger, Dr. Michael Diamond, Dr. Kamil Godula, Dr. Suzanne Fleiszig, and
Dr. P. Robert Beatty) to acquire additional training in biochemistry, advanced-microcopy, glycobiology, and in
vivo models of virus infection which will enhance his current research proposal and the research in his future
lab. This, coupled with the additional courses and trainings outlined in his training plan, will prepare Dr. Biering
for a successful transition to a primary investigator role able to prepare data for a competitive R01 proposal.
Terms: <1-Phosphatidylinositol 3-Kinase><Address><Adrenergic Receptor><Adrenoceptors><Agonist><Binding><Biochemistry><Biological Chemistry><Blood><Blood Reticuloendothelial System><Blood Vessels><Body Tissues><Breakbone Fever Virus><California><Catecholamine Receptor><Cell Body><Cell Coat><Cell Communication and Signaling><Cell Junctions><Cell Signaling><Cell Surface Glycoproteins><Cells><Cellular biology><Chicago><Clathrin><Complex><Coupled><DENV><DENV infection><Data><Dengue><Dengue Fever><Dengue Infection><Dengue Virus><Dengue disease><Dengue fever virus><Dengue virus infection><Development Plans><Diamond><Disease><Disorder><Distal><Dysfunction><EGF Receptor><EGFR><ERBB Protein><Endocytosis><Endothelial Cells><Endothelium><Environment><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Epinephrine Receptors><Family><Flaviviridae><Flavivirus><Functional disorder><Future><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><GPCR><Glycans><Glycobiology><Glycocalyx><Goals><Group B Arbovirus><Growth Factor Receptors><HER1><Heparan Sulfate><Heparitin Sulfate><Hospital Admission><Hospitalization><Host Factor><Host Factor Protein><IFN><In Vitro><Infection><Integral Membrane Protein><Integration Host Factors><Intercellular Junctions><Interferons><Intracellular Communication and Signaling><Intrinsic Membrane Protein><Investigation><Investigators><K22 Award><Link><Lipids><Los Angeles><MMPs><Matrix Metalloproteinases><Mediating><Medical><Membrane><Membrane Glycoproteins><Mentors><Metallopeptidases><Metalloproteases><Metalloproteinases><Mice><Mice Mammals><Molecular><Molecular Genetics><Molecular Interaction><Murine><Mus><Nipah Virus><Nipah henipavirus><Non-structural Protein><Nonstructural Protein><Organ><Orthoflavivirus><Outcome><PI-3 Kinase><PI3-Kinase><PI3CG><PI3KGamma><PI3k><PIK3><PIK3CG><PIK3CG gene><PTK Receptors><Pathogenesis><Pathogenicity Factors><Pathology><Pathway interactions><Patients><Phosphatidylinositol 3-Kinase><Phosphatidylinositol-3-OH Kinase><Phosphoinositide 3-Hydroxykinase><Physiopathology><Polysaccharides><Postdoc><Postdoctoral Fellow><Productivity><Proteins><PtdIns 3-Kinase><Public Health><R-Series Research Projects><R01 Mechanism><R01 Program><Receptor Protein><Receptor Protein-Tyrosine Kinases><Receptor Tyrosine Kinase Gene><Reporting><Research><Research Associate><Research Grants><Research Personnel><Research Project Grants><Research Projects><Research Proposals><Researchers><Role><Serotyping><Severity of illness><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Surface Glycoproteins><TGF-alpha Receptor><Techniques><Testing><Tissues><Toxin><Training><Transactivation><Transforming Growth Factor alpha Receptor><Transmembrane Protein><Transmembrane Protein Gene><Transmembrane Receptor Protein Tyrosine Kinase><Tropism><Type I Phosphatidylinositol Kinase><Type III Phosphoinositide 3-Kinase><Tyrosine Kinase Linked Receptors><Tyrosine Kinase Receptors><Universities><Urogastrone Receptor><Vaccination><Viral><Viral Diseases><Viral Pathogenesis><Virulence Factors><Virus><Virus Diseases><Virus Replication><Work><adenoreceptor><beta-2 Adrenergic Receptors><biological signal transduction><breakbone fever><c-erbB-1><c-erbB-1 Protein><candidate identification><career><career development><cell biology><clinical biomarkers><clinically useful biomarkers><cytokine release syndrome><cytokine storm><dengue viral infection><dimer><disease severity><endothelial dysfunction><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><extracellular><graduate student><in vivo><in vivo Model><inhibiting antibody><innate immune mechanisms><live cell image><live cell imaging><live cellular image><live cellular imaging><membrane structure><mosquito-borne><mosquitoborne><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><pathogen><pathogenic virus><pathophysiology><pathway><post-doc><post-doctoral><post-doctoral trainee><protein protein interaction><protein purification><proto-oncogene protein c-erbB-1><receptor><receptor mediated endocytosis><research associates><severe dengue><social role><src Kinases><src Protein-Tyrosine Kinases><src Tyrosine Kinases><src-Family Kinases><src-Family Tyrosine Kinases><therapeutic target><tissue tropism><trans-activation><undergrad><undergraduate><undergraduate student><uptake><vascular><viral infection><viral multiplication><viral pathogen><viral replication><virus infection><virus multiplication><virus pathogen><virus pathogenesis><virus-induced disease><β-2 Adrenoceptor><β2 Adrenergic Receptor>