Comparative Pathogenesis of Influenza in Ferrets

Abstract

Influenza is an enveloped, segmented, single-stranded, negative sense RNA virus that causes annual seasonal epidemics and occasional pandemics. Influenza causes roughly 200,000 to 500,000 deaths per year globally and affects up to 15% of the world’s population annually. Influenza is a major public health concern. Influenza presents a spectrum of clinical signs including: fever, sneezing, lethargy and can range from a mild to a severe disease. It also leads to death in high-risk individuals such as pregnant women, the elderly and very young, the immunocompromised and those with underlying medical conditions. Seasonal influenza viruses continuously evolve antigenically meaning individuals can become infected on numerous occasions throughout their lives. Due to the rapid evolution of these viruses, the influenza vaccine composition needs to be updated regularly to protect against current circulating strains. The ferret is the gold standard model for influenza infections in the laboratory. The model produces similar clinical readouts to humans; sneezing, nasal discharge, fever and malaise. Human isolates can be used to infect ferrets with no prior need for adaptation. This PhD investigates the pathogenesis of H3N2 A/Perth/16/2009 and its ability to cause disease in the ferret using three different models of infection; intranasal, nose-only aerosol and non-contact transmission. Scrutiny of these models using a range of virological and immunological techniques showed while there are some small differences between routes of infection, using the same influenza virus strain results in similar disease in ferrets. Further analysis of the intranasal route of inoculation and comparison with H1N1 A/California/04/2009, showed distinctions in pathogenesis between viruses despite identical routes of infection, highlighting the differences in the viral kinetics and cellular immune response between H3N2 and H1N1 in the ferret model. This work enhances and improves the versatility of the ferret model for studying the pathogenesis of influenza.