Economic losses due to swine influenza infections are substantial and affect the swine industry globally. Swine influenza ranks among the top three major health challenges in the swine industry. Swine influenza is an acute respiratory disease caused by influenza type A virus (IAV) of the family Orthomyxoviridae. IAV’s genome consists of eight RNA strands in the negative sense orientation encoding for at least 12-13 proteins (PB2, PB1, PB1-F2, PB1-N40, PA, PA-X, HA, NP, NA, M1, M2, NS1 and NS2/NEP). Swine influenza infections are often characterized by rapid onset of high fever, lethargy, loss of appetite, labored abdominal breathing, and coughing (Van Reeth, 2007; Van Reeth et al., 2002). The disease lasts for 2-6 days and although mortality is low and most animals recover, weight loss can be severe. Swine influenza can contribute to the occurrence of more chronic respiratory disease problems associated with other viruses and bacteria in a manner similar to that observed in humans. Swine influenza is a contributing factor in the presentation of Porcine Respiratory Disease Complex, a disease syndrome resulting from co-infection with two or more respiratory pathogens. Equally important is the occurrence of subclinical infections in which swine can become infected with one or more influenza subtypes without overt signs of disease. Swine influenza is occasionally associated with fever-induced abortion in sows. IAV infection in pigs involves epithelial cells of the nasal mucosa, tonsils, trachea and lungs. The epithelial cells of the bronchi, bronchioli, and alveoli can be severely compromised during swine influenza infection. An influx of neutrophils and other inflammatory cells can lead to epithelial cell necrosis and obstruction of the airways.
Brief Natural History of Swine Influenza Viruses Around the World
Based on the antigenic differences of the two major surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA), IAVs are classified numerically into subtypes. Sixteen HA and 9 NA subtypes have been described in wild aquatic birds of the world, commonly accepted as IAVs’ natural reservoirs. The natural evolution of IAVs is intimately associated to the inherent error prone characteristics of the viral polymerase and the segmented nature of their genome. IAVs are continuously evolving and diversifying through a combination of mechanisms in which point mutations and gene segment reassortment play a major role. Point mutations on the viral surface proteins, particularly the HA, result in strains with the capacity to escape immune responses, a process know as ‘antigenic drift’. When two or more strains infect the same cell, the opportunity for segment exchange leads to gene segment reassortment and the emergence of new strains. When this exchange involves replacing for a new HA subtype, the process is known as ‘antigenic shift’. Pigs are hosts to a limited but highly dynamic IAV population in which point mutations and reassortment continue to shape up the evolution of swine IAVs. Three major influenza subtype combinations circulate in swine worldwide; H1N1, H3N2, and H1N2 (Brown et al., 1998; Cappuccio et al., 2011; Choi et al., 2002; Ito et al., 1998; Jung and Chae, 2004; Jung et al., 2005; Jung and Song, 2007; Karasin et al., 2006; Karasin et al., 2002; Karasin et al., 2000a; Karasin et al., 2000b; Lam et al., 2008; Lekcharoensuk et al., 2006; Ma et al., 2006; Maldonado et al., 2006; Olsen et al., 2003; Olsen et al., 2006; Pereda et al., 2010; Pereda et al., 2011; Qi and Lu, 2006; Shin et al., 2006; Suarez et al., 2002; Tsai and Pan, 2003; Webby et al., 2000; Zhou et al., 2000); however, their origin, gene constellation, and antigenic make up vary greatly on different continents.
