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Transmission of virus from another species to pigs may lead eventually to the establishment of a new virus strain in pigs
Pigs serve as major reservoirs of H1N1 and H3N2 influenza viruses and are often involved in interspecies transmission of influenza viruses. The maintenance of these viruses in pigs and the frequent introduction of new viruses from other species could be important in the generation of pandemic strains of human influenza.
Transmission between humans and pigs
Early theories suggesting the transmission of virus from pigs to humans resulted in the 1918 pandemic were at the time speculative and it was not until 1976 that further evidence for such transmissions became available. Pigs were implicated as the source of infection when an H1N1 virus was isolated from a soldier who had died of influenza at Fort Dix, New Jersey, USA. The virus was identical to viruses isolated from pigs in the USA. Furthermore, five other servicemen were shown to be infected by virus isolation, and serological evidence suggested that some 500 personnel at Fort Dix were, or had been, infected with the same virus (Hodder et al 1977;Top et al 1977).
The Fort Dix incident cannot be regarded as evidence of zoonosis, since although it was likely that pigs were the source of the virus this was never established. However, there is considerable evidence that transmission from pigs to humans does occur as a result of the detection of antibodies to swine H1 viruses in people who have had close contact with pigs (Kluska et al 1961; Schnurrenberger et al 1970).
Final confirmation of the zoonotic nature of H1N1 influenza viruses from pigs came in 1976, when following an influenza epizootic in pigs, viruses isolated from the pigs and a human contact were shown to be both antigenically and genetically identical swine H1N1 influenza viruses (Hinshaw et al 1978, Easterday 1980b). Subsequently there have been several reports from North America of swine virus being isolated from humans with respiratory illness (Easterday 1978; Dasco et al 1984), occasionally with fatal consequences (Rota et al 1989; Wentworth et al 1994).
All cases examined followed contact with sick pigs and were due to viruses related most closely to classical swine H1N1 influenza virus. Perhaps of greater significance for humans is a report of two distinct cases of infection of children in the Netherlands during 1993 with H3N2 viruses whose genes encoding internal proteins were of avian origin (Claas et al 1994).
Influenza viruses of subtype H3N2 are ubiquitous in animals and endemic in most pig populations worldwide, where they persist many years after their antigenic counterparts have disappeared from humans (Shortridge et al 1977; Haesebrouck et al 1985; Wibberley et al 1988; Brown et al 1995b) and therefore present a reservoir of virus which may in the future infect a susceptible human population. There is no apparent evidence of pigs being infected with this subtype prior to the pandemic in humans in 1968. Indeed the appearance of a H3N2 subtype variant strain in the pig population of a country appears to coincide with the epidemic strain infecting the human population at that time (Aymard et al 1980; Nerome et al 1981; Brown et al 1995b).
Further evidence of the spread of influenza viruses from humans to pigs was the appearance in pigs of H1N1 viruses (or antibodies to H1N1) related to those circulating in the human population since 1977 (Aymard et al 1980; Nerome et al 1982; Goto et al 1992; Brown et al 1995b). Genetic analysis of two strains of H1N1 virus isolated from pigs in Japan revealed that the HA and NA genes were most closely related to those of human H1N1 viruses circulating in the human population at that time (Katsuda et al 1995a). In addition reassortant viruses with some characteristics of human H1 viruses have been isolated from pigs in England (Brown et al 1995a; Brown et al 1998).
Transmission between Pigs and Birds
The probable introduction of classical swine H1N1 influenza viruses to turkeys from infected pigs has been reported from North America (Mohan et al 1981; Pomeroy 1982; Halvorson et al 1992) and in some cases influenza-like illness in pigs has been followed immediately by disease signs in turkeys.
Serological studies have revealed antibodies to classical swine H1 influenza virus in both turkeys and pigs. Genetic analyses of H1N1 viruses from turkeys in the United States has revealed a high degree of genetic exchange and reassortment of influenza A viruses from turkeys and pigs, in the former species (Wright et al 1992). Hinshaw et al (1983) report the isolation of swine H1N1 virus from turkeys and the subsequent transmission to a laboratory technician who displayed fever, respiratory illness, virus shedding and seroconversion.
These findings raise the possibility that viruses from pigs, humans, turkeys and ducks may serve as source of virus for the other three. In Europe, avian H1N1 viruses were transmitted to pigs (see ‘avian-like’ H1N1 viruses), established a stable lineage and have subsequently been reintroduced to turkeys from pigs causing economic losses (Ludwig et al 1994; Wood et al 1997). Recently, H9N2 viruses have been introduced to pigs in south east Asia apparently from poultry (Shortridge personal communication) although their potential to spread and persist in pigs remains unknown.
