Innate Immune Responses to RSV Infection Facilitated by OGG1, an Enzyme Repairing Oxidatively Modified DNA Base Lesions

Xu Zheng, Ke Wang, Lang Pan, Wenjing Hao, Yaoyao Xue, Attila Bacsi, Spiros A. Vlahopoulos, Zsolt Radak, Tapas K. Hazra, Allan R. Brasier, Lloyd Tanner, Xueqing Ba, Istvan Boldogh*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The primary cause of morbidity and mortality from infection with respiratory syncytial virus (RSV) is the excessive innate immune response(s) (IIR) in which reactive oxygen species (ROS) play key role(s). However, the mechanisms for these processes are not fully understood. We hypothesized that expressions of IIR genes are controlled by the ROS-generated epigenetic-like mark 7,8-dihydro-8-oxo(d)guanine (8-oxo(d)Gua) and 8-oxoguanine DNA glycosylase1 (OGG1). Here, we report that ROS not only generates intrahelical 8-oxo(d)Gua, but also enzymatically disables OGG1 in RSV-infected human airway epithelial cells and mouse lungs. OGG1 bound to 8-oxo(d)Gua in gene regulatory sequences promotes expression of IIR genes, and consequently exacerbates lung inflammation, histological changes, and body weight loss of experimental animals. Pharmacological inhibition of OGG1 substrate binding decreased expression of RSV-induced chemokine and cytokines and significantly lessened clinical symptoms. Results of mechanistic studies show that OGG1 binding at 8-oxo(d)Gua promoter regions modulated loading of transcription factors via transient cooperative interactions in RSV-infected lungs and airway epithelial cells. Other base specific DNA repair proteins had no effects. Collectively, this study identifies unprecedented roles of ROS-generated DNA base lesion(s) and cognate repair protein as a determinant of RSV-induced exuberant inflammation. Pharmaceutical inhibition of OGG1 interaction with its DNA substrate may represent a novel strategy in prevention/intervention of respiratory viral infections.

Original languageEnglish
JournalJournal of Innate Immunity
DOIs
Publication statusAccepted/In press - 2022

Keywords

  • Innate immune response
  • OGG1
  • Oxidative DNA base damage
  • Respiratory syncytial virus infection

ASJC Scopus subject areas

  • Immunology and Allergy

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