Abstract
Seasonal influenza virus infections cause yearly epidemics which are the source of a significant public health burden worldwide. The ferret model for human influenza A virus (IAV) is widely used and has several advantages over other animal models such as comparable symptomology, similar receptor distribution in the respiratory tract to humans and the ability to be infected with human isolates without the need for adaptation. However, a major disadvantage of the model has been a paucity of reagents for the evaluation of the cellular immune response. Investigation of T-cell mediated immunity in ferrets is crucial to vaccine development and efficacy studies. In this study we have used commercially produced antibodies to ferret interferon gamma (IFN-γ) allowing us to reliably measure influenza-specific IFN-γ as a marker of the cellular immune response using both enzyme-linked immunospot (ELISpot) and enzyme-linked immunosorbent (ELISA) techniques. Here we demonstrate the application of these tools to evaluate cellular immunity in ferrets infected with clinically relevant seasonal H1N1 and H3N2 IAV subtypes at equivalent doses. Using small heparinised blood samples we were able to observe the longitudinal influenza-specific IFN-γ responses of ferrets infected with both seasonal subtypes of IAV and found a notable increase in influenza-specific IFN-γ responses in circulating peripheral blood within 8 days post-infection. Both seasonal strains caused a well-defined pattern of influenza-specific IFN-γ responses in infected ferrets when compared to naïve animals. Additionally, we found that while the influenza specific IFN-γ responses found in peripheral circulating blood were comparable between subtypes, the influenza specific IFN-γ responses found in lung lymphocytes significantly differed. Our results suggest that there is a distinct difference between the ability of the two seasonal influenza strains to establish an infection in the lung of ferrets associated with distinct signatures of acquired immunity.
Highlights
Influenza is a significant global health problem with 5–15% of the population infected each year, leading to approximately 200,000 to 500,000 influenza attributed deaths [1, 2]
Influenza A virus infection can result in a spectrum of disease outcomes in humans, ranging from sub-clinical with seasonal strains to lethal with subtypes such as H5N1 and H7N9
The ability of seasonal influenza A viruses to continuously evolve antigenically means individuals can become infected on numerous occasions throughout their lives despite having immunity to previous strains
Summary
Influenza is a significant global health problem with 5–15% of the population infected each year, leading to approximately 200,000 to 500,000 influenza attributed deaths [1, 2]. Cellular immune response to human influenza in the ferret lung has an RNA genome and this allows the virus to mutate rapidly leading to antigenic drift and shift. Antigenic drift occurs via the gradual change of viral surface epitopes, leading to yearly epidemics, whilst antigenic shift is caused by the reassortment of genomes between two or more strains of influenza, which can lead to new and potentially pandemic strains. The H1N1 virus originated from the 2009 influenza pandemic caused by a reassortment of human, swine and bird type A influenza[3], while the current seasonal H3N2 strain originated from the 1968 Hong Kong pandemic when genomic exchange of RNA occurred between human and avian viruses[4]. Vaccination is the most efficient method to protect the population from influenza; understanding seasonal influenza strains is important since they dictate annual vaccine strategies
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