Regulation of host factor γ-H2AX level and location by enterovirus A71 for viral replication

• Published in: Virulence 2022-12, Vol.13 (1), p.241-257
• Main Authors: Yu, Jinghua, Zhang, Wenyan, Huo, Wenbo, Meng, Xiangling, Zhong, Ting, Su, Ying, Liu, Yumeng, Liu, Jinming, Wang, Zengyan, Song, Fengmei, Zhang, Shuxia, Li, Zhaolong, Yu, Xiaoyan, Yu, Xiaofang, Hua, Shucheng
• Format: Article
• Language: English
• Subjects: Animals; Ataxia Telangiectasia Mutated Proteins - genetics; Ataxia Telangiectasia Mutated Proteins - metabolism; Caffeine; DNA; DNA Damage; DNA damage response; Enterovirus - genetics; Enterovirus A71 (EVA71); Enterovirus Infections; Histones - genetics; Histones - metabolism; Mice; Research Paper; viral genome replication; viral production; Viral Proteins - genetics; Virus Replication - physiology; γ-H2AX level; γ-H2ax location
• ISSN: 2150-5594; 2150-5608
• DOI: 10.1080/21505594.2022.2028482

Numerous viruses manipulate host factors for viral production. We demonstrated that human enterovirus A71 (EVA71), a primary causative agent for hand, foot, and mouth disease (HFMD), increased the level of the DNA damage response (DDR) marker γ-H2AX. DDR is primarily mediated by the ataxia telangiectasia mutated (ATM), ATM and Rad3-related (ATR), or DNA-dependent protein kinase (DNA-PK) pathways. Upregulation of γ-H2AX by EVA71 was dependent on the ATR but not the ATM or DNA-PK pathway. As a nuclear factor, there is no previous evidence of cytoplasmic distribution of γ-H2AX. However, the present findings demonstrated that EVA71 encouraged the localization of γ-H2AX to the cytoplasm. Of note, γ-H2AX formed a complex with structural protein VP3, non-structural protein 3D, and the viral genome. Treatment with an inhibitor or CRISPR/Cas9 technology to decrease or silence the expression of γ-H2AX decreased viral genome replication in host cells; this effect was accompanied by decreased viral protein expression and virions. In animal experiments, caffeine was used to inhibit DDR; the results revealed that caffeine protected neonatal mice from death after infection with EVA71, laying the foundation for new therapeutic applications of caffeine. More importantly, in children with HFMD, γ-H2AX was upregulated in peripheral blood lymphocytes. The consistent in vitro and in vivo data on γ-H2AX from this study suggested that caffeine or other inhibitors of DDR might be novel therapeutic agents for HFMD.