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

A novel lung explant model for the ex vivo study of efficacy and mechanisms of anti-influenza drugs
A novel lung explant model for the ex vivo study of efficacy and mechanisms of anti-influenza drugs
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.
0022-1767
1-12
Nicholas, Ben
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Staples, Karl J.
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Moese, Stefan
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Meldrum, Eric
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Ward, Jon
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Dennison, Patrick
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Havelock, Tom
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Hinks, Timothy S.C.
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Amer, Khalid
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Woo, Edwin
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Chamberlain, Martin
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Singh, Neeta
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North, Malcolm
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Pink, Sandy
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Wilkinson, Tom M.A.
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Djukanović, Ratko
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Nicholas, Ben
785c44fb-6536-4189-803b-4545425e9385
Staples, Karl J.
e0e9d80f-0aed-435f-bd75-0c8818491fee
Moese, Stefan
b23fd94d-322c-43e1-9a13-0d5413bd294b
Meldrum, Eric
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Ward, Jon
d1ec2453-e1f2-47f9-9679-066f798f6cad
Dennison, Patrick
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Havelock, Tom
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Hinks, Timothy S.C.
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Amer, Khalid
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Woo, Edwin
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Chamberlain, Martin
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Singh, Neeta
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North, Malcolm
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Pink, Sandy
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Wilkinson, Tom M.A.
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Djukanović, Ratko
d9a45ee7-6a80-4d84-a0ed-10962660a98d

Nicholas, Ben, Staples, Karl J., Moese, Stefan, Meldrum, Eric, Ward, Jon, Dennison, Patrick, Havelock, Tom, Hinks, Timothy S.C., Amer, Khalid, Woo, Edwin, Chamberlain, Martin, Singh, Neeta, North, Malcolm, Pink, Sandy, Wilkinson, Tom M.A. and Djukanović, Ratko (2015) A novel lung explant model for the ex vivo study of efficacy and mechanisms of anti-influenza drugs. Journal of Immunology, 1-12. (doi:10.4049/jimmunol.1402283). (PMID:25934861)

Record type: Article

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.

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Published date: 1 May 2015
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 376965
URI: https://eprints.soton.ac.uk/id/eprint/376965
ISSN: 0022-1767
PURE UUID: 80374d2f-e7eb-4319-8ed0-6db8984936b1
ORCID for Karl J. Staples: ORCID iD orcid.org/0000-0003-3844-6457
ORCID for Ratko Djukanović: ORCID iD orcid.org/0000-0001-6039-5612

Catalogue record

Date deposited: 11 May 2015 14:12
Last modified: 06 Jun 2018 13:16

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Contributors

Author: Ben Nicholas
Author: Karl J. Staples ORCID iD
Author: Stefan Moese
Author: Eric Meldrum
Author: Jon Ward
Author: Patrick Dennison
Author: Tom Havelock
Author: Timothy S.C. Hinks
Author: Khalid Amer
Author: Edwin Woo
Author: Martin Chamberlain
Author: Neeta Singh
Author: Malcolm North
Author: Sandy Pink

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