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.
Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton General Hospital, Southampton SO16 6YD, United Kingdom; Southampton National Institute for Health Research Respiratory Biomedical Research Unit, Southampton General Hospital, Southampton SO16 6YD, United Kingdom; bln1@soton.ac.uk.
Ben
B
Nicholas
Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton General Hospital, Southampton SO16 6YD, United Kingdom; Southampton National Institute for Health Research Respiratory Biomedical Research Unit, Southampton General Hospital, Southampton SO16 6YD, United Kingdom;
Karl J
KJ
Staples
3-V Biosciences, Menlo Park, CA 94025;
Stefan
S
Moese
3-V Biosciences, Menlo Park, CA 94025;
Eric
E
Meldrum
Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton General Hospital, Southampton SO16 6YD, United Kingdom;
Jon
J
Ward
Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton General Hospital, Southampton SO16 6YD, United Kingdom; Southampton National Institute for Health Research Respiratory Biomedical Research Unit, Southampton General Hospital, Southampton SO16 6YD, United Kingdom;
Patrick
P
Dennison
Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton General Hospital, Southampton SO16 6YD, United Kingdom; Southampton National Institute for Health Research Respiratory Biomedical Research Unit, Southampton General Hospital, Southampton SO16 6YD, United Kingdom;
Tom
T
Havelock
Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton General Hospital, Southampton SO16 6YD, United Kingdom; Southampton National Institute for Health Research Respiratory Biomedical Research Unit, Southampton General Hospital, Southampton SO16 6YD, United Kingdom;
Timothy S C
TS
Hinks
Department of Cardiothoracic Surgery, Southampton General Hospital, Southampton SO16 6YD, United Kingdom; and.
Khalid
K
Amer
Department of Cardiothoracic Surgery, Southampton General Hospital, Southampton SO16 6YD, United Kingdom; and.
Edwin
E
Woo
Department of Cardiothoracic Surgery, Southampton General Hospital, Southampton SO16 6YD, United Kingdom; and.
Martin
M
Chamberlain
Department of Cellular Pathology, Southampton General Hospital, Southampton SO16 6YD, United Kingdom.
Neeta
N
Singh
Southampton National Institute for Health Research Respiratory Biomedical Research Unit, Southampton General Hospital, Southampton SO16 6YD, United Kingdom;
Malcolm
M
North
Southampton National Institute for Health Research Respiratory Biomedical Research Unit, Southampton General Hospital, Southampton SO16 6YD, United Kingdom;
Sandy
S
Pink
Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton General Hospital, Southampton SO16 6YD, United Kingdom; Southampton National Institute for Health Research Respiratory Biomedical Research Unit, Southampton General Hospital, Southampton SO16 6YD, United Kingdom;
Tom M A
TM
Wilkinson
Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton General Hospital, Southampton SO16 6YD, United Kingdom; Southampton National Institute for Health Research Respiratory Biomedical Research Unit, Southampton General Hospital, Southampton SO16 6YD, United Kingdom;
Ratko
R
Djukanović
D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005434:Flow Cytometry; D006801:Humans; D016130:Immunophenotyping; D009980:Influenza A virus / Q000187:drug effects* / Q000502:physiology; D007251:Influenza, Human / Q000188:drug therapy / Q000821:virology*; D008168:Lung / Q000187:drug effects* / Q000821:virology*; D009924:Organ Culture Techniques; D010641:Phenotype
D000998:Antiviral Agents