Airborne Transmission of Highly Pathogenic H7N1 Influenza Virus in Ferrets

Abstract

Avian H7 influenza viruses are recognized as potential pandemic viruses, as personnel often become infected during poultry outbreaks. H7 infections in humans typically cause mild conjunctivitis; however, the H7N9 outbreak in the spring of 2013 has resulted in severe respiratory disease. To date, no H7 viruses have acquired the ability for sustained transmission among humans. Airborne transmission is considered a requirement for the emergence of pandemic influenza, and advanced knowledge of the molecular changes or signature required for transmission would allow early identification of pandemic vaccine seed stocks, screening and stockpiling of antiviral compounds, and eradication efforts focused on flocks harboring threatening viruses. Thus, we sought to determine if a highly pathogenic influenza A H7N1 (A/H7N1) virus with no history of human infection could become capable of airborne transmission among ferrets. We show that after 10 serial passages, A/H7N1 developed the ability to be transmitted to cohoused and airborne contact ferrets. Four amino acid mutations (PB2 T81I, NP V284M, and M1 R95K and Q211K) in the internal genes and a minimal amino acid mutation (K/R313R) in the stalk region of the hemagglutinin protein were associated with airborne transmission. Furthermore, transmission was not associated with loss of virulence. These findings highlight the importance of the internal genes in host adaptation and suggest that natural isolates carrying these mutations be further evaluated. Our results demonstrate that a highly pathogenic avian H7 virus can become capable of airborne transmission in a mammalian host, and they support ongoing surveillance and pandemic H7 vaccine development. IMPORTANCEThe major findings of this report are that a highly pathogenic strain of H7N1 avian influenza virus can be adapted to become capable of airborne transmission in mammals without mutations altering receptor specificity. Changes in receptor specificity have been shown to play a role in the ability of avian influenza viruses to cross the species barrier, and these changes are assumed to be essential. The work reported here challenges this paradigm, at least for the influenza viruses of the H7 subtype, which have recently become the focus of major attention, as they have crossed to humans.

Replication and transmission of mammalian-adapted H9 subtype influenza virus in pigs and quail

“…In this regard, it is important to note that the ferret is widely used as an animal model to study airborne transmission of influenza viruses; adaptive changes that lead to such a phenotype have been identified in the H9, H7 and H5 subtypes (Herfst et al, 2012;Imai et al, 2013;Kimble et al, 2011;Ku et al, 2014;Li et al, 2014;Sorrell et al, 2009;Sutton et al, 2014;Wan et al, 2008). However, further studies are lacking to demonstrate whether the ferret-adaptive mutations increase or restrict the host range of the virus.…”

A Unique Multibasic Proteolytic Cleavage Site and Three Mutations in the HA2 Domain Confer High Virulence of H7N1 Avian Influenza Virus in Chickens

“…The effects of the immune response on virus replication and virulence were not investigated in this study. A mutation in the stalk region (among other mutations in the internal gene segments) was also obtained after serial passages of a similar Italian HPAIV H7N1 in ferrets, which rendered the virus transmissible by air (36). Mutations in the stem region, very close to T436, destabilized the structure of HA2 (37), suggesting that stabilization probably requires R536 and L450.…”

Complexities in Ferret Influenza Virus Pathogenesis and Transmission Models

“…However, several studies have modulated this parameter, creating contact pairs for short periods of time during the acute phase of infection to better understand the temporal dynamics of virus transmission in the ferret model (49,70) or establishing contact at different times throughout the acute phase of infection to determine links between virus shedding in inoculated ferrets and virus transmissibility (71). Donor chains, where virus is serially transmitted or passaged from ferret to ferret, have also been employed to model the selective pressure that may occur by sustained transmission of viruses through a population (72)(73)(74).…”