Early Transcriptomic Response of Human Iris Stromal Cells During Herpes Simplex Virus Entry Reveals Interplay Between Cell Glycocalyx and Viral Exploitation

Herpes simplex virus type 1 (HSV-1) initiates infection through sequential interactions with host receptors, yet the early transcriptional responses driving HSV-mediated iritis remain poorly understood. Given the clinical burden of HSV-induced anterior uveitis and the lack of targeted therapies, we sought to define the initial host response to infection. We performed temporal transcriptomic profiling of primary human iris stromal (HIS) cells at 1, 3, and 6 h post-infection. HSV-1 triggered rapid and extensive gene expression changes, with early activation of IL-17, TNFα, MAPK, and NF-κB signaling pathways, all associated with inflammation and stress responses. At later time points, pathways related to epithelial–mesenchymal transition and the G2/M checkpoint were upregulated, alongside sustained inflammatory signaling, suggesting a balance between stromal integrity and stress adaptation. Imaging studies, together with transcriptomic data, revealed modulation of HS3ST enzymes and a corresponding loss of heparan sulfate and syndecans. These transcriptional dynamics mirror those observed in HSV-1-induced keratitis, indicating a conserved ocular response across cell types. By mapping these early events, this study identifies potential molecular targets for therapies aimed at mitigating inflammation during HSV-induced iritis.