Howaldt, Antonia - CAP 38

Innate viral immune response and cell death mechanisms in HSV-1 keratitis

Dr. Antonia Howaldt

Dept. of Ophthalmology

CMMC - PI - CAP 38

antonia.howaldt@uk-koeln.de

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Curriculum Vitae (CV)

Publications on PubMed

Dept. of Ophthalmology

Kerpener Str. 62

50937 Köln

Introduction

Corneal avascularity is required for corneal transparency and optimal visual function. This corneal (lymph)-angiogenic privilege, preserved through a balance of anti-(lymph)angiogenic factors counteracting pro-(lymph)angiogenic stimuli, protects the cornea from pathologic immune responses. Herpes Simplex Virus 1 (HSV-1) can induce strong proinflammatory immune responses in the corneal stroma via activation of mature proinflammatory dendritic cells and macrophages leading to herpetic stromal keratitis (HSK). Characterized by inflammation and opacification of the corneal stroma, invasion of blood and lymphatic vessels, corneal scar formation and potential blindness, it is a frequent cause of corneal transplantation. We will investigate how CD83- and ZBP1-mediated immune responses influence the development of HSK and concomitant corneal hem- and lymphangiogenesis and whether targeting these pathways can offer new therapeutic possibilities.

Clinical Relevance

HSV-1 keratitis is the leading cause of infectious corneal blindness in industrialized countries and a common indication for corneal transplantation due to corneal scar formation and corneal hem- and lymphangiogenesis. Antiviral therapies can suppress viral replication, however there is a great unmet medical need for novel therapeutic treatment options targeting inflammatory immune responses in the cornea. CD83 is expressed on activated dendritic cells, macrophages, and regulatory T cells. It regulates maturation, activation, and homeostasis of immune cells, e.g. stabilizes MHCII and CD86 expression on mature dendritic cells. HSV-1 has been shown to rapidly degrade CD83 on dendritic cells, indicating evasion of the host innate immune response. Regulated cell death is relevant for the host antiviral immune response limiting viral replication. Previous work has demonstrated that ZBP1 facilitates RIPK3-MLKL-necroptosis to limit HSV-1 replication exclusively when the virus either lacks ICP6 expression or carriers a mutated version of ICP6 (FmutRHIM).

Aims

We aim to investigate the role of CD83-mediated immune regulation and ZBP1-mediated necroptosis in HSV-1 keratitis. We are particularly interested in understanding the mechanisms driving pathological (lymph)angiogenesis and immune responses in the cornea.

We will address the questions:

How does mCD83 influence HSV-1 keratitis and inflammatory corneal hem- and lymphangiogenesis? Is there an anti-inflammatory or tissue-regenerative effect of sCD83?
What is the role of ZBP1-mediated necroptosis in HSV-1 keratitis comparing ICP6-mutated vs. wildtype HSV-1?

We will investigate CD83 conditional knockout mice for Cx3cr1, Cd11c, and FoxP3 provided by Prof. A. Steinkasserer (Friedrich Alexander University Erlangen), and different ZBP1 mutant mice, provided by Prof. M. Pasparakis (CECAD).

Perspective

The long-term goal is to contribute to the development of potential immune-modulatory therapeutic targets for inflammatory immune responses in herpetic stromal keratitis. We will investigate whether CD83-based immune-modulation and ZBP1-dependent restriction of herpesvirus replication can serve as a therapeutic target in herpetic keratitis. Understanding the mechanisms of ZBP1 activation and CD83 immune modulation in HSV-1 mediated corneal disease could potentially uncover novel therapeutic targets for the recurrent disease.