In North America, swine influenza was historically associated with classical swine influenza virus (cs-H1N1), a virus whose ancestor likely entered into the swine population at the same time of the 1918 H1N1 Spanish flu pandemic. The cs-H1N1 circulated virtually unscathed for almost 80 years until 1998 when swine H3N2 IAVs emerged. The new H3N2 viruses were triple reassortant IAVs (tr-H3N2) with HA, NA, and polymerase basic 1 (PB1) gene segments derived from a seasonal human influenza virus, polymerase basic 2 (PB2) and polymerase acidic (PA) gene segments derived from an avian IAV, and nucleoprotein (NP), matrix (M), and nonstructural (NS) gene segments from the classical-swine H1N1 (Olsen, 2002; Zhou et al., 1999). The emergence and perpetuation of swine IAVs carrying the triple reassortant gene (TRIG) cassette with genomic components from human, swine, and avian influenza strains has changed the ecology of swine influenza not only in North America but also around the world and highlights the important niche that swine occupy as a mixing vessel for IAV reassortment (Scholtissek et al., 1998; Webby et al., 2000). Further co-circulation of tr-H3N2 and cs-H1N1, as well as additional introductions of HA and/or NA genes from seasonal human IAVs has led to the emergence of novel H1N1, H1N2, and H3N1 genotypes (Rajao et al., 2015; Vincent et al., 2009). The epitome of these events is highlighted by the emergence of the 2009 H1N1 pandemic virus (pdm-H1N1), a TRIG swine IAV that underwent additional reassortment by incorporating the NA and M gene segments from an Eurasian swine IAV strain (Fisher, 2009; Peiris et al., 2009). The virus was first detected in humans and recent evidence has shown that viruses with a similar genetic composition to the pdm-H1N1 virus may have been circulating in pigs in central-west Mexico for more than a decade prior (Mena et al., 2016). Its emergence underline the complexities associated with emergence of viruses in a highly dynamic commercial animal production system. Whether the virus itself originated in a pig or a human, there is little doubt that the swine-human interface played a major role in this event. The spillover of the pdm-H1N1 virus back to pigs in many countries (Nelson et al., 2012b) and the realization that these viruses (or their gene segments) continue to reassort in pigs have renewed worldwide swine surveillance efforts. In the US, the USDA amped its surveillance system to better characterize the genetic diversity of swine IAVs (Anderson et al., 2013). There are currently seven different H1 HA genetic clades in the US classified as δ-1, δ-2, α, β, γ, γ2, and pandemic. The γ and δ-1 genetic cluster appear the most predominant in the US (Lorusso et al., 2011a; Nelson et al., 2012a; Nelson et al., 2012b; Nelson et al., 2011; Nelson et al., 2012c). The H3 viruses are divided into eight different HA genetic clades (IV, IV-A, IV-B, IV-C, IV-D, IV-E, IV-F, and human-like H3s), with clade IV-A representing the majority of circulating H3 in production herds. The different H1 and H3 genetic lineages currently circulating in the US are most commonly paired with the either the N2 NA gene segment from a 2002 human H3N2 seasonal influenza virus (Nelson et al., 2012c) or the N1 NA gene segment from the cs-H1N1 virus (Anderson et al., 2013). A small proportion of swine isolates contain N1 gene segments from human seasonal H1N1 (prior to 2009) or N2 segments from a 1998 human seasonal H3N2 virus (Anderson et al., 2013; Nelson et al., 2012c).
North American cs-H1N1 virus migrated to Europe in the late 1930’s. The virus’ presence, associated with pneumonia in piglets, was reported from Belgium, the former Czechoslovakia, Germany, and the UK. In 1976, a cs-H1N1 from North America was re-introduced in continental Europe but it was soon replaced in 1979 by an avian-origin H1N1. The so-called “avian-like” (av-H1N1) swine IAV continues to persist in Europe, whereas the cs-H1N1 virus disappeared from the European swine population. In addition, swine “human-like” H3N2 (hu-H3N2) IAVs descendants of the human strain A/Port Chalmers/1/1973 (H3N2) have become established in pigs in Europe. The currently circulating hu-H3N2 viruses are in fact reassortants that inherited the internal gene constellation from an av-H1N1 virus in the mid-1980s. The swine av-H1N1 and hu-H3N2 IAVs continue to evolve in pigs in Europe and frequently exchange gene segments between each other and with other human H1 and H3 subtype viruses. In 1994, a H1N2 virus emerged in the UK and spread across Western Europe. The new H1N2 virus (hu-H1N2) derived from a multiple reassortant event involving human seasonal H1N1 from the 1980’s, and swine hu-H3N2 and swine av-H1N1 viruses. The av-H1N1, hu-H3N2 and hu-H1N2 viruses, all of them with avian-like internal gene segments from the av-H1N1 virus continue to circulate in European pig populations with patterns of incidence that varies by country or region. The av-H1N1 and hu-H1N2 viruses, but not the hu-H3N2 virus have been found in the UK and France, whereas all three viruses have been detected in Belgium, Italy, and Spain. More recent surveillance studies indicate widespread circulation of swine IAVs across Europe and the presence of additional reassortant viruses. The emergence of the pdm-H1N1 virus with multiple independent introductions back into pigs has led to novel reassortants, particularly H1N1 and H1N2 viruses with various gene segment compositions. These novel reassortants appear constrained to small areas or countries and it remains to be seen whether any one of these viruses will become established or spread further in pigs.
