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Principal Investigator: Jae U Jung
Organization: CLEVELAND CLINIC LERNER COM-CWRU
Fiscal Year: 2022
Award: $604,163
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary/Abstract
Severe fever with thrombocytopenia syndrome virus (SFTSV) listed in the World Health
Organization 9 most dangerous pathogens is an emerging Phlebovirus in the Phenuiviridae family.
Due to the lack of therapy and vaccine against SFTSV infection, there is a pressing need to
understand the pathogenesis of SFTSV to develop effective antiviral agents. Designated as
Biosafety level 3 agent, SFTSV contains a genome comprised of three segments of negative or
ambisense RNA designated as large, medium, and small. The S segment encodes a nucleoprotein
and a nonstructural protein (NSs) via an ambisense coding strategy. (Aim 1) We have discovered
that NSs targets the Vps15-Vps34 lipid kinase complex to form virus-induced autophagosome-like
inclusion bodies (IB), subsequently sequestrating IFN signaling effectors (RIG-I, TRIM25, and
TBK1) to the IB and thereby suppressing IFN production. (Aim 2) We have also found that SFTSV
NSs plays an essential role in viral immunopathogenesis by targeting the TPL2-ABIN2-p105 kinase
complex to robustly induce expression of immune suppressive genes, specifically IL-10 cytokine.
(Aim 3) We combined viral reverse genetics, a TPL2 kinase inhibitor, Tpl2-/- and il10-/- mouse
models to show that the NSs-mediated activation of TPL2 signaling pathway robustly induced IL-10
production that was essential for viral pathogenesis. For the first time, we developed an age-
dependent ferret model: young adult ferrets (<2 years old) did not show any clinical symptoms and
mortality; however, SFTSV-infected aged ferrets (>4 years old) demonstrated severe
thrombocytopenia, reduced white blood cells, and high fever with ~90% mortality rate, fully
recapitulating human clinical manifestation. With well-established in vitro experimental conditions
and novel in vivo animal models, the proposed study not only demonstrates the critical role of
SFTSV NSs in viral immune evasion and pathogenesis, but also identifies potential therapeutic
approaches to treat SFTSV-infected patients.
Terms: <2 year old><2 years of age><4 year old><4 years of age><ATP-protein phosphotransferase><Age><Animal Model><Animal Models and Related Studies><Animals><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antiinflammatories><Antiinflammatory Agents><Antiviral Agents><Antiviral Drugs><Antivirals><Autophagosome><Blood leukocyte><COT Gene><COT protein><CSIF><CSIF-10><Cancer Osaka Thyroid Oncogene><Cancer Osaka Thyroid Oncogene Protein><Cell Communication and Signaling><Cell Signaling><Cellular Inclusions><Characteristics><China><Clinical><Code><Coding System><Complex><Country><Cytokine Synthesis Inhibitory Factor><Dangerousness><Disease><Disorder><EFP Gene><EFP protein><EST gene><EST protein><East Asia><Eastern Asia><Estrogen-Responsive Finger Protein><Ewing Sarcoma Transformant><FLJ11330><Family><Far East><Fatality rate><Ferrets><Fever><Genes><Genome><Genus Phlebovirus><Host Defense><Human><IFN><IL-10><IL10><IL10A><Immune><Immune Evasion><Immunes><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><In Vitro><Inclusion Bodies><Infection><Interferon Type I><Interferons><Interleukin 10 Precursor><Interleukin-10><Intracellular Communication and Signaling><Ixodida><Kinase Family Gene><Kinases><Leukocytes><Leukocytes Reticuloendothelial System><Lipids><MAP Kinase Kinase Kinase 8><MAP3K8><MAP3K8 gene><Mainland China><Marrow leukocyte><Mediating><Mice><Mice Mammals><Mitogen-Activated Protein Kinase Kinase Kinase 8><Modeling><Modern Man><Molecular><Morbidity><Morbidity - disease rate><Murine><Mus><NF-Kb-Activating Kinase Gene><Non-Polyadenylated RNA><Non-structural Protein><Nonstructural Protein><Nucleoproteins><Oncogene COT><Pathogenesis><Pathway interactions><Patients><Phlebovirus><Phosphotransferase Gene><Phosphotransferases><Play><Production><Protein Kinase><Pyrexia><RNA><RNA Gene Products><Recombinants><Reporting><Ribonucleic Acid><Risk Factors><Role><Severe Fever with Thrombocytopenia Syndrome Virus><Severe Fever with Thrombocytopenia virus><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Source><Symptoms><T2K><TBK1><TBK1 gene><TPL-2><TPL2><TRIM25><TRIM25 gene><Therapeutic><Thrombocytopenia><Thrombopenia><Ticks><Time><Transmission><Transphosphorylases><Treatment Efficacy><Tripartite Motif-Containing Protein 25><Tumor Progression Locus-2><Vaccines><Viral><Viral Diseases><Viral Pathogenesis><Virus><Virus Diseases><White Blood Cells><White Cell><World Health Organization><ZNF147><Zinc Finger Protein 147><adult youth><age 2 years><age 4 years><age dependent><age related><aged><aged 2 years><aged two years><ages><anti-viral agents><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><antiinflammatory><antiviral compound><antiviral medication><antiviral therapeutic><base><biological signal transduction><clinical diagnosis><cytokine><febrile><febris><four year old><four years of age><glycogen synthase a kinase><hydroxyalkyl protein kinase><immune suppression><immune suppressive activity><immune suppressive function><immunosuppressive activity><immunosuppressive function><in vivo><intervention efficacy><kinase inhibitor><model of animal><model organism><mortality><mouse model><murine model><mutant><neutralizing antibody><novel><pathogen><pathway><phosphorylase b kinase kinase><protein kinase inhibitor><response><reverse genetics><sandfly fever virus group><social role><therapeutic efficacy><therapy efficacy><transmission process><two year old><two years of age><viral infection><virus infection><virus pathogenesis><virus-induced disease><white blood cell><white blood corpuscle><young adult><young adulthood>