Mammalian models for the study of H7 virus pathogenesis and transmission

Abstract

Mammalian models, most notably the mouse and ferret, have been instrumental in the assessment of avian influenza virus pathogenicity and transmissibility, and have been used widely to characterize the molecular determinants that confer H5N1 virulence in mammals. However, while H7 influenza viruses have typically been associated with conjunctivitis and/or mild respiratory disease in humans, severe disease and death is also possible, as underscored by the recent emergence of H7N9 viruses in China. Despite the public health need to understand the pandemic potential of this virus subtype, H7 virus pathogenesis and transmission has not been as extensively studied. In this review, we discuss the heterogeneity of H7 subtype viruses isolated from humans, and the characterization of mammalian models to study the virulence of H7 subtype viruses associated with human infection, including viruses of both high and low pathogenicity and following multiple inoculation routes. The use of the ferret transmission model to assess the influence of receptor binding preference among contemporary H7 influenza viruses is described. These models have enabled the study of preventative and therapeutic agents, including vaccines and antivirals, to reduce disease burden, and have permitted a greater appreciation that not all highly pathogenic influenza viruses are created equal.

Fig. 1

Diversity of emerging influenza viruses associated with human infection. Confirmed or presumed (serologic evidence only) cases of avian influenza virus infection in humans since 1996. *, includes cases with serologic evidence only. Red border surrounding H5N1 human cases from 2003 to present indicates that there is substantial clade-specific and geographic diversity among this virus subtype not represented in this image (Abdel-Ghafar et al. 2008)

Fig. 2

Contribution of receptor binding preference on virus transmissibility in the ferret model. Virus receptor binding is depicted as maintaining a strong avian binding preference (three α2-3 icons), maintaining an avian binding preference with detectable binding to human receptors (two α2-3 icons, one α2-6 icon), enhanced binding to human receptors while maintaining binding to avian receptors (two α2-6 icons, one α2-3 icon) or strong human binding preference (three α2-6 icons) and is not meant to be quantitative. “DC transmission” indicates one inoculated ferret and one naïve ferret co-housed in the same cage, sharing food, water, and bedding; “RD transmission” indicates one inoculated ferret and one naïve ferret housed in adjacent cages separated by a perforated side-wall (3–5 mm in diameter) allowing air exchange only in the absence of direct or indirect contact