# Lumpy skin disease virus protein LSDV122 impairs IFN-I receptor complex formation to evade host innate immunity

## TL;DR

This study identifies a protein in lumpy skin disease virus that helps it avoid the immune system by blocking interferon signaling, which could help in developing better vaccines.

## Contribution

The study reveals LSDV122 as a novel viral protein that disrupts interferon receptor complex formation to evade host immunity.

## Key findings

- LSDV122 interacts with IFNAR1 and IFNAR2, preventing the recruitment of JAK1 and TYK2.
- Deleting LSDV122 enhances antiviral responses in vitro and in a mouse model.
- LSDV122 is essential for efficient immune evasion and could inform vaccine design.

## Abstract

Lumpy skin disease virus (LSDV) is a pathogenic poxvirus that causes systemic disease in cattle. Although LSDV encodes multiple proteins that are predicted to regulate host defense, the underlying mechanisms of its immune evasion strategies remain largely elusive. Here we identify the LSDV-encoded protein LSDV122 as an antagonist of type I interferon (IFN-I)-mediated innate immunity. LSDV122 interacts with both subunits of the IFN-I receptor, IFNAR1 and IFNAR2, disrupting their proper assembly and preventing the recruitment of the downstream kinases JAK1 and TYK2, leading to impairment of IFN-β-mediated JAK-STAT signaling and induction of antiviral IFN-stimulated genes (ISGs). Deletion of the LSDV122 gene (LSDVΔ122) led to stronger antiviral response by restoring IFN-β-induced signaling in vitro and in a mouse model. Our study suggests that LSDV122 plays a critical role in antagonizing IFN-I signaling and is essential for efficient viral immune evasion, offering new insights into the rational design of live-attenuated LSDV vaccines.

Lumpy skin disease virus (LSDV) causes severe disease in cattle and poses a growing threat to global livestock health and production. How LSDV evades the host defense remains enigmatic. In this study, we identify LSDV122 as a viral immunomodulatory protein that specifically antagonizes IFN-β-triggered JAK-STAT signaling by impairing the formation of the IFNAR-JAK signaling complex. Deletion of LSDV122 enhances antiviral response both in vitro and in vivo, highlighting its essential role in immune evasion. These findings may guide the development of attenuated vaccines or novel antiviral strategies targeting immune modulators encoded by LSDV.