Regulating the Detection of Reovirus Infection

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: Pranav  Danthi
Organization: TRUSTEES OF INDIANA UNIVERSITY
Fiscal Year: 2024
Award: $379,747
Funding agency: National Institute of Allergy and Infectious Diseases

Mammalian orthoreovirus (MRV) genomic RNA is detected by host cells to induce an innate immune response. Detection of MRV RNA also contributes to the induction of cell death. Because viral genomic RNA remains contained within particles throughout infection, how the RNA becomes exposed and accumulates to the level that induces a host response remains unknown. In this proposal, we will uncover how viral RNA becomes detectable by the host cell. In Aim 1 of this proposal, we will build on the data that specific endosomal uptake pathways, endosomal protease activity, and endosomal maturation are required for exposure of viral genomic RNA from incoming particles. We will identify how these endosomal properties influence genomic RNA exposure. We will also determine how viral determinants control exposure and transport of viral genomic dsRNA for detection by cytoplasmic sensors. In Aim 2, we will determine how the assembly of the viral µ1 capsid protein on progeny cores blocks excessive accumulation of viral RNA. We will perform biochemical and virological experiments to identify structure-function relationships in µ1 that mediate these effects. We will also define the structural basis of µ1-mediated shut down of viral RNA transcription by solving the structure of a MRV assembly intermediates. In Aim 3 of the proposal, we will follow up on our preliminary data indicating that cellular RNA transporter SIDT2 controls MRV RNA levels. We will define whether the RNautophagy function of SIDT2 governs its antiviral effect and determine whether viral RNA turnover is influenced by RNautophagy. Finally, we will define how RNAs are specifically recognized by the RNautophagy machinery. Completion of this work will reveal viral and cellular factors that control the detection of MRV and other related dsRNA viruses by host cells.

Terms: <Acids><Active Follow-up><Affect><Biochemical><Biological><Blue Tongue Virus><Bluetongue virus><CATL><CTSL Protein><Capsid><Capsid Proteins><Cathepsin B1><Cathepsin L><Cathepsins><Cathepsins B><Celiac Disease><Celiac Sprue><Cell Body><Cell Communication and Signaling><Cell Culture Techniques><Cell Death><Cell Death Induction><Cell Signaling><Cells><Cessation of life><Coat Proteins><Coeliac Disease><Cryo-electron Microscopy><Cryoelectron Microscopy><Cytoplasm><Data><Death><Degradation Pathway><Degradative Pathway><Detection><Double Stranded RNA Virus><Double-Stranded RNA><EC 3.4.22.1><Electron Cryomicroscopy><Endosomes><Engineering><Enzyme Gene><Enzymes><Esteroproteases><Event><Experimental Models><Exposure to><Family><Gene Transcription><Genetic Transcription><Genome><Genomics><Gluten Enteropathy><Gluten-Sensitive Enteropathy><IFN><Immune><Immune response><Immunes><Immunological response><Infection><Innate Immune Response><Interferons><Intracellular Communication and Signaling><Lysosomes><Major Excreted Protein><Mammalian Orthoreovirus><Mediating><Membrane><Messenger RNA><Molecular><Non-Polyadenylated RNA><Non-tropical Sprue><Nontropical Sprue><Oncolytic><Ovine Catarrhal Fever Virus><Pathway interactions><Pattern><Penetration><Peptidases><Peptide Hydrolases><Predisposition><Process><Production><Property><Protease Gene><Proteases><Protein Biosynthesis><Proteinases><Proteins><Proteolytic Enzymes><Publishing><RNA><RNA Degradation><RNA Expression><RNA Gene Products><RNA Stability><RNA Transport><RNA chemical synthesis><RNA synthesis><Receptosomes><Reovirus><Reovirus Infections><Research><Respiratory Enteric Orphan Viruses><Ribonucleic Acid><Ribonucleic Acid Transport><Ribosomal Peptide Biosynthesis><Ribosomal Protein Biosynthesis><Ribosomal Protein Synthesis><Role><Rotavirus><Signal Transduction><Signal Transduction Systems><Signaling><Structure><Structure-Activity Relationship><Susceptibility><Transcription><Translating><Viral><Viral Coat Proteins><Viral Diseases><Viral Gene Products><Viral Gene Proteins><Viral Outer Coat Protein><Viral Proteins><Virion><Virus><Virus Assembly><Virus Diseases><Virus Particle><Virus Replication><Work><Zoonoses><Zoonotic><Zoonotic Infection><active followup><bat-borne><batborne><biologic><biological signal transduction><cell culture><cell cultures><chemical structure function><cryo-EM><cryoEM><cryogenic electron microscopy><dsRNA><dsRNA Virus><experiment><experimental research><experimental study><experiments><follow up><follow-up><followed up><followup><genomic RNA><host response><idiopathic steatorrhea><immune system response><immunoresponse><in vivo><knock-down><knockdown><mRNA><mRNA capping><membrane structure><mutant><necrocytosis><particle><particle exposure><pathogen><pathogenic virus><pathway><programs><protein synthesis><response><sensor><social role><structure function relationship><uptake><vaccine platform><vector><viral RNA><viral assembly><viral genomics><viral infection><viral multiplication><viral pathogen><viral replication><virus RNA><virus genomics><virus infection><virus multiplication><virus pathogen><virus protein><virus-induced disease>