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Herpetic keratitis is a stepwise pathological condition caused by features of the life cycle of Herpes Simplex Virus (HSV) and the immune system’s response. The pathogenesis is divided into three key phases: latent infection, reactivation, and tissue damage. Each phase is driven by complex interactions between viral factors and host defense mechanisms.

1. Latent Infection

After the primary infection, HSV travels through sensory nerves to regional ganglia where it enters latency.

A) Process of Transition to Latency:

• Virus migration to ganglia:

– After infecting the cornea, the virus is transported via axonal flow into sensory neurons, predominantly the trigeminal nerve (ganglion trigeminale).

– Here, viral DNA remains as an episome, not integrated into the host cell genome.

• Mechanisms of latency:

– During latency, only certain non-coding RNAs called Latency-Associated Transcripts (LAT) are expressed. These transcripts:

• Suppress viral replication.

• Block apoptosis of infected neurons.

• Reduce immune activity around the ganglion.

•Epigenetic modifications of viral DNA play a critical role in regulating its transcription during latency.

B) Immune Control of Latent Infection:

• Latency is maintained by immune surveillance primarily through CD8+ T-cells residing in the ganglia.

• Effector cytokines such as interferon-gamma (IFN-γ) create a microenvironment that inhibits viral reactivation.

2. Reactivation: Triggers and Mechanisms

In the latent state, under certain triggers, the virus reactivates leading to active replication and migration back to the corneal tissues.

A) Major Triggers of Reactivation:

Stress:

• Emotional or physical overexertion activates the hypothalamic-pituitary-adrenal axis, leading to the release of glucocorticoids.

• Stress hormones weaken immune control and increase the likelihood of viral reactivation.

Ultraviolet Radiation (UV):

• UV rays induce localized inflammation and tissue damage.

– There is increased production of pro-inflammatory cytokines such as IL-1 and IL-6, which reduce the activity of immune cells controlling the virus.

• UV radiation also activates MAPK signaling pathways that promote viral replication.

Immunosuppression:

• Immunodeficiency states (e.g., HIV infection, malignancies, chemotherapy) impair cellular immunity, creating conditions for viral reactivation.

• The use of systemic corticosteroids or other immunosuppressants significantly raises the risk of reactivation.

B) Mechanism of Reactivation:

• Reactivation is initiated by suppression of immune control within ganglia, leading to activation of viral replication.

• The active virus migrates back along sensory nerve endings to the cornea, causing tissue damage.

3. Tissue Damage: Viral and Immune Contributions

Tissue destruction in HSV keratitis is caused by two main mechanisms: direct cytotoxic effects of the virus and immune-mediated injury.

A) Cytotoxic Effect of the Virus:

1. Epithelial Cell Destruction:

• HSV replicates in corneal epithelial cells, leading to cell death via necrosis and apoptosis.

• Dendritic and geographic ulcers form as a result of focal epithelial degeneration.

2. Viral Protein Activity:

• The virus encodes proteins that suppress immune responses, such as ICP47, which inhibits antigen presentation on MHC-I.

• US3 and UL41 proteins protect infected cells from apoptosis, prolonging their viability for viral replication.

B) Immune Response as a Source of Damage:

Role of Innate Immunity:

• Neutrophils and macrophages recruited to the infection site release reactive oxygen species and pro-inflammatory cytokines (IL-1, TNF-α).

• This enhances inflammation but also causes collateral tissue damage.

Adaptive Immune Response:

• CD4+ and CD8+ T lymphocytes infiltrate stromal layers of the cornea, provoking chronic inflammation.

• Overactivation of T cells, especially TH1 and TH17 subsets, leads to production of interferon-gamma (IFN-γ) and IL-17, intensifying inflammation.

Fibrosis and Neovascularization:

– Chronic inflammation stimulates corneal neovascularization and fibrous tissue formation, disrupting transparency and reducing vision.

C) Final Pathology:

– In severe recurrences, inflammation may spread to deeper ocular structures (e.g., anterior chamber) causing keratouveitis, increased intraocular pressure, and secondary glaucoma development.