File(s) under embargo

1

year(s)

5

month(s)

12

day(s)

until file(s) become available

Optineurin is Neuroprotective against Herpes simplex Virus Type-1 Infection

thesis
posted on 01.08.2021, 00:00 by Joshua Ames
OPTN is a conserved protein that regulates selective autophagy and signaling through ubiquitin binding. Patients with mutations in OPTN often develop glaucoma, amyotrophic lateral sclerosis, or other neurodegenerative diseases. Fast-replicating neurotropic herpesviruses naturally infect the CNS. However, most individuals suppress the virus during a primary infection, preventing potential CNS damage. Using both in vitro and in vivo OPTN knockout and knockdown models, this study presents the first evidence that OPTN is required for restriction of the neurotropic virus, herpes simplex virus-1 (HSV-1). We show that OPTN selectively targeted HSV-1 tegument protein, VP16, and the fusion glycoprotein, gB, to degradation by autophagy in vitro. Ocular HSV-1 infection was lethal in vivo for Optn-/- mice. OPTN was required for optimal lymph node activation and T-lymphocyte recruitment and for suppression of neuronal necroptosis. Treatment with a necroptosis inhibitor rescued Optn-/- mice from herpes encephalitis. Examination of ocular pathology revealed that Optn-/- mice rapidly and permanently lose corneal and whisker sensitivity and have more severe herpes keratitis. scRNAseq revealed there is a loss of neuronal activity of Optn-/- animals, and pathway analysis highlighted multiple pathways that may underlie the exacerbated pathology of the PNS following HSV-1 infection. These results place OPTN at the crux of neuronal survival from potentially lethal CNS or PNS viral infections and provide direction for future studies.

History

Advisor

Shukla, Deepak

Chair

Shukla, Deepak

Department

Microbiology and Immunology

Degree Grantor

University of Illinois at Chicago

Degree Level

Doctoral

Degree name

PhD, Doctor of Philosophy

Committee Member

Bouvier, Marlene Freitag, Nancy Chen, Zheng Valyi-Nagy, Tibor

Submitted date

August 2021

Thesis type

application/pdf

Language

en

Usage metrics

Categories

Keywords

Exports