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Principal Investigator: BRUCE J SHENKER
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2020
Award: $243,125
Funding agency: National Institute of Dental and Craniofacial Research
We are requesting a one year administrative supplement to our RO1 grant DE006014 entitled Bacteria and lymphocyte suppression in periodontitis. The purpose of this request is to expand the scope of the grant to take advantage of recent observations made on the cytolethal distending toxin (Cdt) and apply them to advancing our knowledge of and identifying novel therapeutic pathways for preventing SARS-CoV-2 infection. Specifically, we have identified a novel role for a host cell protein, cellugyrin (synaptogyrin-2; discussed below), which plays a requisite role in the internalization and endososmal trafficking of the active subunit of Cdt, CdtB; these events are critical to toxicity. Like the internalization process utilized by exotoxins, viruses must gain entry into host cells; this process involves the interaction between viral glycoprotein, such as SARS-CoV-2 spike protein. This protein, like other viral spike proteins, provides a receptor binding domain that confers host cell specificity (e.g, ACE2) and also fusogenic function critical to merging the virus envelope with host endosomal membrane during viral entry. Recent studies have indicated that oral epithelial cells express ACE2 and may be a target for SARS- CoV-2 infection. Therefore, this study will focus on human oral-pulmonary epithelial cells lines. We propose that cellugyrin is a major component of a universal endocytic process utilized by both virus and exotoxins to achieve entry into host cells. This study will focus on the requirement for cellugyrin for SARS-CoV-2 entry into host cells. In order to contain SARS-CoV-2 infection, it is important to identify early molecular mechanism(s) that contribute to its high infectivity as these likely also represent attractive targets for therapeutic intervention. This proof-of-principle study is aimed at demonstrating a key role for cellugyrin in the pathogenesis of SARS-CoV-2 infection of cells within the oral-respiratory tract. The potential for high impact of these studies is to provide the underpinnings for developing a novel, alternative and potentially transformative therapeutic approach to mitigate SARS-CoV-2 infection. It is in this context that this study directly addresses the spirit and focus of the Notice of Special Interest (NOSI) (NOT-DE-20-022): Urgent Competitive Revisions and Administrative Supplements for Coronavirus Disease 2019 (COVID-19) as it is not only of potential high impact, but also addresses acquisition of a more robust understanding of SARS-CoV-2 pathogenesis. Moreover, the proposal addresses one of the bulleted targets of this funding announcement: examination of the role of oral/nasal microbiota and ACE2 receptor on SARS-CoV-2 infectivity and carriage in oral fluids and nasal secretions, as gateways to the spread
of infection into the respiratory tract via proof of principle studies.
Terms: <1-Phosphatidylinositol 3-Kinase><2019 novel coronavirus><2019-nCoV><A actinomycetemcomitans><A. actinomycetemcomitans><Accounting><Actinobacillus actinomycetemcomitans><Address><Administrative Supplement><Aggregatibacter actinomycetemcomitans><Amino Acids><Apoptosis><Apoptosis Pathway><Bacteria><Bacterium actinomycetem comitans><Bacterium comitans><Binding><Binding Sites><CAP20 protein><CDC2><CDC2 Protein Kinase><CDC2 gene><CDK1><CDK2-associated protein 20 kDa><CDT-III><CLD-toxin><COVID-19><COVID19><Campylobacter><Cdk2 inhibitor protein><CdtB protein><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Cycle Arrest><Cell Cycle Controller CDC2 Gene><Cell Cycle Controller cdc2><Cell Cycle Proteins><Cell Death><Cell Division Control Protein 2 Homolog><Cell Division Cycle 2><Cell Division Cycle 2 Protein><Cell Division Cycle Proteins><Cell Interaction><Cell Line><Cell Signaling><Cell surface><Cell-Cycle Regulatory Proteins><Cell-to-Cell Interaction><CellLine><Cells><Cellular Expansion><Cellular Growth><Chancroids><Chiro-Inositol><Cholesterol><Chromosomes><Chronic Periodontitis><Combining Site><Cyclin-Dependent Kinase 1><Cyclin-Dependent