Reverse zoonosis of influenza to swine: new perspectives on the human-animal interface

Abstract

The origins of the 2009 influenza A (H1N1) pandemic in swine are unknown, highlighting gaps in our understanding of influenza A virus (IAV) ecology and evolution. We review how recently strengthened influenza virus surveillance in pigs has revealed that influenza virus transmission from humans to swine is far more frequent than swine-to-human zoonosis, and is central in seeding swine globally with new viral diversity. The scale of global human-to-swine transmission represents the largest 'reverse zoonosis' of a pathogen documented to date. Overcoming the bias towards perceiving swine as sources of human viruses, rather than recipients, is key to understanding how the bidirectional nature of the human-animal interface produces influenza threats to both hosts.

Keywords: evolution; human–animal interface; influenza A virus; pandemic; swine.

Figure 1. IAV sequence data available for swine, birds, and humans

(a) Number of IAV sequences available at GenBank’s Influenza Virus Resource [120] for swine, birds, and humans for the full-length HA segment, full-length NA segment, whole genome, and main antigenic region of the HA (HA1), by region. The bars representing the number of viral sequences from Europe are shaded blue, Asia = light brown, North America = green, South America = red, Pacific region = black, and Africa = orange. (b) Number of swine influenza virus sequences available at GenBank for the full-length HA segment, full-length NA segment, whole genome, and partial HA gene, for the time periods 1931–2008 and 2009–2013.

Figure 2. Introductions of human seasonal influenza viruses into swine, 1965–2013

A summary of the 20 introductions of seasonal human IAVs into swine resulting in sustained transmission in swine (for at least one year) by segment and region. Introductions involving the HA and NA segments are depicted in the upper portion of the figure, and the subset involving internal gene segments are presented in the lower portion. Each colored line represents a human-to-swine transmission event of a segment (H1 = blue, H3 = green, N1 = red, N2 = orange, PB1 = light brown, and the full constellation of all six internal gene segments = dark brown). Each introduction is numbered 1–20. Human internal gene segments have persisted in swine for four introductions (introductions 1, 8, 9, and 18), as shown at the bottom of the figure. The timing of each human-to-swine transmission event is estimated from the times to the Most Recent Common Ancestor (tMRCAs) inferred from the maximum clade credibility (MCC) trees, with grey boxes indicating the 95% highest posterior density (HPD) interval between the swine clade and most closely related human viruses, and the black box indicating the 95% HPD interval for the swine clade only. Each line extends forward in time up to the most recently sampled swine virus of that lineage. Copyright © American Society for Microbiology, [Journal of Virology, 88, 2014, 10110–10119, doi: 10.1128/JVI.01080-14] [42] reprinted with permission.

Figure 3. Phylogenetic relationships between human and swine N2 segments

Time-scaled Bayesian MCC tree inferred for the NA (N2) sequences of 350 swine influenza viruses identified as of human seasonal virus origin and 325 human H3N2, H2N2, and H1N2 seasonal influenza viruses, collected 1957–2013. Branches of human seasonal H3N2 influenza virus origin are shaded black, while branches associated with viruses from swine are shaded by country of origin: Argentina (ARG) = red; Canada (CAN) = orange; China (CHN, including Hong Kong SAR and Taiwan) = yellow; Europe (EUR) = light green; South Korea (KOR) = teal; JPN = dark green; Mexico (MEX) = light blue; Thailand (THA) = dark blue; USA = purple; Vietnam (VNM) = pink. Posterior probabilities > 0.9 are included for key nodes, and the 13 discrete introductions of the human N2 segment into swine that are supported by high posterior probabilities and long branch lengths are identified with solid black circles. Copyright © American Society for Microbiology, [Journal of Virology, 88, 2014, 10110–10119, doi: 10.1128/JVI.01080-14] [42] reprinted with permission.

Figure 4. Countries where pH1N1 has been identified in swine

See also Table 1. Countries shaded in purple represent those where pH1N1 viruses of human origin have been detected in swine since 2009.

Figure 5. A model for the ecology of influenza A viruses

(a) Cross-species transmission between avian species (thought to be the main reservoir for IAV diversity) and humans (H1N1, H2N2, and H3N2), equines [H3N8 (2x) and H7N7], canines (H3N2), and swine (H1N1 and triple reassortant PB2/PA), as well as transmission between mammalian species: equine-to-canine (H3N8), swine-to-human (H1N1), and human-to-swine (H1N1, H1N2, and H3N2, at least 20 times). Width of arrows is proportional to the number of IAV transmission events between species that result in endemic circulation of a virus in a new host (transient spillovers not included). (b) Model for the role of swine as ‘mixing vessels’ for the evolution of pandemic viruses (width of arrows also are proportional to the frequency of transmission). (c) Model for the evolution of H3N2v viruses in swine. Large-scale transmission of pH1N1 viruses from humans to swine seeds pH1N1 in swine populations globally (I); reassortment between pH1N1 viruses and co-circulating triple reassortant H3N2 viruses in the United States, generating novel reassortant H3N2v variants with seven triple reassortant H3N2 virus segments and the MP segment of pH1N1 origin (II); and transmission of > 300 H3N2v viruses from swine to humans, resulting in one adult fatality, in the United States during 2011–2013 (III).