Evolution of swine IAVs in Asia is quite complex. Cs-H1N1 viruses were isolated in China in 1974 but evidence of swine influenza-like disease was realized in the country as far back as 1918 during the Spanish flu pandemic. The cs-H1N1 viruses are enzootic in China. Soon after the human H3N2 pandemic (1968 Hong Kong flu), the virus was reported in pigs in several Asian countries where it persisted for few years. Descendants of human H3N2 viruses (A/Hong Kong/1/68-like; A/Port Chalmers/1/73-like; A/Sydney/05/97-like) have repeatedly transmitted to and remained in pigs long after the parental human strains had been replaced in the human population (Shortridge et al., 1977; Peiris et al., 2001). H1N2 viruses, classical swine H1 viruses that acquired an N2 of contemporary human virus origin have also circulated during this time. China is the largest pork producer in the world with a population of ~720 million pigs. China has been steadily transitioning from small hog farms to larger, more specialized, operations but it is not a significant pork exporter. Pork consumption in China relies significantly on both local production and on imports of large quantities of pork, pig byproducts, and live pigs from many different countries. Unidirectional flow of pigs into China allows swine IAVs of North American and European lineages to make many incursions into the country. European H3N2 and H1N1 viruses were first detected in China in 1999 and 2001, respectively, and North American TRIG viruses were first found in 2002. In general, phylogenetic analyses show the lack of single monophyletic groups for many of these viruses, indicative of multiple independent introductions. These viruses are constantly exchanging gene segments, which further increases their diversity. Surveillance data indicated the presence and circulation of local and imported swine IAV strains as well as multiple different reassortants. H3N2 reassortants with pdm-H1N1-like internal genes and tr-H3N2 surface segments were isolated in Southeast China and are considered potential progenitors of the 2009 pdm-H1N1 virus.
Only few other countries in Asia have had surveillance systems in place to properly monitor swine IAV activity. Swine IAVs in other Asian countries have their own complex natural history resulting also from multiple introduction events. Interestingly, China has not been the major source of viruses for other Asian countries. Swine IAVs have been consistently detected in South Korea, Japan, Thailand, and Vietnam.
In South Korea, swine IAVs of North American origin, TRIG reassortants of the H1N1, H1N2, and H3N2 subtypes are common in the pig population. In addition, H3N1 influenza A viruses were isolated from pigs that acquired the HA gene from a human seasonal H3N2 virus and other genes from the circulating Korean swine AIVs. Since December 2009, pdm-H1N1 viruses have been frequently isolated from pigs South Korea.
The cs-H1N1 virus was reported in pigs in Japan in 1977. Multiple introductions of human H3N2 viruses into pigs in Japan have been reported but the most prevalent virus is an H1N2 reassortant that emerged in 1980 with the N2 from a human seasonal H3N2 virus and other gene segments from a cs-H1N1 virus. The pdm-H1N1 has also been found in pigs in Japan where it reassorted with local H1N2 strains.
Swine IAVs of North American (mainly cs-H1N1) and Eurasian lineages were detected in Thailand in the 1980s and have comingled to produce multiple reassortants with various gene constellations. Swine H3N2 viruses with human seasonal HA and NA segments, Eurasian swine PB1, PB2, PA and M segments and cs-H1N1 NP and NS segments circulated in pigs in Thailand from early 2000 to 2007 (Takemae et al., 2008). From 2000, reassortant H1N1 viruses with the cs-H1N1 HA segment (and some with the NS segment) and seven (or six) segments from European av-H1N1 have been found in Thailand (Th-H1N1). H1N2 viruses were first isolated from pigs in 2005 in Thailand (Chutinimitkul et al., 2008) and contained combinations of segments from the endemic human-like H3N2 and Th-H1N1 viruses (Takemae et al., 2008). With the emergence of the pdm-H1N1 virus, novel reassortants were identified in pigs in Thailand containing the NA segment from the Th-H1N1 virus and seven segments from the pdm-H1N1 strain.
In Vietnam, reassortant H3N2 viruses with the North American TRIG cassette and H3 and N2 segments acquired from 2004-2006 human seasonal viruses were reported in pigs. An H1N2 virus with the N2 and TRIG cassette in association with an H1 from human seasonal 2006 strain was isolated from pigs in Vietnam in 2010. The pdm-H1N1 virus and H3N2 reassortants with pdm-H1N1-like internal genes has been occasionally isolated from pigs in Vietnam.
Most other Asian countries have relied on serologic screening to establish exposure to swine IAVs and, therefore, the genetic profile of these viruses is unknown. As Asian countries move from small farm operations to larger, more integrated systems, the disease and swine IAV dynamics are likely to change.
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