H5N1 pathogenesis studies in mammalian models

Abstract

H5N1 influenza viruses are capable of causing severe disease and death in humans, and represent a potential pandemic subtype should they acquire a transmissible phenotype. Due to the expanding host and geographic range of this virus subtype, there is an urgent need to better understand the contribution of both virus and host responses following H5N1 virus infection to prevent and control human disease. The use of mammalian models, notably the mouse and ferret, has enabled the detailed study of both complex virus-host interactions as well as the contribution of individual viral proteins and point mutations which influence virulence. In this review, we describe the behavior of H5N1 viruses which exhibit high and low virulence in numerous mammalian species, and highlight the contribution of inoculation route to virus pathogenicity. The involvement of host responses as studied in both inbred and outbred mammalian models is discussed. The roles of individual viral gene products and molecular determinants which modulate the severity of H5N1 disease in vivo are presented. This research contributes not only to our understanding of influenza virus pathogenesis, but also identifies novel preventative and therapeutic targets to mitigate the disease burden caused by avian influenza viruses.

Keywords: Avian influenza; Ferret; H5N1; Influenza; Mammalian; Mice; Pathogenesis.

Fig. 1

The use of different inoculation routes to investigate H5N1 virus pathogenesis. H5N1 viruses are capable of causing systemic and lethal disease following multiple inoculation routes in mammalian models. Mouse studies represented in this illustration: Belser et al. (2009b), Bright et al. (2003), Lipatov et al. (2009), Lu et al. (1999) and Sun et al. (2009). Ferret studies represented in this illustration: Belser et al. (2012), Bodewes et al. (2011), Gustin et al. (2011a), Lednicky et al. (2010), Lipatov et al. (2009), Maines et al. (2005) and Shinya et al. (2011b).

Fig. 2

H5N1 pathogenesis in mammals. Virus and host features associated with H5N1 viruses which exhibit low or high virulence in the ferret model. Inset of lung histopathology is from Maines et al. (2005). Low titer generally represents ≤10³ EID₅₀/g or ml, high titer generally represents ≥10⁵ EID₅₀/g or ml (Maines et al., 2005).

Fig. 3

Selected molecular determinants of H5N1 pathogenesis in vivo. Shown are selected viral and host components associated with changes in virulence in mammalian species.

Fig. 3

Selected molecular determinants of H5N1 pathogenesis in vivo. Shown are selected viral and host components associated with changes in virulence in mammalian species.