Developing Broad-Spectrum Antivirals Using Porcine and Rhesus Macaque Models
Open Access
- 22 October 2019
- journal article
- research article
- Published by Oxford University Press (OUP) in The Journal of Infectious Diseases
- Vol. 221 (6), 890-894
- https://doi.org/10.1093/infdis/jiz549
Abstract
ISG15-deficient humans exhibit permanent, low-level expression of antiviral effectors that safely protect them from various viruses. Because the murine ISG15 axis functions differently, we identified animal models that recapitulate the human condition for the development of ISG15-targeting broad-spectrum antivirals. Canine, porcine, and rhesus macaque ISG15, such as human ISG15, stabilize USP18, a potent inhibitor of type I interferon (IFN)-I. Type I Interferon-primed ISG15-knockout porcine and rhesus cells demonstrate enhanced ISG expression and protection against vesicular stomatitis Indiana virus infection compared with wild type. Collectively, we unveil the interspecies diversity of the ability of ISG15/USP18 axis to control IFN-I signaling and reveal the therapeutic potential of ISG15-deficient porcine and rhesus models.Keywords
Funding Information
- National Institute of Allergy and Infectious Diseases (R01AI127372, R21AI134366, R21AI129827)
- March of Dimes
- Ruth L. Kirschstein Predoctoral Individual National Research Service Award (FAI138363A)
This publication has 13 references indexed in Scilit:
- Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndromeThe Journal of Experimental Medicine, 2016
- ISG15 deficiency and increased viral resistance in humans but not miceNature Communications, 2016
- Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammationNature, 2014
- Mycobacterial Disease and Impaired IFN-γ Immunity in Humans with Inherited ISG15 DeficiencyScience, 2012
- USP18 establishes the transcriptional and anti-proliferative interferon α/β differentialBiochemical Journal, 2012
- USP18-Based Negative Feedback Control Is Induced by Type I and Type III Interferons and Specifically Inactivates Interferon α ResponsePLOS ONE, 2011
- Interferon-Stimulated Gene 15 and the Protein ISGylation SystemJournal of Interferon & Cytokine Research, 2011
- Complex Modulation of Cell Type-Specific Signaling in Response to Type I InterferonsImmunity, 2006
- Type I Interferons in Host DefenseImmunity, 2006
- UBP43 is a novel regulator of interferon signaling independent of its ISG15 isopeptidase activityThe EMBO Journal, 2006