Spatial Dynamics of Human-Origin H1 Influenza A Virus in North American Swine

et al. (2011) Spatial Dynamics of Human-Origin H1 Influenza A Virus in North American Swine. PLoS Pathog 7(6): e1002077. doi:10.1371/journal.ppat.1002077 Spatial Dynamics of Human-Origin H1 Influenza A Virus in North American Swine Martha I. Nelson Philippe Lemey Yi Tan Amy Vincent Tommy Tsan-Yuk Lam Susan Detmer Ce cile Viboud Marc A. Suchard Andrew Rambaut Edward C. Holmes Marie Gramer Claus O. Wilke, University of Texas at Austin, United States of America The emergence and rapid global spread of the swine-origin H1N1/09 pandemic influenza A virus in humans underscores the importance of swine populations as reservoirs for genetically diverse influenza viruses with the potential to infect humans. However, despite their significance for animal and human health, relatively little is known about the phylogeography of swine influenza viruses in the United States. This study utilizes an expansive data set of hemagglutinin (HA1) sequences (n = 1516) from swine influenza viruses collected in North America during the period 2003-2010. With these data we investigate the spatial dissemination of a novel influenza virus of the H1 subtype that was introduced into the North American swine population via two separate human-to-swine transmission events around 2003. Bayesian phylogeographic analysis reveals that the spatial dissemination of this influenza virus in the US swine population follows long-distance swine movements from the Southern US to the Midwest, a corn-rich commercial center that imports millions of swine annually. Hence, multiple genetically diverse influenza viruses are introduced and co-circulate in the Midwest, providing the opportunity for genomic reassortment. Overall, the Midwest serves primarily as an ecological sink for swine influenza in the US, with sources of virus genetic diversity instead located in the Southeast (mainly North Carolina) and South-central (mainly Oklahoma) regions. Understanding the importance of long-distance pig transportation in the evolution and spatial dissemination of the influenza virus in swine may inform future strategies for the surveillance and control of influenza, and perhaps other swine pathogens. - Funding: The research leading to these results has received funding in part from the European Research Council under the European Communitys Seventh Framework Programme (FP7/2007-2013)/ERC Grant agreement no. 260864; NIH grant R01 GM080533; NSF grant DMS 0856099; NIH grant R01 GM086887; and the National Evolutionary Synthesis Center (NESCent), NSF EF-0423641. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Swine influenza A viruses cause severe respiratory disease in pigs, similar to that which presents in humans, and constitute an important economic concern for the US swine industry and threat to public health. Influenza was first clinically recognized in pigs in the Midwestern US in conjunction with the severe 1918 Spanish flu H1N1 pandemic in humans [1], although whether the pandemic originated in humans or pigs remains unresolved [2]. Periodic transmission of influenza viruses between humans and swine occurs in both directions, including such notable cases as the 1976 outbreak of swine A/H1N1 influenza virus in humans in Fort Dix, New Jersey [3] and the 2009 swine-origin A/H1N1 pandemic virus in humans [4,5]. The 1918-origin classical H1N1 swine influenza virus circulated in US swine for 80 years with relatively few antigenic changes [6], but in the last decade the antigenic diversity of swine influenza viruses in the US has multiplied, stimulating research, development, and uptake of influenza vaccines in the US swine industry. Currently, influenza A viruses of the H1N1, H1N2, and H3N2 subtypes all co-circulate in US swine. In 19981999, a triple reassortant H3N2 influenza virus emerged in US swine that possessed HA (H3), NA (N2), and PB1 segments of human H3N2 virus origin, PB2 and PA segments of avian virus origin, and NP, M1/2, and NS1/2 segments of classical swine virus origin [7] (Fig. 1). Over the next decade these H3N2 triple reassortant swine viruses further reassorted with human H3N2 viruses [8,9], as well as with the cocirculating H1N1 classical swine viruses [10,11]. Mainly these reassortment events involved the HA and NA segments, preserving what has been termed the triple reassortant internal genes (TRIG) constellation (avian-origin PB2 and PA, human H3N2-origin PB1, and classical swine-origin NP, M1/2, and NS1/2). In 2003 influenza A virus of entirely human H1N2 origin was identified in Canadian swine [12], and in 2005 H1N1 viruses with human-origin H1 and N1 segments were identified in the United States, representing two separate introductions of human H1 virus into swine that were referred to as d-1 (H1N2) and d -2 (H1N1) Since 1998, genetically and antigenically diverse influenza A viruses have circulated in North American swine due to continuous cross-species transmission and reassortment with avian and human influenza viruses, presenting a pandemic threat to humans. Millions of swine are transported year-round from the southern United States into the corn-rich Midwest, but the importance of these movements in the spatial dissemination and evolution of the influenza virus in swine is unknown. Using a large data set of influenza virus sequences collected in North American swine during 20032010, we investigated the spatial dynamics of two influenza viruses of the H1 subtype that were introduced into swine from humans around 2003. Employing recently developed Bayesian phylogeography methods, we find that the spread of this influenza virus follows the large-scale transport of swine from the South to the Midwest. Based on this pattern of viral migration, we suggest that the genetic diversity of swine influenza viruses in the Midwest is continually augmented by the importation of viruses from source populations located in the South. Understanding the importance of long-distance pig movements in the evolution and spatial dissemination of influenza virus in swine may inform future strategies for the surveillance and control of influenza, and perhaps other swine pathogens. lineages based on the order of identification [13]. These human-H1 origin swine viruses also acquired novel genome segments via reassortment with other swine and human influenza viruses [12,13]. Globally, the swine influenza virus population is spatially separated into the North American and Eurasian lineages, although both lineages co-circulate in Asia, which imports swine from North America and Europe. In the US the traditional center of swine production is located in the Corn Belt of the Midwest, including Iowa, Illinois, Indiana, and Minnesota [14]. Beginning in the 1970s, swine production expanded into large new facilities located in the Southeastern US, mainly North Carolin (...truncated)