# SFTSV nonstructural protein NSs-mediated immunopathogenesis

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2021 · $604,163

## Abstract

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.

## Key facts

- **NIH application ID:** 10162492
- **Project number:** 5R01AI140705-05
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Jae U Jung
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $604,163
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10162492

## Citation

> US National Institutes of Health, RePORTER application 10162492, SFTSV nonstructural protein NSs-mediated immunopathogenesis (5R01AI140705-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10162492. Licensed CC0.

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