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

Zheng, X. ; Wang, K. ; Pan, L. ; Hao, W. ; Xue, Y. ; Bacsi, A. ; Vlahopoulos, S. ; Radak, Z. ; Hazra, T. and Brasier, A. , et al. (2022) In Journal of Innate Immunity 14(6). p.593-614
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Innate Immunity
volume
14
issue
6
pages
593 - 614
publisher
Karger
external identifiers
  • scopus:85130441289
  • pmid:35512649
ISSN
1662-811X
DOI
10.1159/000524186
language
English
LU publication?
yes
id
dfe16b56-3ffd-4d57-8dc7-9c24a9fdee83
date added to LUP
2022-08-05 13:16:42
date last changed
2023-01-16 10:16:47
@article{dfe16b56-3ffd-4d57-8dc7-9c24a9fdee83,
  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.}},
  author       = {{Zheng, X. and Wang, K. and Pan, L. and Hao, W. and Xue, Y. and Bacsi, A. and Vlahopoulos, S. and Radak, Z. and Hazra, T. and Brasier, A. and Tanner, L. and Ba, X. and Boldogh, I.}},
  issn         = {{1662-811X}},
  language     = {{eng}},
  number       = {{6}},
  pages        = {{593--614}},
  publisher    = {{Karger}},
  series       = {{Journal of Innate Immunity}},
  title        = {{Innate Immune Responses to RSV Infection Facilitated by OGG1, an Enzyme Repairing Oxidatively Modified DNA Base Lesions}},
  url          = {{http://dx.doi.org/10.1159/000524186}},
  doi          = {{10.1159/000524186}},
  volume       = {{14}},
  year         = {{2022}},
}