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² Division of Virology, Department of Infectious Diseases, St. Jude Children’s Research Hospital, 332 North Lauderdale, Memphis, Tennessee 38105, USA
³ Corresponding author (email: robert.webster{at}stjude.org)

	ABSTRACT

TOP ABSTRACT INTRODUCTION Evolutionary strategies The ecology of influenza... LITERATURE CITED

 
ABSTRACT:   The emergence of highly pathogenic (HP) H5 influenza A viruses in Asia and the increase of HP H7 viruses in Europe and the Americas focused greater attention on the ecology of influenza in wild birds. Influenza virus surveillance studies in wild bird populations in the Americas, Europe, and Asia confirmed that wild aquatic birds are the reservoir for all known influenza A viruses. Phylogenetic analysis groups the influenza viruses in wild aquatic birds into two distinct superfamilies—one in the Americas and one in Eurasia. The separation of viruses into American and Eurasian clades implies that transmission of HP H5 into the Americas by wild birds is likely to be a rare event. The rapid evolution of the Eurasian H5N1 viruses makes them a continued threat to poultry and humans worldwide.
  Key words:  Avian influenza virus, ecology, evolution, H5N1, highly pathogenic avian influenza.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION Evolutionary strategies The ecology of influenza... LITERATURE CITED

 
Influenza viruses are classified with the orthomyxoviruses and are divided into influenza A, B, and C viruses, and thogoviruses. The genome of influenza viruses is comprised of eight negative-sense RNA segments that code for 11 proteins. During replication there is no quality control on fidelity; consequently the viruses are very error prone and exist as a quasispecies (Lamb and Choppin, 1983; Krystal et al., 1986). In this article we consider only the ecology of influenza A viruses and their evolutionary strategies in their natural reservoir hosts—the aquatic birds of the world.

	Evolutionary strategies

TOP ABSTRACT INTRODUCTION Evolutionary strategies The ecology of influenza... LITERATURE CITED

 
Influenza A viruses are extremely variable and utilize each of the known strategies including mutation, reassortment, insertion, deletion, and classical recombination. To date reassortment has been detected in influenza viruses in wild birds, but recombination has not (Obenauer et al., 2006). Insertion, deletion, and recombination have been detected in influenza viruses from mammals and domestic poultry. Insertions occur in the H5 and H7 viruses when additional basic amino acids are inserted into the cleavage site of the hemagglutinin (HA) proteins and are associated with increases in pathogenicity for gallinaceous poultry (Rott, 1980). Deletions occur in the stalk of the neuraminidase (NA) and are associated with balance in the function of the HA and NA during adaptation to domestic poultry (Matrosovich et al., 1999). Classical recombination has been detected in the emergence of highly pathogenic (HP) H7N3 influenza viruses in Chile and Canada and involve the lengthening of the connecting peptide of the HA by incorporation of a portion of another gene segment (Suarez et al., 2004; Pasick et al., 2005). To date insertion, deletion, or recombination have not been detected in influenza viruses in wild birds.

	The ecology of influenza viruses in wild birds

TOP ABSTRACT INTRODUCTION Evolutionary strategies The ecology of influenza... LITERATURE CITED

 
The search for the source of influenza viruses that emerge at irregular intervals and cause pandemics in humans began after the emergence of the A/Hong Kong/1/68 (H3N2) virus. The detection of antibodies in humans to the N2 neuraminidase found in avian influenza viruses (Pereira et al., 1967) in wild pelagic birds in Australia (Laver and Webster, 1972) and the detection of influenza A viruses in wild ducks in California (Slemons et al., 1974) provided the initial pointers to the presence of influenza viruses in wild birds. Subsequent studies in Canadian wild ducks (Hinshaw et al., 1978; Webster et al., 1992) and in gulls and shorebirds (Kawaoka et al., 1988) established many of the principals of the ecology of influenza viruses. These principals can be summarized as follows:

1. Wild aquatic birds are the natural reservoirs of all influenza A viruses.
   
2. In wild aquatic birds the influenza viruses of all subtypes cause no disease signs, replicate predominantly in the intestinal tract, are shed in the feces, and are transmitted by fecal-oral transmission through water.
   
3. There are a limited number of host-specific lineages of influenza viruses—these are confined to wild aquatic birds that harbor all subtypes, humans that currently harbor two subtypes (H1, H3), pigs that harbor two subtypes (H1, H3), horses that harbor one subtype (H3N8—the older subtype H7N7-equine-1 has probably disappeared from horses), and domestic poultry that harbor a variety of subtypes (predominantly H9N2 in Eurasia and different subtypes in different regions but probably none permanently). There are relatively frequent transmissions of influenza viruses to other species, including sea mammals, mink, and novel subtypes to pigs, but these are usually transient and do not establish permanent lineages.
   
