Inhibitors of metalloprotease, γ-sectretase, protein kinase C and Rho kinase inhibit wild-type adenoviral replication
Open Access
- 22 July 2020
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 15 (7), e0236175
- https://doi.org/10.1371/journal.pone.0236175
Abstract
Adenoviruses cause upper respiratory infections, conjunctivitis, keratitis, and gastrointestinal illness. These can be fatal in immunocompromised individuals. Adenoviruses have also been engineered into viral vectors to deliver therapeutic genes or induce immunity as vaccine carriers. The success of ocular gene therapy is driven partly by the immunologic and biochemical influences of the intraocular environment. We have shown that versican and hyaluronan modulate adenoviral vector transgene expression through CD44 signaling. Herein we explored the role of these pathways on virus replication and viral protein expression of wild type adenovirus. We report that the addition of vitreous humor (which contains both versican and hyaluronan) increases viral hexon protein levels. Vitreous humor also increased wild type adenovirus DNA replicationin vitro. Metalloproteinase and gamma-secretase inhibitors, which inhibit CD44 proteolytic activation, blocked adenoviral replicationin vitro. Similarly, protein kinase C and RhoA kinase inhibitors, both proteins associated with CD44 mediated pathways, also inhibited wild type adenoviral replicationin vitro. Application of metalloproteinase and gamma-secretase inhibitors to human conjunctival explants sharply decreased adenoviral vector gene expression. Our results demonstrate that pharmacologic delivery of these inhibitors is easily achievable. The inhibition of these enzymes should be explored as potential therapies of wild type adenoviral infections.Keywords
Funding Information
- National Institutes of Health (GM 085793)
- Retina Research Foundation (Mary Ellen Wilson Research Project)
- Golfers Against Cancer (Award)
This publication has 34 references indexed in Scilit:
- Identification of Function for CD44 Intracytoplasmic Domain (CD44-ICD)Journal of Biological Chemistry, 2012
- Absence of Systemic Immune Response to Adenovectors After Intraocular Administration to Children With RetinoblastomaMolecular Therapy, 2010
- Hyaluronan-CD44 Interaction with Protein Kinase Cϵ Promotes Oncogenic Signaling by the Stem Cell Marker Nanog and the Production of MicroRNA-21, Leading to Down-regulation of the Tumor Suppressor Protein PDCD4, Anti-apoptosis, and Chemotherapy Resistance in Breast Tumor CellsPublished by Elsevier BV ,2009
- Treatment of Adenovirus Pneumonia With Cidofovir in Pediatric Lung Transplant RecipientsThe Journal of Heart and Lung Transplantation, 2007
- Modulation of Adenoviral Transduction In Vitro and In Vivo by Hyaluronan and its Receptor CD44Molecular Therapy, 2007
- Treatment of Adenovirus Disease in Stem Cell Transplant Recipients with CidofovirTransplantation and Cellular Therapy, 2007
- Response of Retinoblastoma With Vitreous Tumor Seeding to Adenovirus-Mediated Delivery of Thymidine Kinase Followed by GanciclovirJournal of Clinical Oncology, 2005
- Hyaluronan-mediated CD44 Interaction with RhoGEF and Rho Kinase Promotes Grb2-associated Binder-1 Phosphorylation and Phosphatidylinositol 3-Kinase Signaling Leading to Cytokine (Macrophage-Colony Stimulating Factor) Production and Breast Tumor ProgressionPublished by Elsevier BV ,2003
- Cidofovir for adenovirus infections after allogeneic hematopoietic stem cell transplantation: a survey by the Infectious Diseases Working Party of the European Group for Blood and Marrow TransplantationBone Marrow Transplantation, 2003
- CD44 Interaction with c-Src Kinase Promotes Cortactin-mediated Cytoskeleton Function and Hyaluronic Acid-dependent Ovarian Tumor Cell MigrationJournal of Biological Chemistry, 2001