Low dose influenza virus challenge in the ferret leads to increased virus shedding and greater sensitivity to oseltamivir.
Ferrets are widely used to study human influenza virus infection. Their airway physiology and cell receptor distribution makes them ideal for the analysis of pathogenesis and virus transmission, and for testing the efficacy of anti-influenza interventions and vaccines. The 2009 pandemic influenza virus (H1N1pdm09) induces mild to moderate respiratory disease in infected ferrets, following inoculation with 106 plaque-forming units (pfu) of virus. We have demonstrated that reducing the challenge dose to 102 pfu delays the onset of clinical signs by 1 day, and results in a modest reduction in clinical signs, and a less rapid nasal cavity innate immune response. There was also a delay in virus production in the upper respiratory tract, this was up to 9-fold greater and virus shedding was prolonged. Progression of infection to the lower respiratory tract was not noticeably delayed by the reduction in virus challenge. A dose of 104 pfu gave an infection that was intermediate between those of the 106 pfu and 102 pfu doses. To address the hypothesis that using a more authentic low challenge dose would facilitate a more sensitive model for antiviral efficacy, we used the well-known neuraminidase inhibitor, oseltamivir. Oseltamivir-treated and untreated ferrets were challenged with high (106 pfu) and low (102 pfu) doses of influenza H1N1pdm09 virus. The low dose treated ferrets showed significant delays in innate immune response and virus shedding, delayed onset of pathological changes in the nasal cavity, and reduced pathological changes and viral RNA load in the lung, relative to untreated ferrets. Importantly, these observations were not seen in treated animals when the high dose challenge was used. In summary, low dose challenge gives a disease that more closely parallels the disease parameters of human influenza infection, and provides an improved pre-clinical model for the assessment of influenza therapeutics, and potentially, influenza vaccines.
Public Health England, Salisbury, United Kingdom.
Anthony C
AC
Marriott
Public Health England, Salisbury, United Kingdom.
Brian K
BK
Dove
Public Health England, Salisbury, United Kingdom.
Catherine J
CJ
Whittaker
Public Health England, Salisbury, United Kingdom.
Christine
C
Bruce
Public Health England, Salisbury, United Kingdom.
Kathryn A
KA
Ryan
Public Health England, Salisbury, United Kingdom.
Thomas J
TJ
Bean
Public Health England, Salisbury, United Kingdom.
Emma
E
Rayner
Public Health England, Salisbury, United Kingdom.
Geoff
G
Pearson
Public Health England, Salisbury, United Kingdom.
Irene
I
Taylor
Public Health England, Salisbury, United Kingdom.
Stuart
S
Dowall
Public Health England, Salisbury, United Kingdom.
Jenna
J
Plank
Public Health England, Salisbury, United Kingdom.
Edmund
E
Newman
Division of Infectious Disease, Imperial College London, London, United Kingdom.
Wendy S
WS
Barclay
School of Life Sciences, University of Warwick, Coventry, United Kingdom.
Nigel J
NJ
Dimmock
School of Life Sciences, University of Warwick, Coventry, United Kingdom.
Andrew J
AJ
Easton
Public Health England, Salisbury, United Kingdom.
Bassam
B
Hallis
Public Health England, Salisbury, United Kingdom.
Nigel J
NJ
Silman
Public Health England, Salisbury, United Kingdom.
Miles W
MW
Carroll
D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005289:Ferrets; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D009976:Orthomyxoviridae Infections / Q000188:drug therapy*; D053139:Oseltamivir / Q000627:therapeutic use*; D016896:Treatment Outcome; D017201:Virus Shedding
D000998:Antiviral Agents; D053139:Oseltamivir