Investigating Dendritic Cell Autophagy as a Viral Targeted Determinant of Herpetic Stromal Keratitis

Jiang, Yike

Abstract

Herpes Simplex Keratitis (HSK) is a major cause of infectious blindness in industrialized countries. Induced by herpes simplex virus type 1 (HSV-1) infection of the ocular surface, HSK is a chronic inflammation of the cornea that results in neovascularization and opacity, compromising visual acuity. Interestingly, HSV-1 is rarely found in HSK lesions; instead, the lesions are predominantly infiltrated by immune cells like neutrophils and CD4 T cells. However, the mechanism by which HSV-1 induces and manipulates HSK immunopathology is poorly understood. Previous work in our lab and preliminary studies show that a potential immune pathway, when targeted by the virus, may attenuate HSK. HSV-1 is known to inhibit autophagy, a cellular recycling process universal to all eukaryotic cells. When HSV-1 infects dendritic cells in vitro, downstream activation of CD4 T cells is compromised. This corroborates the in vivo finding that infection with a mutant virus that can't modulate autophagy induces a greater CD4 T cell response. Furthermore, our preliminary studies show that the genetic deletion of dendritic cell autophagy results in reduced HSK disease in vivo. Taken together, these data link an immunomodulatory function of HSV-1 to HSK disease through viral control of autophagy in dendritic cells. Our proposal will test our overarching hypothesis that autophagy in dendritic cells is a determinant of HSK immunopathology and is targeted by HSV-1. To test this hypothesis, we propose the following aims:
Specific Aim 1 : To test the hypothesis that autophagy in dendritic cells promotes HSK immunopathology.
Specific Aim 2 : To test the hypothesis that HSV-1 antagonism of autophagy in dendritic cells modulates HSK disease. If our hypotheses are correct, we will have identified a unique paradigm in which an immunomodulatory action of HSV-1 antagonizes HSK disease. This avenue of research could lead to bioengineered viral proteins, repurposed as therapy for combating HSK disease. Additionally, completion of this research proposal and rigorous training plan will fulfill the broader objective of enhancing physician-scientist career development. This fellowship will enable the trainee to develop advanced skills in basic, clinical, and translational research that facilitate integration of clinical and research interests in infectious ocular diseas.

Public Health Relevance

Herpetic Stromal Keratitis is the leading cause of infectious blindness in the United States. HSK is induced by herpes simplex virus type 1 but is primarily a disease of inappropriate immune activation, so the goal of our proposal is to understand the immunopathology underlying HSK. Better understanding of HSK pathogenesis will bolster the development of new therapies against this recurrent cause of blindness.