A novel lung explant model for the ex vivo study of efficacy and mechanisms of anti-influenza drugs.

Abstract

Influenza A virus causes considerable morbidity and mortality largely because of a lack of effective antiviral drugs. Viral neuraminidase inhibitors, which inhibit viral release from the infected cell, are currently the only approved drugs for influenza, but have recently been shown to be less effective than previously thought. Growing resistance to therapies that target viral proteins has led to increased urgency in the search for novel anti-influenza compounds. However, discovery and development of new drugs have been restricted because of differences in susceptibility to influenza between animal models and humans and a lack of translation between cell culture and in vivo measures of efficacy. To circumvent these limitations, we developed an experimental approach based on ex vivo infection of human bronchial tissue explants and optimized a method of flow cytometric analysis to directly quantify infection rates in bronchial epithelial tissues. This allowed testing of the effectiveness of TVB024, a vATPase inhibitor that inhibits viral replication rather than virus release, and to compare efficacy with the current frontline neuraminidase inhibitor, oseltamivir. The study showed that the vATPase inhibitor completely abrogated epithelial cell infection, virus shedding, and the associated induction of proinflammatory mediators, whereas oseltamivir was only partially effective at reducing these mediators and ineffective against innate responses. We propose, therefore, that this explant model could be used to predict the efficacy of novel anti-influenza compounds targeting diverse stages of the viral replication cycle, thereby complementing animal models and facilitating progression of new drugs into clinical trials.

• Authors: Ben Nicholas, Karl J Staples, Stefan Moese, Eric Meldrum, Jon Ward, Patrick Dennison, Tom Havelock, Timothy S C Hinks, Khalid Amer, Edwin Woo, Martin Chamberlain, Neeta Singh, Malcolm North, Sandy Pink, Tom M A Wilkinson, Ratko Djukanović
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 194 Issue 12 Pg. 6144-54 (Jun 15 2015) ISSN: 1550-6606 [Electronic] United States
• PMID: 25934861 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 The Authors.

Chemical References

• Antiviral Agents

Topics

• Antiviral Agents (administration & dosage, pharmacology)
• Drug Evaluation, Preclinical (methods)
• Flow Cytometry
• Humans
• Immunophenotyping
• Influenza A virus (drug effects, physiology)
• Influenza, Human (drug therapy, virology)
• Lung (drug effects, virology)
• Organ Culture Techniques
• Phenotype