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<p>Herpes simplex virus type 1 (HSV-1) infection remains a major global health challenge, yet the mechanisms underlying strain-specific innate immune responses are poorly understood. Here, we show that distinct HSV-1 strains differentially activate the absent in melanoma 2 (AIM2) inflammasome. The HF strain robustly induces AIM2-dependent inflammasome activation, whereas the F and KOS strains elicit minimal responses despite comparable infection efficiency. We demonstrate that this difference is driven by viral genomic features rather than replication capacity. Genomic analyses identify a poly(T) DNA sequence within the UL25-UL26 intergenic region that is enriched in the HF strain. Deletion of a 14-mer poly(T) sequence markedly impairs inflammasome activation, cytokine release, and host protection in vivo, whereas introduction of a poly(T) tract into the F strain is sufficient to confer AIM2 activation and enhanced host defense. Furthermore, poly(T)-mediated AIM2 activation is length-dependent, conserved in human macrophages, and requires a cGAS-STING-IRF1 licensing axis. Together, these findings identify viral poly(T) DNA as a key determinant of strain-specific AIM2 inflammasome activation and reveal how viral genomic variation shapes innate immune recognition.</p>

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Herpes simplex virus 1 harboring poly(T) DNA sequences as a key ligand for AIM2 inflammasome activation and host defense

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月13日

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  • SuHyeon Oh,
  • Jueun Oh,
  • Kyeongchan Im,
  • Tae Hyoung Kim,
  • Jihye Lee,
  • Kihye Shin,
  • Nabukenya Mariam,
  • Cheong Seok,
  • Jaewoo Park,
  • GyeongJu Yu,
  • Hayeon Kim,
  • Suhyun Kim,
  • Seyun Shin,
  • Jinwoo Gil,
  • Sehee Park,
  • Yoon-Seok Chung,
  • Daesik Kim,
  • Young Ki Choi,
  • Eui Tae Kim,
  • Joo Sang Lee,
  • SangJoon Lee

摘要

Herpes simplex virus type 1 (HSV-1) infection remains a major global health challenge, yet the mechanisms underlying strain-specific innate immune responses are poorly understood. Here, we show that distinct HSV-1 strains differentially activate the absent in melanoma 2 (AIM2) inflammasome. The HF strain robustly induces AIM2-dependent inflammasome activation, whereas the F and KOS strains elicit minimal responses despite comparable infection efficiency. We demonstrate that this difference is driven by viral genomic features rather than replication capacity. Genomic analyses identify a poly(T) DNA sequence within the UL25-UL26 intergenic region that is enriched in the HF strain. Deletion of a 14-mer poly(T) sequence markedly impairs inflammasome activation, cytokine release, and host protection in vivo, whereas introduction of a poly(T) tract into the F strain is sufficient to confer AIM2 activation and enhanced host defense. Furthermore, poly(T)-mediated AIM2 activation is length-dependent, conserved in human macrophages, and requires a cGAS-STING-IRF1 licensing axis. Together, these findings identify viral poly(T) DNA as a key determinant of strain-specific AIM2 inflammasome activation and reveal how viral genomic variation shapes innate immune recognition.