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Principal Investigator: John W. Schoggins
Organization: UT SOUTHWESTERN MEDICAL CENTER
Fiscal Year: 2022
Award: $468,599
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
Enteroviruses A, B, C, D are important pathogens that can cause a range of diseases including myocarditis,
encephalitis, meningitis, conjunctivitis, hand, foot and mouth disease, and acute flaccid myelitis. Disease
outcomes can be severe or fatal, particularly in neonates and children. The host innate immune response
generally controls these viruses. However, the cell intrinsic antiviral mechanisms that mediate this host
defense are not well defined. Here, we propose to identify and characterize host antiviral genes encoding
both constitutively expressed (non-inducible) and interferon-stimulated gene (ISG) antiviral effectors. In
Aim1, we will examine TRIM7, a constitutively expressed E3 ligase that we recently showed inhibits
enterovirus replication by targeting a viral protein for degradation. We hypothesize that TRIM7 is a pan-
enterovirus restriction factor in vitro and in vivo. In Aim 2, we will leverage our expertise in ISG screening
technology to test the hypothesis that only a limited set of genes are true effectors of the interferon-induced
antiviral response to enteroviruses A-D. We will characterize antiviral effector mechanisms of action, and we
will use novel lipid nanoparticle gene delivery strategies to demonstrate antiviral efficacy in vivo. Both Aims
will be achieved by a combination of biochemical, virological, and genetic approaches in cell-based assays
and in mouse models of enterovirus infection and pathogenesis. Completion of the proposed aims will
provide fundamental knowledge about the specific molecules that confer cell intrinsic protection against
these enteroviruses. These studies may additionally inform the development of pan-enterovirus therapies
based on the mechanisms of these naturally occurring antiviral defense proteins.
Terms: <0-11 years old><Address><Affect><Alpha Virus><Alphavirus><Amino Acids><Anti-Viral Response><Antiviral Agents><Antiviral Drugs><Antiviral Response><Antivirals><Assay><Attenuated><Binding><Bioassay><Biochemical><Biochemical Genetics><Biologic Assays><Biological><Biological Assay><Biology><Body Tissues><Brain Inflammation><CRISPR><CRISPR/Cas system><Cell Body><Cell Culture Techniques><Cells><Child><Child Youth><Children (0-21)><Clustered Regularly Interspaced Short Palindromic Repeats><Conjunctivitis><Defense Mechanisms><Development><Disease><Disease Outbreaks><Disease Outcome><Disorder><E3 Ligase><E3 Ubiquitin Ligase><Echo Viruses><Echovirus><Ectopic Expression><Encephalitis><Enterovirus><Enterovirus Infections><Family Picornaviridae><Flavivirus><Gene Delivery><Gene Targeting><Genes><Genetic study><Goals><Group A Arboviruses><Group B Arbovirus><Hand, Foot and Mouth Disease><Host Defense><Host Defense Mechanism><Human><IFN><Impairment><In Vitro><Innate Immune Response><Innate Immune System><Innate Immunity><Interferons><Intuition><KO mice><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Knowledge><Libraries><Mediating><Meningitis><Messenger RNA><Metabolic Protein Degradation><Mice><Mice Mammals><Microbe><Microbiology><Modeling><Modern Man><Molecular><Molecular Interaction><Murine><Mus><Myocarditis><Native Immunity><Natural Immunity><Nature><Non-Specific Immunity><Nonspecific Immunity><Normal Cell><Null Mouse><Outbreaks><Outcome><Pancreatitis><Pathogenesis><Pathogenicity><Picornaviridae><Picornaviruses><Protein Turnover><Proteins><Publishing><RNA Viruses><Regulatory Protein Degradation><Resistance><Role><Technology><Testing><Therapeutic><Tissues><Ubiquitilation><Ubiquitin Protein Ligase><Ubiquitin-Protein Ligase Complexes><Ubiquitin-Protein Ligase E3><Ubiquitination><Ubiquitinoylation><Viral><Viral Diseases><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Virus><Virus Diseases><Virus Replication><Work><acute flaccid myelitis><aminoacid><anti-viral agents><anti-viral compound><anti-viral drugs><anti-viral efficacy><anti-viral medication><anti-viral therapeutic><anti-virals><antiviral compound><antiviral efficacy><antiviral medication><antiviral therapeutic><base><biologic><boys><cDNA Library><cardiac inflammation><cell culture><cell cultures><cost><develop therapy><developmental><early screening><fitness><gain of function><genetic approach><genetic strategy><genome scale><genome-wide><genomewide><healing><human pathogen><in vivo><intervention development><lipid based nanoparticle><lipid nanoparticle><loss of function><mRNA><mouse model><murine model><neonate><novel><pathogen><pathogenic virus><pressure><protein degradation><psychological defense mechanism><resistant><screening><social role><therapy development><treatment development><trend><ubiquination><ubiquitin conjugation><ubiquitin-protein ligase><viral infection><viral multiplication><viral pathogen><viral replication><virus infection><virus multiplication><virus pathogen><virus protein><virus-induced disease><youngster>