Project: X03
The role of ZBP1 in the host immune response in Herpes Simplex Virus 1 (HSV-1) keratitis
This crosslinking project investigates the role of Z-DNA binding protein 1 (ZBP1) in the immune response to Herpes Simplex Virus 1 (HSV-1) keratitis, a major cause of corneal inflammation, visual impairment, and blindness worldwide. HSV-1 infection of the cornea can induce severe inflammatory responses leading to corneal hem- and lymphangiogenesis, scar formation, tissue opacification, and impaired corneal graft survival. Despite current treatment options, controlling HSV-1-induced inflammation and pathological neovascularization remains a major unmet clinical need.
The project combines expertise from projects B01 and B03 with interdisciplinary links to C07, B02, and A02 to investigate how ZBP1-mediated cell death pathways contribute to inflammasome activation, antiviral immunity, and inflammatory angiogenesis in herpetic stromal keratitis. ZBP1 acts as a sensor of viral nucleic acids and regulates necroptosis and apoptosis through interactions with key immune signaling molecules. While these mechanisms can contribute to antiviral defense, excessive activation may also promote tissue damage and chronic inflammation.
A central hypothesis of the project is that ADAR1- and ZBP1-controlled cell death responses mechanistically connect NLRP3 inflammasome activation, cGAS/STING signaling, and corneal hem- and lymphangiogenesis during HSV-1 infection. To address this, the project employs genetically modified mouse models with targeted alterations in ZBP1 signaling as well as primary murine cells and human cell lines. Experimental HSV-1 keratitis models will be used to identify molecular drivers of corneal neovascularization, immune cell infiltration, tissue opacification, and metabolic changes associated with HSV-1-induced corneal pathology.
By integrating antiviral immunity, inflammasome biology, and inflammatory angiogenesis, this project establishes a novel mechanistic framework within SFB 1607. The findings are expected to uncover new therapeutic targets for limiting HSV-1-induced corneal inflammation and neovascularization, improving corneal graft survival, and preventing vision loss in patients suffering from recurrent herpetic eye disease.
Key Methods
- Experimental mouse models of HSV-1 keratitis
- Genetically modified ZBP1 and ADAR1 mouse models
- RNA sequencing (RNA-seq) and transcriptomic profiling