4. There is geographical separation of the influenza viruses in the world into two superfamilies—one superfamily in Eurasia, the other in the Americas. Phylogenetic analysis of influenza viruses permits a clear separation into these two superfamilies. Although the migratory bird flyways in the world are predominantly latitudinal, they do overlap particularly in Alaska and in Labrador. Despite these overlaps phylogenetic analysis of influenza viruses clearly divides them into two geographically separate clades. Development of such clades probably occurs over an extended time frame, implying that influenza viruses do not mix extensively between these superfamilies.
   
5. Influenza viruses in their natural reservoirs show limited amino acid changes, limited antigenic drift, and have been described as being in evolutionary stasis (Gorman et al., 1992). This is interpreted as indicating that in their natural reservoir species the viruses are nearly perfectly adapted and that the continuing mutations provide no selective advantage and are not favored. The absence of change at the amino-acid level in some influenza viruses in their natural hosts suggests that these viruses have been in wild bird hosts for a protracted time and that the association is probably very ancient.
   
6. After transmission to another host, be it another wild bird, domestic poultry, or mammalian host, influenza viruses show rapid evolution (Ludwig et al., 1995). This can occur in all gene segments but is most apparent in the HA and NA, where the changes can result in antigenic drift. In some H5 and H7 viruses additional insertions of basic amino acids at the cleavage site of the HA can contribute to development of HP strains. It is noteworthy that the insertion of basic amino acids alone is not sufficient to make a H5 or H7 virus HP; this is a polygenic trait involving multiple polymerase (P) genes and other matrix (M) and nonstructural (NS) combinations, depending on the strain (Rott, 1980).
   

Support for the above principles of the ecology of influenza comes from surveillance of wild birds in many countries, including Japan (Mikami et al., 1987; Yasuda et al., 1991; Ito et al., 1995), Russia (Lvov and Zhdanov, 1983; Yamnikova et al., 1993), and a continued longitudinal study of the ecology of influenza viruses in the Americas (Krauss et al., 2004). Studies spanning 30 years in wild ducks and 22 years in shorebirds migrating from South America in the spring (May) and from Alberta, Canada in the fall (August) confirmed and expanded our understanding of the ecological principals of influenza in wild birds. The main findings of the longitudinal studies in the Americas can be summarized:

• Ducks and shorebirds (waders of the families Charadriidae and Scolopaeidae) are the major reservoirs of influenza viruses.
  
• All influenza A subtypes H1–H16 have been isolated from wild aquatic birds in Eurasia.
  
• The H14, H15, and H16 subtypes have not been detected to date in the Americas.
  
• Shorebirds in the Americas have a higher percentage of H5, H7, and H9 viruses than ducks.
  
• Shorebirds have a higher frequency of isolation of influenza in spring (USA).
  
• Wild ducks have a higher frequency of influenza virus isolation in autumn (USA).
  
• The predominant viruses in wild ducks (H3, H4, and H6) show a 2-year pattern of periodicity.
  

In the 10 years since the emergence of H5 in Asia in 1996 and the apparent increase in frequency of HP H7 viruses in both Europe and the Americas (Fouchier et al., 2004; Jones and Swayne, 2004), much attention focused on the ecology of influenza in wild birds. A recent review of studies in Europe (Olsen et al., 2006) provides more details of the influenza virus isolations from specific bird species. The expanded information from these studies confirms that aquatic bird species of the world are the predominant natural reservoirs of influenza viruses and is consistent largely with the previous ecological principals. There was one notable difference between the European and American studies—the absence of a significant reservoir of influenza viruses in European shorebirds.

Perpetuation of influenza viruses in wild bird reservoirs

The peak influenza virus isolation frequency for wild ducks is after the breeding season, specifically after the molt and at the time of marshalling prior to migration—a time when many susceptible juveniles share the same waters with adult birds. For shorebirds in the Americas, peak influenza isolation occurs in the spring, when the migrating birds congregate on the horseshoe crab (Limulus polyphemus) feeding grounds of Delaware Bay, USA. The ruddy turnstone (Arenaria interpres) is probably the key spreader of influenza viruses to other species during the feeding frenzy, when birds gain one-third of their body weight in about 2 wk. The frequency of influenza viruses in the ducks and shorebirds falls to very low levels later in the year. It has been proposed that the viruses are maintained frozen in the winter months in the breeding grounds of Alaska and Siberia (Ito et al., 1995; Okazaki et al., 2000). An alternate proposal is that they are perpetuated at low levels in flocks of birds and brought back each year to the breeding grounds (Krauss et al., 2004). There is evidence from the field to support both proposals.