The potential role of the pig as a 'reassortment vessel'
The pig has been the leading contender for the role of intermediate host for reassortment of influenza A viruses. Pigs are the only mammalian species which are domesticated, reared in abundance and are susceptible to, and allow productive replication of avian (Hinshaw et al 1981; Schultz et al 1991) and human (Chambers et al 1991) influenza viruses. This susceptibility is due to the presence of both 2,3- and 2,6-galactose sialic acid linkages in cells lining the pig trachea which can result in modification of the receptor binding specificities of avian influenza viruses from 2,6 linkage (Ito et al 1998), which is the native linkage in humans, thereby providing a potential link from birds to humans.
The ability of an influenza virus to cross between species is controlled by the viral genes and the prevalence of transmission will depend on the animal species.
The success of interspecies transmission of influenza viruses depends on the viral gene constellation. Successful transmission between species can follow genetic reassortment, with a progeny virus containing a specific gene constellation having the ability to replicate in the new host.
Reassorted viruses with other gene constellations may have a relatively low fitness, and will not be able to perpetuate in the new host (Webster et al 1992).
It has been shown that humans occasionally contract influenza viruses from pigs (see transmission). The internal protein genes of human influenza viruses share a common ancestor with the genes of some swine influenza viruses. A number of authors have proposed the nucleoprotein (NP) gene as a determinant of host range which can restrict or attenuate virus replication (Scholtissek et al 1985; Tian et al 1985; Snyder et al 1987) thereby controlling the successful transmission of virus to a ‘new’ host. These observations support the potential role of the pig as a mixing vessel of influenza viruses from avian and human sources. The pig appears to have a broader host range in the compatibility of the NP gene in reassortant viruses (Scholtissek et al 1985) than both humans and birds. Studies by Kida et al (1994), investigating experimentallythe growth potential of a wide diversity of avian influenza viruses in pigs, indicated that these viruses (including representatives of subtypes H1 to H13), with or without HA types known to infect humans, can be transmitted to pigs. Therefore the possibility for the introduction of avian influenza virus genes to humans via pigs could occur. Furthermore, these studies showed that avian viruses which do not replicate in pigs can contribute genes in the generation of reassortants when cinfecting pigs with a swine influenza virus.
Evidence for the pig as a mixing vessel of influenza viruses of non-swine origin has been demonstrated in Europe by Castrucci et al (1993), who detected reassortment of human and avian viruses in Italian pigs. Phylogenetic analyses of human H3N2 viruses circulating in Italian pigs revealed that genetic reassortment had been occurring between avian and ‘human-like’ viruses since 1983 (Castrucci et al 1993). The unique co-circulation of influenza A viruses within European swine may lead to pigs serving as a mixing vessel for reassortment between influenza viruses from mammalian and avian hosts with unknown implications for both humans and pigs. It would appear that human H1 viruses are able to perpetuate in pigs following genetic reassortment. Furthermore, these viruses may be maintained in pigs long after one or both of the progenitor viruses have disappeared from their natural hosts. Reassortant viruses of H1N2 subtype derived from human and avian viruses (Brown et al 1998) or H1N7 subtype derived from human and equine viruses (Brown et al 1994) have been isolated from pigs in Great Britain. The H1N2 viruses derived from a multiple reassortant event and spread widely within pigs in Great Britain. The H1N7 virus, comprised six genes from a human H1N1 virus which circulated in the human population during the late 1970's and two genes (NA and M) derived from an equine H7N7 virus which has not been isolated from horses since 1980, although there is serological evidence that this virus may be circulating in horses at marginal levels in some parts of the world (Mumford and Wood 1992; Madic et al 1996). Genetic analyses of the HA and NA indicated a low rate of antigenic drift following transmission to pigs in contrast to the higher rate in the natural hosts. Other studies of influenza viruses isolated from pigs in North America (Wright et al 1992) and Southern China (Shu et al 1994) failed to detect any reassortant viruses containing internal protein gene segments of non swine origin, although genetic heterogeneity of the HA of swine H3 influenza viruses occurs in nature in China (Kida et al 1988).