Kinases><Cyclin-Dependent Protein Kinases><DNA Damage><DNA Damage Repair><DNA Injury><DNA Nucleases><DNA Repair><DNase><Deoxyribonucleases><Disease><Disorder><Dose><E coli><E. coli><Epithelial><Epithelial Cells><Epithelium><Epithelium Part><Escherichia coli><Event><Exotoxins><Exposure to><Family><Funding><GeneHomolog><Genital><Genital system><Glycoproteins><Goals><Grant><H ducreyi><H. ducreyi><Haemophilus ducreyi><HeLa><Hela Cells><Helicobacter><Hemophilus ducreyi><Homolog><Homologous Gene><Homologue><Host Defense><Human><Immune response><Immunological response><Impairment><Infection><Inflammation><Inositide Phospholipids><Inositol><Inositol Phosphoglycerides><Inositol Phospholipids><Intracellular Communication and Signaling><Knowledge><Lead><Link><Liquid substance><Lung><Lung Respiratory System><Lymphocyte><Lymphocyte Suppression><Lymphocytic><Lymphoid Cell><MDA 6><MMAC1><Mediating><Membrane><Mesoinositol><Modern Man><Molecular><Molecular Interaction><Mutated in Multiple Advanced Cancers 1><Nasal><Nasal Passages Nose><Nose><Nuclear><Oral><PHTS gene><PHTS protein><PI-3 Kinase><PI-3K><PI3-Kinase><PTEN><PTEN Hamartoma Tumor Syndrome><PTEN Hamartoma Tumor Syndrome With Granular Cell Tumor><PTEN gene><PTEN1><Pathogenesis><Pathogenicity Factors><Pathway interactions><Pb element><Peptides><Periodontitis><Phosphatase and Tensin Homolog><Phosphatase and Tensin Homolog Deleted on Chromosome 10><Phosphatases><Phosphatidyl Inositol><Phosphatidylinositol 3-Kinase><Phosphatidylinositol-3-OH Kinase><Phosphatidylinositols><Phosphohydrolases><Phosphoinositide 3-Hydroxykinase><Phosphoinositides><Phosphomonoesterases><Phosphoric Monoester Hydrolases><Play><Process><Programmed Cell Death><Progress Reports><Proteins><Proteobacteria><PtdIns><PtdIns 3-Kinase><Pulmonary Body System><Pulmonary Organ System><Purple Bacteria><Reactive Site><Receptor Protein><Respiratory System><Respiratory System, Nose, Nasal Passages><Respiratory Tracts><Respiratory tract structure><Role><S enterica><S. enterica><SARS-CoV-2><SARS-CoV2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><Salmonella enterica><Severe acute respiratory syndrome coronavirus 2><Sexual Transmission><Shigella><Ships><Signal Transduction><Signal Transduction Systems><Signaling><Specificity><Stomach><Strains Cell Lines><Structure><Synaptic Vesicles><Testing><Therapeutic><Therapeutic Intervention><Toxic effect><Toxicities><Toxin><Tumor Suppressor Proteins><Type I Phosphatidylinositol Kinase><Type III Phosphoinositide 3-Kinase><Unscheduled DNA Synthesis><Viral><Virulence Factors><Virus><WAF1 CIP1><Work><Wuhan coronavirus><Y enterocolitica><Y. enterocolitica><Yersinia enterocolitica><acquired immunity><aminoacid><base><biological signal transduction><carcinogenicity><cdc Proteins><cdc2 gene product><cdc2+ Protein><cdk Proteins><cdk1 Kinase><cdn1 protein><cell growth><cell type><cellugyrin><corona virus disease 2019><coronavirus disease 2019><cultured cell line><cyclin-dependent kinase Inhibitor p21><cytokine><cytolethal distending toxin><fluid><gastric><heavy metal Pb><heavy metal lead><host response><human pathogen><immune clearance><immune elimination><immunogenic><immunoresponse><inhibitor><inhibitor/antagonist><insight><interest><intervention therapy><keratinocyte><liquid><lymph cell><macrophage><mda-6 protein><membrane structure><nasal microbial community><nasal microbiota><necrocytosis><neutralizing antibody><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel therapeutics><novel therapy><oncoprotein p21><oral cavity epithelium><oral epithelia><oral epithelium><oral pathogen><p21 cell cycle regulator><p21 cyclin kinase inhibitor><p21(cip1)><p21(waf1-cip1)><p21-WAF1><p34 Protein Kinase><p34 Protein Kinase Gene><p34(CDC2) Gene><p34CDC2><paralog><paralogous gene><pathogen><pathway><prevent><preventing><protein expression><pulmonary><receptor><receptor binding><receptor bound><response><retrograde transport><senescent cell-derived inhibitor protein 1><sexually transmitted><sinonasal microbiota><social role><suppress lymphocytes><synaptic vesicle protein p29><synaptogyrin><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><tensin><tensin1><trafficking><triphosphate><tripolyphosphate><tumor suppressor><vesicle transport><vesicular transport><virus envelope>