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Principal Investigator: Vaithilingaraja Arumugaswami
Organization: UNIVERSITY OF CALIFORNIA LOS ANGELES
Fiscal Year: 2024
Award: $520,349
Funding agency: National Eye Institute
PROJECT SUMMARY: Zika virus (ZIKV) is a teratogenic human pathogen that causes congenital eye and brain
diseases. Affected babies exhibit vision impairment and associated ocular pathology, including loss of foveal
reflex and macular pigment mottling, chorioretinal scarring, and macular atrophy. ZIKV has become endemic
and local transmissions in the USA have been reported previously. The long-term effects of structural damage
on vision, as well as the pathogenic processes of congenital ZIKV eye diseases are beginning to be understood.
The signaling pathways governing normal eye development, which are dysregulated during ZIKV infection, are
not well characterized. We recently carried out a series of experiments by establishing a ZIKV infectious ocular
cell culture system and mouse models to understand the structural and molecular perturbations. For successful
replication, viruses have evolved various strategies to evade innate immune response as well as to enhance the
availability of cellular metabolites required to meet the heightened energy demand for viral genome synthesis.
We found that the AMPKα, a cellular master energy sensor, is activated in the ZIKV-infected retinal cells.
Moreover, pharmacological activation of AMPK resulted in attenuated ZIKV replication. Another interesting
finding is that the YAP/TAZ factors in the tumor suppressor Hippo/SWH signaling pathway were induced early
on, but degraded at later stage of ZIKV infection in RPE cells. Silencing YAP/TAZ resulted in reduced ZIKV
replication. Since the energy sensor AMPK and Hippo signaling pathways control key cellular processes,
including host antiviral responses, it is critical to understand the fundamental mechanism of these two pathways
deregulation. We hypothesize that ZIKV modulates AMPK and Hippo signaling pathways in ocular cells to 1)
increase intracellular metabolic resources, and 2) inhibit TBK1 to antagonize antiviral defense. These molecular
changes can be orchestrated through viral coded factors resulting in the pathogenesis of ocular cell injury. The
following specific aims will be investigated. Aim 1 focuses on systematically evaluating the role of AMPK-
Hippo signaling on regulating antiviral response to ZIKV infection in RPE cells. The cross talk between
these pathways will be investigated at the YAP/TAZ level. Pharmacological activation/inhibition, and gene
knockout approaches in RPE cells will be carried out. Aim 2 is designed to elucidate the effect of ZIKV on
Hippo and AMPK signaling pathways during retinal development. Human iPSC-derived 3D-retinal cup
organoids will be used to investigate the link between retinal development and ZIKV-mediated deregulation of
these key pathways. The ZIKV-encoded virulence factors regulating these pathways will be characterized. Aim
3 is to determine the effect of RPE-specific ablation of AMPK, TBK1, and Hippo signaling on the
pathogenesis of ZIKV-induced chorioretinal atrophy in mice. This proposed study would yield novel insights
into the pathogenesis of ZIKV in ocular diseases and identification of potential therapeutic targets.
