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<p>Chronic infection of <i>Toxoplasma gondii</i> has been established as a contributor to cognitive impairment via inducing sustained neuroinflammation and synaptic damage. However, the underlying mechanisms remain poorly understood. As a key regulator of both neuroinflammation and cellular senescence, Cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is implicated in pathogenesis induced by <i>T. gondii</i> infection. Here, we found that cGAS-STING pathway was activated in the cerebral cortex of mouse chronically infected with <i>T. gondii</i>, as indicated by the elevated protein levels of cGAS and STING, and increased phosphorylation of TBK1 and IRF3. Pharmacological inhibition of this pathway with RU.521 and H151, specific inhibitors of cGAS and STING, significantly alleviated <i>T. gondii</i>-induced cognitive impairment and neuronal damage. Moreover, chronic <i>T. gondii</i> infection was shown to trigger senescence characterized by increased expression of senescence markers P16, P21 and P53, and senescence-associated secretory phenotypes (SASPs), including <i>Il-1β</i>, <i>Il-6</i>,<i> Tnf-α</i>, <i>Cxcl1</i>, <i>Cxcl10</i> and <i>Mmp9</i>. In addition, elevated expression of β-galactosidase, a senescence marker, was predominantly observed in neurons compared to microglia and astrocytes, indicating a primary role for neurons in infection-associated senescence. Notably, these phenotypes of senescence were rescued by inhibition of the cGAS-STING pathway. Collectively, our findings demonstrate that chronic infection of <i>T. gondii</i> activates the cGAS-STING pathway, which in turn drives neuroinflammation and cognitive dysfunction in which neuronal senescence plays a contributory role. Targeting this pathway alleviates <i>T. gondii</i>-induced cognitive decline, highlighting its therapeutic potential against infection-triggered neurodegenerative diseases.</p>

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Targeting the cGAS-STING pathway alleviates neuroinflammation and cognitive impairment induced by chronic infection of Toxoplasma gondii

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月4日

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  • Yihui Xing,
  • Huiling Lv,
  • Peixuan He,
  • Yongyao Xu,
  • Weifan Shen,
  • Ziyan Gu,
  • Fan Zeng,
  • Yifan Zhang,
  • Kai Sui,
  • Yurui Shi,
  • Yinghua Yu,
  • Wei Pan,
  • Cheng He

摘要

Chronic infection of Toxoplasma gondii has been established as a contributor to cognitive impairment via inducing sustained neuroinflammation and synaptic damage. However, the underlying mechanisms remain poorly understood. As a key regulator of both neuroinflammation and cellular senescence, Cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is implicated in pathogenesis induced by T. gondii infection. Here, we found that cGAS-STING pathway was activated in the cerebral cortex of mouse chronically infected with T. gondii, as indicated by the elevated protein levels of cGAS and STING, and increased phosphorylation of TBK1 and IRF3. Pharmacological inhibition of this pathway with RU.521 and H151, specific inhibitors of cGAS and STING, significantly alleviated T. gondii-induced cognitive impairment and neuronal damage. Moreover, chronic T. gondii infection was shown to trigger senescence characterized by increased expression of senescence markers P16, P21 and P53, and senescence-associated secretory phenotypes (SASPs), including Il-1β, Il-6, Tnf-α, Cxcl1, Cxcl10 and Mmp9. In addition, elevated expression of β-galactosidase, a senescence marker, was predominantly observed in neurons compared to microglia and astrocytes, indicating a primary role for neurons in infection-associated senescence. Notably, these phenotypes of senescence were rescued by inhibition of the cGAS-STING pathway. Collectively, our findings demonstrate that chronic infection of T. gondii activates the cGAS-STING pathway, which in turn drives neuroinflammation and cognitive dysfunction in which neuronal senescence plays a contributory role. Targeting this pathway alleviates T. gondii-induced cognitive decline, highlighting its therapeutic potential against infection-triggered neurodegenerative diseases.