Co- option of mitochondrial nucleic acid-sensing pathways by HSV-1 UL12.5 for reactivation from latent infection

• 成果类型: Article
• 署名作者: Krakowiak, Patryk A.; Flores, Matthew E.; Cuddy, Sean R.; Whitford, Abigail L.; Dochnal, Sara A.; Babnis, Aleksandra; Miyake, Tsuyoshi; Tigano, Marco; Engel, Daniel A.; Cliffe, Anna R.
• 署名单位: University of Virginia; University of Virginia; Thomas Jefferson University; University of California System; University of California San Diego
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8528
• DOI: 10.1073/pnas.2413965122
• 发表日期: 2025-01-28
• 关键词: simplex-virus type-1; alzheimers-disease brain; i interferon; alkaline nuclease; structural basis; dna-sequences; gene; activation; cgas; product

摘要

Although viruses subvert innate immune pathways for their replication, there is evidence they can also co- opt antiviral responses for their benefit. The ubiquitous human pathogen, Herpes simplex virus- 1 (HSV- 1), encodes a protein (UL12.5) that induces the release of mitochondrial nucleic acid into the cytosol, which activates immune- sensing pathways and reduces productive replication in nonneuronal cells. HSV- 1 establishes latency in neurons and can reactivate to cause disease. We found that UL12.5 is required for HSV- 1 reactivation in neurons and acts to directly promote viral lytic gene expression during initial exit from latency. Further, the direct activation of innate immune- sensing pathways triggered HSV- 1 reactivation and compensated for a lack of UL12.5. Finally, we found that the induction of HSV- 1 lytic genes during reactivation required intact RNA- and DNA- sensing pathways, demonstrating that HSV- 1 can respond to and active antiviral nucleic acid-sensing pathways to reactivate from a latent infection.