Virus adaptation and pathogenesis
Pigs infected with human H1N1 or H3N2 influenza virus readily develop specific antibodies to these viruses. As a result the transmission of human influenza viruses to pigs has been studied widely and monitored using serosurveillance methods. However, it has been shown that pigs infected with some avian influenza viruses may not always produce a detectable antibody response due to the resulting transient infection inducing no or low levels of humoral antibody (Hinshaw et al 1981; Kida et al 1994). These findings are of importance in studying the epidemiology of influenza virus in pigs, suggesting that serosurveillance may not be suitable for the detection of some reassortant or 'new' influenza viruses in pigs. Natural and experimental infection of pigs with an H1N7 human-equine reassortant virus did not induce detectable humoral antibody but the virus was able to transmit between pigs (Brown et al 1994). These findings demonstrate the potential value of monitoring pigs for influenza viruses using virus isolation.
Successful cross-species transmission of influenza virus is dependent on both host and virus genetic factors and subsequent spread within the new host population requires a period of adaptation of the virus to the new host (Webster et al 1992). It is possible that following the transmission of an avian H1N1 virus to pigs in continental Europe in 1979 (Pensaert et al 1981), subsequent infection of pigs was usually subclinical since the virus was not well adapted to its new host. It would appear that the introduction from continental Europe of an ‘avian-like’ swine H1N1 virus well adapted to its new host (Brown et al 1997), into an immunologically naive pig population, such as found in GB in 1992, may partly explain the rapid spread of the virus and its widespread association with disease outbreaks (Brown et al 1993), which was consistent with the epidemiology of the virus in pigs in Europe as a whole. Interestingly, the widespread prevalence of antigenically related classical swine H1N1 viruses in pigs in GB (Brown et al 1995b) and continental Europe (Bachmann 1989) apparently failed to prevent infection with ‘avian-like’ swine H1N1 viruses.
The evolution and adaptation of human H3N2 viruses in pigs following transmission in the early 1970’s appeared similar to that of avian H1N1 viruses. In Europe, the presence of these human H3N2 viruses in pigs was for at least ten years based on antibody detection and it was not until 1984 that the virus was first associated directly with outbreaks of respiratory disease in pigs (Haesebrouck et al 1985) and such occurrences became increasingly more frequent thereafter (Wibberley et al 1988; Castrucci et al 1994). Locally in many parts of Europe ‘swine adapted’ human H3N2 viruses became the predominant epidemic strain and still remain so for example in the ‘Low countries’ (De Jong et al 1999; Van Reeth, personal communication). Interestingly, H3N2 viruses circulating in pigs in Italy since 1983 all contain internal protein genes of avian origin, having replaced H3N2 viruses whose genotype is entirely human (Campitelli et al 1997), suggesting that the acquisition of internal protein genes from an avian virus adapted to pigs afforded a selection advantage to these reassorted viruses.
The results of serosurveillance studies have indicated that the prevailing human viruses of both H1N1 and H3N2 subtypes are transmitted to pigs, but fail to persist. The frequent close contact between humans and pigs would facilitate the transmission of virus from humans to pigs. It is not clear why these viruses fail to persist in pigs, but since immune selection is not considered important in pigs, strains with different antigenic characteristics may be disadvantaged compared to the 'highly-adapted' established viruses which continually circulate within a large susceptible population. However, the recent detection of an H1N2 influenza virus in pigs in GB whose HA is related most closely to that of a human H1 virus from the early 1980's, suggests that the genes of human viruses may persist after reassortment with a one or more influenza viruses endemic in pigs, and following adaptation to pigs may often be associated with outbreaks of respiratory disease (Brown et al 1998).
Following interspecies transmission and/or genetic reassortment an influenza virus may undergo many pig to pig transmissions because of the continual availability of susceptible pigs. The mechanisms whereby an avian virus is able to establish a new lineage in pigs remain unknown, although following the introduction of an avian virus into European pigs in 1979, the mutation rate of this virus did not subsequently increase (Stech et al 1999). It would appear that the adaptive processes can take many years as occurred following transmission of both avian H1N1 and human H3N2 viruses to pigs. In future studies of the epidemiology of influenza viruses in pigs it would be desirable to characterise all the gene segments of viruses isolated to detect changing genotypes with potential implications for pathogenicity to pigs and/or other species.
