Ocular herpes simplex virus 1 (HSV-1) infection can lead to multiple complications, including iritis, an inflammation of the iris. Here, we use human iris stroma cells as a novel in vitro model to demonstrate HSV-1 entry and the inflammatory mediators that can damage the iris. The upregulated cytokines observed in this study provide a new understanding of the intrinsic immune mechanisms that can contribute to the onset of iritis.
Herpes simplex virus 1 (HSV-1) is a significant ocular pathogen affecting multiple regions, including the iris (1). The iris, a specialized eye tissue, is affected in various inflammatory ophthalmic conditions (2, 3). For instance, inflammation of the iris following HSV-1 infection may be associated with elevated intraocular pressure, ultimately resulting in glaucoma, although the possibility remains that this may be steroid induced (4-6). The iris has been shown to have histopathologic involvement in HSV-1 infection of the corneal stroma, herpetic stromal keratitis (HSK) (3). Inflammation of the iris is also seen in herpetic anterior uveitis, a condition that often presents as an inflammation of the iris and ciliary body (iridocyclitis) and is the leading cause of infectious anterior uveitis worldwide (2). In addition to iris involvement in primary inflammatory conditions of various ocular tissues, there had previously been a longstanding question as to whether HSV-induced iritis could occur without concurrent or precedent keratitis. Studies performed since have indicated that HSV may cause iritis that predisposes to glaucoma without necessarily causing keratitis (6). Although these results indicate the possible pathogenesis mediated by primary HSV-1 infection of the iris, primary infection of human iris stromal (HIS) cells has not been previously investigated. Likewise, chemokine signaling, which plays a significant role in many inflammatory eye conditions (7), has been poorly studied in the context of HSV-1 infection of HIS cells. The current study demonstrates the potential of an in vitro HIS cell model to uncover the molecular basis of viral entry and the identity of the inflammatory mediators involved.HSV-1 starts its infectious journey into cells via interactions of its envelope glycoproteins with their respective host cell receptors (8). The initial attachment involves glycoprotein B (gB) and glycoprotein C (gC) interactions with host cell surface heparan sulfate proteoglycans (9, 10). HSV-1 glycoprotein D (gD), with its subsequent conformational changes, can bind to any of its host cell receptors, such as nectin-1, herpesvirus entry mediator (HVEM) (11), or 3-O-sulfated heparan sulfate (3-OS HS) (12). This conformational change is important since it allows for the gD-host cell receptor complex to associate with the heterodimer complex of glycoprotein H-glycoprotein L (gH-gL). This allows gH-gL to bind gB, a process that allows the viral and host cell membranes to fuse (12,13).Following infection by HSV-1, the intrinsic inflammatory responses contribute strongly to subsequent di...