Determining Ribavirin’s mechanism of action against Lassa virus infection
Open Access
- 15 September 2017
- journal article
- research article
- Published by Springer Science and Business Media LLC in Scientific Reports
- Vol. 7 (1), 11693
- https://doi.org/10.1038/s41598-017-10198-0
Abstract
Ribavirin is a broad spectrum antiviral which inhibits Lassa virus (LASV) replication in vitro but exhibits a minor effect on viremia in vivo. However, ribavirin significantly improves the disease outcome when administered in combination with sub-optimal doses of favipiravir, a strong antiviral drug. The mechanisms explaining these conflicting findings have not been determined, so far. Here, we used an interdisciplinary approach combining mathematical models and experimental data in LASV-infected mice that were treated with ribavirin alone or in combination with the drug favipiravir to explore different putative mechanisms of action for ribavirin. We test four different hypotheses that have been previously suggested for ribavirin’s mode of action: (i) acting as a mutagen, thereby limiting the infectivity of new virions; (ii) reducing viremia by impairing viral production; (iii) modulating cell damage, i.e., by reducing inflammation, and (iv) enhancing antiviral immunity. Our analysis indicates that enhancement of antiviral immunity, as well as effects on viral production or transmission are unlikely to be ribavirin’s main mechanism mediating its antiviral effectiveness against LASV infection. Instead, the modeled viral kinetics suggest that the main mode of action of ribavirin is to protect infected cells from dying, possibly reducing the inflammatory response.Keywords
This publication has 50 references indexed in Scilit:
- Immune Responses and Lassa Virus InfectionViruses, 2012
- Pathogenesis of lassa fever in cynomolgus macaquesVirology Journal, 2011
- Ribavirin potentiates interferon action by augmenting interferon-stimulated gene induction in hepatitis C virus cell culture modelsHepatology, 2010
- Ribavirin Improves Early Responses to Peginterferon Through Improved Interferon SignalingGastroenterology, 2010
- T Cell-Dependence of Lassa Fever PathogenesisPLoS Pathogens, 2010
- Cellular organization of normal mouse liver: a histological, quantitative immunocytochemical, and fine structural analysisHistochemistry and Cell Biology, 2009
- Mechanism of Action of T-705 against Influenza VirusAntimicrobial Agents and Chemotherapy, 2005
- Prospects for Treatment of Viral Hemorrhagic Fevers with Ribavirin, a Broad-Spectrum Antiviral DrugClinical Infectious Diseases, 1989
- Lassa FeverNew England Journal of Medicine, 1986
- The broad spectrum antiviral agent ribavirin inhibits capping of mRNABiochemical and Biophysical Research Communications, 1979