Impaired heterologous immunity in aged ferrets during sequential influenza A H1N1 infection

Stéphane G Paquette,Stephen S.H Huang,David Banner,Luoling Xu,Alberto Leόn,Alyson A Kelvin,David J Kelvin

doi:10.1016/j.virol.2014.07.013

Stéphane G Paquette, Stephen S.H Huang + Show 5 more

Open Access

https://doi.org/10.1016/j.virol.2014.07.013

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Abstract

The major burden of influenza morbidity resides within the elderly population. The challenge managing influenza-associated illness in the elderly is the decline of immune function, where mechanisms leading to immunological senescence have not been elucidated. To better represent the immune environment, we investigated clinical morbidity and immune function during sequential homologous and heterologous H1N1 influenza infection in an aged ferret model. Our findings demonstrated experimentally that aged ferrets had significant morbidity during monosubtypic heterologous 2° challenge with significant weight loss and respiratory symptoms. Furthermore, increased clinical morbidity was associated with slower and shorter hemagglutinin antibody generation and attenuated type 1 T-cell gene responses in peripheral blood. These results revealed dampened immune activation during sequential influenza infection in aged ferrets. With the presence of an aged model, dissecting clinical morbidity, viral dynamics and immune response during influenza infection will aid the development of future prophylactics such as age specific influenza vaccines.

Highlights

The elderly influenza disease rate in humans carries a heavy burden on healthcare systems and perpetuates virus circulation in the general population
Ferrets closely mimic the clinical manifestations of influenza infection in humans as shown previously (Banner and Kelvin, 2012; Belser et al, 2011; Huang et al, 2011; Huang et al, 2013; Rowe et al, 2010)
First we investigated humoral responses in our cohort by assaying sera taken from the ferrets at designated time points for haemagglutination inhibition (HI) against Bris/59 or Mex/4108 viruses

Summary

Introduction

The elderly influenza disease rate in humans carries a heavy burden on healthcare systems and perpetuates virus circulation in the general population. Post-thymic homeostatic T-cell proliferation compensates for production deficit (Aw and Palmer, 2011; Buchholz et al, 2011), but long-term T-cell replication leads to cell-intrinsic dysfunction highlighted by progressive loss of repertoire diversity and weakened responses (Buchholz et al, 2011) This directly influences cell-mediated T-cell responses, most evident during viral infection (Buchholz et al, 2011; Deng et al, 2004; Effros et al, 2003), while indirectly affecting humoral responses (Eaton et al, 2004). Together with high rates of antigenic change of circulating virus population, this process puts the elderly at greater risk of recurring influenza infection (Bridges et al, 2000)

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