Properties of highly pathogenic avian influenza viruses

Highly pathogenic avian influenza viruses emerge from the low pathogenic viruses that occur in wild bird reservoirs. The main factors are:

• To date only H5 and H7 viruses have shown the capacity to become HP.
  
• HP viruses emerge in domestic poultry.
  
• Each HP strain of H5 and H7 emerges from a low pathogenic precursor.
  
• HP viruses are not perpetuated in aquatic bird reservoirs.
  
• HP viruses are either stamped out or burn out; they are not perpetuated.
  
• The mechanism of evolution of HP viruses is either by insertion (Perdue et al., 1997), mutation (Ludwig et al., 1995), or recombination (Suarez et al., 2004; Pasick et al., 2005).
  
• HP viruses have differing levels of pathogenicity for gallinaceous poultry but are usually nonpathogenic in waterfowl.
  
• Glycosylation in the vicinity of basic amino acids in the connecting peptide of the HA can mask high pathogenicity (Kawaoka and Webster, 1989)
  

Transmission of avian influenza between wild birds in Eurasia and the Americas

There is no doubt that transmission of avian influenza viruses occurs between the two different clades in Eurasia and the Americas and visa versa. There are documented examples of such transfer (Schafer et al., 1993; Makarova et al., 1999; Widjaja et al., 2004). However, the existence of two clearly separable genetic clades suggests that the frequency of transmission is not high. One consequence of these findings is that it may be more likely for the current H5N1 in Eurasia to be introduced into the Americas by illegal trade or smuggling of birds than by wild birds. Regardless, planning for all contingencies is fully merited.

The role of the intermediate host

Most interspecies transmission of avian influenza viruses to other hosts, including mammals, is transitory, and stable lineages rarely are established. This tends to be changing with the globalized domestic chicken industry. H9N2 is now endemic in domestic chickens in Eurasia and H6N2 and H3N2 are becoming more preeminent globally (Alexander, 2003; Choi et al., 2005).

A number of hosts, including pig, chicken, and quail, have receptors for both avian and mammalian influenza viruses and have been proposed as intermediate hosts between wild birds and other mammals, including humans. There is increasing evidence for the presence of both 2–6 sialic acid (human-like influenza receptors) and 2–3 sialic acid (avian-like influenza receptors) in human lungs (Shinya et al., 2006; van Riel et al., 2006), which explains the direct transfer of avian influenza viruses to humans and suggests that pigs are not a required intermediate host, although they could still serve to facilitate adaptation and continued transmissibility in humans.

H5N1 is breaking the rules!

Evolution is a continuing process and the principals discussed above are based on existing knowledge. It is clear that the H5N1 viruses that emerged in southeastern Asia are changing the rules and continue to evolve. These changes include:

• Direct transmission of H5N1 viruses from wild birds to humans (presumably by collection of feathers from dead wild swans in Azerbaijan) (World Health Organization, 2006).
  
• Transmission of influenza virus genes from domestic poultry to migratory waterfowl.
  
• Increased tracheal virus shedding in aquatic birds, suggesting that viruses may transmit mainly via the respiratory route.
  
• Increased thermal stability (Hulse-Post, unpubl. data).
  
• Extensive diversity in pathogenicity for waterfowl, ranging from nonpathogenic to highly lethal.
  
• Transmission to felids (Kuiken et al., 2004) and stone martens (Martes foina) (Eurosurveillance, 2006).
  
• In the past 3 yr at least three distinguishable clades of H5N1 have developed.
  
• Is highly pathogenic H5N1 endemic in wild waterfowl?
  

The above rule breaking indicates continuing evolution.

In conclusion, the Asian H5N1 virus is in rapid evolution—it has already acquired the geographical and host range to make it a pandemic threat in poultry and the potential exists for this virus to acquire consistent human-to-human transmissibility and cause a human pandemic. It would be a mistake to become complacent about the threat of these viruses to poultry and humans.

	ACKNOWLEDGMENTS

 
We thank David Walker and Kelly Jones for excellent technical support, and Carol Walsh for manuscript preparation and editorial assistance. This work was supported by Public Health Service grants AI-95357 and by the American Lebanese Syrian Associated Charities (ALSAC).

	FOOTNOTES

 
¹ Presentation at the FAO and OIE International Scientific Conference on Avian Influenza and Wild Birds, FAO, Rome, 30 and 31 May 2006.

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Received for publication 15 December 2006.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Webster, R. G. Articles by Sturm-Ramirez, K. Search for Related Content PubMed Articles by Webster, R. G. Articles by Sturm-Ramirez, K.