Class IIa Histone Deacetylase (HDAC) Inhibitor TMP269 Suppresses Lumpy Skin Disease Virus Replication by Regulating Host Lysophosphatidic Acid Metabolism

Overview

Journal J Virol

Publisher American Society for Microbiology

Date 2025 Jan 22

PMID 39840984

Authors

Pengyuan Cheng

Xiangwei Wang

Shasha Wang

Shanhui Ren

Zhengji Liang

Ke Guo

Min Qu

Xuelian Meng

Yongxi Dou

Xiangping Yin

Yuefeng Sun

Affiliations

Soon will be listed here.

Abstract

Lumpy skin disease virus (LSDV) infection poses a significant threat to global cattle farming. Currently, effective therapeutic agents are lacking. TMP269, a small molecule inhibitor of class IIa histone deacetylase inhibitor, plays a vital role in cancer therapy. In this study, we demonstrated that TMP269 treatment inhibits the early-stage replication of LSDV in a dose-dependent manner. RNA sequencing data revealed that metabolism-related signaling pathways were significantly enriched after LSDV infection. Furthermore, untargeted metabolomics analysis revealed that lysophosphatidic acid (LPA), a key metabolite of the glycerophospholipid pathway, was upregulated following LSDV infection and downregulated after TMP269 treatment. In addition, exogenous LPA promotes LSDV replication by activating the mitogen-activated protein kinase (MEK)/extracellular-signal-regulated kinase (ERK) signaling pathway and suppressing the host's innate immune response. Furthermore, treatment with the LPA receptor inhibitor Ki16425 suppressed LSDV replication and promoted the host's innate immune response. These findings suggest that LSDV infection can induce LPA expression and aid viral activation of the MEK/ERK signaling pathway and escape of the host's innate immune response, whereas TMP269 treatment can inhibit LPA production and limit its promotion of LSDV replication. These data identified the antiviral mechanism of TMP269 and a novel mechanism by which LSDV inhibits host innate immune responses, providing insights into the development of new preventive or therapeutic strategies targeting altered metabolic pathways.IMPORTANCELumpy skin disease virus (LSDV) poses a significant threat to global cattle farming. Owing to insufficient research on LSDV infection, pathogenesis, and immune escape mechanisms, prevention and control methods against LSDV infection are lacking. Here, we found that TMP269, a class IIa histone deacetylase inhibitor, significantly inhibited LSDV replication. We further demonstrated that TMP269 altered LSDV infection-induced host glycerophospholipid metabolism. In addition, TMP269 decreased the accumulation of lysophosphatidic acid (LPA), a key metabolite in glycerophospholipid metabolism, induced by LSDV infection, and exogenous LPA-promoted LSDV replication by activating the mitogen-activated protein kinase (MEK)/extracellular-signal-regulated kinase (ERK) signaling pathway and suppressing the host innate immune response. Our findings identified the antiviral mechanism of TMP269 and a novel mechanism by which LSDV manipulates host signaling pathways to promote its replication, offering insights into the development of novel antiviral agents against LSDV infection.

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