Terms: <(hydroxymethylglutaryl-CoA reductase (NADPH)) kinase><1st trimester><2nd trimester><3-D><3-Dimensional><3D><5'-AMP-activated protein kinase><AMP-activated kinase><AMP-activated protein kinase><AMPK enzyme><Ablation><Address><Affect><Anti-viral Response><Atrophic><Atrophy><Attenuated><Biologic Models><Biological Models><Blood-Retinal Barrier><Body Tissues><Brain Diseases><Brain Disorders><Cell Body><Cell Communication and Signaling><Cell Culture System><Cell Density><Cell Function><Cell Growth in Number><Cell Multiplication><Cell Physiology><Cell Process><Cell Proliferation><Cell Signaling><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular Proliferation><Cellular injury><Cessation of life><Chemicals><Cicatrix><Code><Coding System><Cre Lox technology><Cre LoxP system><Cre lox recombination><Cre lox recombination system><Cre lox system><Cre recombinase/LoxP technology><Cre system><Cytometry><Cytoplasm><Death><Developing fetus><Development><Diminished Vision><Disease Progression><Drosophila Homolog of Large Tumor Suppressor 1><Dysfunction><Early Placental Phase><Encephalon Diseases><Endogenous Interferon Beta><Exhibits><Eye><Eye Development><Eye Injuries><Eye diseases><Eyeball><FLJ11330><Fetal Development><Fibroblast Interferon><First Pregnancy Trimester><First Trimester><Functional disorder><Genes><Genetic><HMG CoA reductase (NADPH) kinase><HMG CoA reductase kinase><HMG coenzyme A reductase (NADPH) kinase><Histology><Human><IFN><IFN-Beta><IFN-β><IFNb><Immune><Immunes><In Vitro><Inflammatory><Injury><Innate Immune Response><Interferon-beta><Interferon-β><Interferons><Intermediary Metabolism><Intracellular Communication and Signaling><Intracranial CNS Disorders><Intracranial Central Nervous System Disorders><Kinases><Knock-out><Knockout><LATS1><LATS1 gene><Link><Long-Term Effects><Longterm Effects><Low Vision><Mediating><Metabolic><Metabolic Processes><Metabolism><Mice><Mice Mammals><Midtrimester><Model System><Modeling><Modern Man><Molecular><Murine><Mus><NF-Kb-Activating Kinase Gene><Natural Interferon Beta><Natural human interferon beta><Nervous System Diseases><Nervous System Disorder><Neurologic Disorders><Neurological Disorders><Ocular Injury><Ocular Pathology><Organoids><Outcome Measure><Outer pigmented layer of retina><Partial Sight><Pathogenesis><Pathogenicity><Pathogenicity Factors><Pathologic><Pathway interactions><Phosphorylation><Phosphotransferase Gene><Phosphotransferases><Physiologic><Physiological><Physiopathology><Pigment cell layer of retina><Pigmented layer of retina><Pigments><Predisposition><Process><Progenitor Cells><Protein Phosphorylation><Proteins><RNA chemical synthesis><RNA synthesis><Reduced Vision><Reflex><Reflex action><Regulation><Reporting><Research Resources><Resources><Retina><Retinal Diseases><Retinal Disorder><Retinal Pigment Epithelium><Retinal pigment epithelial cells><Role><Scars><Second Pregnancy Trimester><Second Trimester><Series><Sight><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Stress><Structure of retinal pigment epithelium><Subcellular Process><Subnormal Vision><Susceptibility><T2K><TBK1><TBK1 gene><Teratogenic><Teratogenicity><Teratogens><Testing><Tissues><Transmission><Transphosphorylases><Tumor Suppressor Proteins><Viral><Viral Genome><Virulence Factors><Virus><Virus Replication><Vision><Visual impairment><ZIKA><ZIKV><ZIKV disease><ZIKV infected><ZIKV infection><ZIKV positive><Zika Virus><Zika virus disease><Zika virus infection><attenuate><attenuates><biological signal transduction><cell damage><cell injury><cell type><cellular damage><conditioning><congenital eye disease><congenital eye disorder><damage to cells><design><designing><developmental><emerging human pathogen><experiment><experimental research><experimental study><experiments><eye disorder><eye morphogenesis><eye trauma><fetal><fetal infection><fundus imaging><hiPSC><human iPS><human iPSC><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><human pathogen><hydroxymethylglutaryl-CoA-reductase kinase><iPS><iPSC><iPSCs><in vivo Model><induced human pluripotent stem cells><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><infected with ZIKV><infected with zika><injuries><injury to cells><innate immune pathways><insight><knockout gene><macula><macular><measurable outcome><mouse model><murine model><neurological disease><novel><ocular development><ocular disease><ocular disorder><ocular trauma><ophthalmopathy><organ development><organ growth><outcome measurement><pathogen><pathophysiology><pathway><pharmacologic><pigment><primary outcome><retina disease><retina disorder><retinal progenitor><retinal progenitor cell><retinal stem cell><retinopathy><sensor><social role><stem><stem cells><therapeutic target><three dimensional><transmission process><tumor suppressor><viral DNA><viral multiplication><viral replication><virus DNA><virus genome><virus multiplication><vision impairment><visual function><visually impaired><zika disease><zika infected><zika infection><zika viral infection><zikav>