Phylogenetic analyses of influenza virus genes have revealed that they have evolved broadly in five major host-specific pathways comprising early and late equine viruses, human/classical swine viruses, H13 gull viruses and all other avian viruses. Geographic patterns of evolution occur amongst bird populations forming sublineages relating to North America, Eurasia and Australasia. Following transmission to pigs influenza virus genes evolve in the pathway of the host of origin but diverge forming a separate sublineage (Gorman et al 1991; Scholtissek et al 1993; Nerome et al 1995). All of the genes of human and classical swine viruses form a sister group since they share a common ancestor and the comparable rate of change in some genes such as NP is very similar (Gorman et al 1991). However, analyses of the genes of avian viruses following their transmission to pigs in Europe revealed the highest evolutionary rates for influenza genes for a period of approximately ten years, and may be due to the virus possessing a mutator mutation in the polymerase complex (Ludwig et al 1995).
Genes that code for the surface proteins HA and NA, are subjected to the highest rates of change. The HA gene of both the classical and ‘avian-like’ swine H1N1 viruses is undergoing genetic drift, being more marked in the latter. However, genetic drift in the HA gene of swine H1N1 viruses is confined generally to regions unrelated to antigenic sites (Luoh et al 1992; Brown et al 1997), which is in marked contrast to genetic drift in the HA gene of human H1N1 viruses (Xu et al 1993). The limited antigenic variation in the HA gene of swine viruses is probably due to the lack of significant immune selection in pigs because of the continual availability of nonimmune pigs. The HA genes of classical swine H1N1 influenza virus isolates in North America have remained conserved both genetically and antigenically (Sheerar et al 1989; Luoh et al 1992; Bikour et al 1995) over a period of at least 25 years, but viruses distinguishable antigenically, although closely related, have been reported by Olsen et al (1993) and Wentworth et al (1994). In addition, Rekik et al (1994) reported antigenic drift in the HA gene of isolates of swine H1N1 influenza virus in Canada associated with altered pathogenesis termed proliferative and necrotising pneumonia (Dea et al 1992). Following new introductions of influenza A virus to pigs, as occurred in south east Asia in 1993, close monitoring of the epizootiology of SI in a population is essential to determine the rate of change, which, if elevated, may facilitate further transmissions across the species barrier with potential implications for disease control in a range of other species including humans.
Influenza viruses of H3N2 subtype continue to circulate widely in pigs worldwide. The majority of these virsues are antigenically, related closely, to early human strains such as A/Port Chalmers/1/73.
The limited immune selection in pigs facilitates the persistence of these viruses, which may in future transmit to a susceptible human population. However, some viruses although related closely to the prototype human viruses have antigenic differences in the surface glycoproteins and may cocirculate with the former strains. (Haesebrouck and Pensaert 1988; Kaiser et al 1991; Brown et al 1995a). ‘Human-like’ swine H3N2 viruses appear to be evolving independently in different lineages to those of human and avian strains (Castrucci et al 1994; De Jong et al 1999).
However, marked genetic drift resulting in considerable antigenic variation in the HA gene of ‘human-like’ H3N2 viruses in European pigs, has led to an apparent increase in epizootics attributable to this virus (De Jong et al 1999). In addition, the prevailing epidemic strains in the human population are transmitted frequently to pigs (Nerome et al 1995; Katsuda et al 1995b; Shu et al 1996) and these viruses are clearly distinguishable antigenically from the early human viruses established in pigs.
Pigs serve as a major reservoirs of H1N1 and H3N2 influenza viruses which are endemic in pig populations worldwide and are responsible for one of the most prevalent respiratory diseases in pigs. The maintenance of these viruses in pigs and the frequent exchange of viruses between pigs and other species is facilitated directly by swine husbandry practices which provide for a continual supply of susceptible pigs which have regular contact with other species particularly humans.
The pig has been a contender for the role of intermediate host for reassortment of influenza A viruses of avian and human origin since they are the only mammalian species which are domesticated, reared in abundance and are susceptible to, and allow productive replication, of avian and human influenza viruses. This could lead to the generation of new strains of influenza some of which may be able to transmit to other species including humans. This concept is supported by the detection of human-avian reassortant viruses in European pigs with some evidence for subsequent transmission to the human population.
Following interspecies transmission to pigs some influenza viruses may be extremely unstable genetically, giving rise to many virus variants, which could be conducive to the species barrier being breached a second time. Eventually a stable lineage derived from the dominant variant may become established in pigs.
Genetic drift occurs in the genes of these viruses, particularly those encoding the external glycoproteins, but does not usually result in the same antigenic variability that occurs in the prevailing strains in the human population. Finally, it would appear that adaptation of a ‘newly’ transmitted influenza virus to pigs can take many years. Both human H3N2 and avian H1N1 were detected in pigs many years before they acquired the ability to spread rapidly and become associated with disease epidemics in pigs.
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