Chapter 1
Influenza A virus

David L. Suarez

Introduction

Influenza A viruses (IAVs) are important veterinary and human health pathogens that are present worldwide. The category of viruses has a diverse host range, including a large number of avian and mammalian species. The ecology and epidemiology of influenza A viruses are very complex, involving various free-living, captive-raised, and domestic bird hosts as well as various wild and domesticated mammalian hosts within diverse environments, including humans, pigs, horses, dogs, bats, and sporadic infections in miscellaneous mammalian hosts (Figure 1.1). The other key characteristic of the virus is the genetic and antigenic variation that occurs through the combination of a high mutation rate and a segmented genome that provides an ability to rapidly change and adapt to new hosts. In the right conditions, an IAV can adapt to a new host such that it replicates and transmits efficiently to become endemic in a particular species. In general, this adaptation process produces a viral lineage that has some level of host specificity, so that it becomes more difficult to infect other species. For example, a virus that becomes endemic in horses becomes less able to infect other species such as swine or humans. The species barrier can be less clear in avian species, as a chicken-adapted virus will typically also infect other gallinaceous species, but other classes of birds, such as ducks or pigeons, may be resistant to infection. The IAV can cause a wide range of clinical disease that generally relates to the pathogenesis of the virus, whether it infects just on mucosal surfaces or causes systemic infection. The control of IAVs in animals has used a variety of tools, including vaccines, quarantines, and even culling of infected animals. The goal of eradication of the virus from a host population can in some situations be achieved, but often at a high cost. In many countries, IAVs are endemic and control efforts are used primarily to mitigate economic losses. Because the primordial reservoir for IAVs is wild birds, the ultimate goal of complete eradication is not feasible, and the potential for introduction of new and unique viruses from the wild bird reservoir is a constant threat.

Figure 1.1 Diagrammatic representation of the source and movement of influenza A viruses or their genes within avian and mammalian ecological and epidemiological situations (updated from [160]). H = hemagglutinin subtype, ( ) = subtype previously common but no longer circulating.

Source: K. Carter, University of Georgia, and D. Swayne, USDA/ARS.

Etiology

Classification

Type A influenza virus (IAV) belongs to the Orthomyxoviridae family of segmented negative-sense RNA viruses that are divided into six different genera accepted by the International Committee on Viral Taxonomy, including influenza types A, B, C, Isavirus, Thogotovirus, and Quaranfilvirus [130]. Two additional segmented RNA viruses have been proposed as potential new genera, including a potential type D virus associated with respiratory disease in swine and cattle, and a virus associated with cyclic mortality events in eiders in North America, named the Wellfleet Bay virus [4, 23]. The IAVs are the most widespread and important members of the group, infecting many different avian and mammalian species. Type B and C influenza viruses are human pathogens that rarely infect other species, although infection of swine and seals has been reported [100]. The Isavirus group includes the important fish pathogen infectious anemia virus [61], the Thogotoviruses are tick-borne arboviruses that have been isolated from both humans and livestock [71], and the Quaranfilviruses are tick-associated viruses that have been detected in humans and birds [117]. The remainder of this chapter will be focused mostly on IAVs of birds and mammals, but with brief coverage of influenza B viruses contained in human influenza vaccines.

Composition

All IAVs have 8 different gene segments that encode at least 10 different viral proteins. The structural proteins in the mature virion can be divided into the surface proteins that include the hemagglutinin (HA), neuraminidase (NA), and membrane ion channel (M2) proteins. The internal proteins include the nucleoprotein (NP), the matrix protein (M1), and the polymerase complex comprised of the polymerase basic protein 1 (PB1), polymerase basic protein 2 (PB2), and polymerase acidic protein (PA) [103]. Two additional proteins produced by IAV are the non-structural proteins, namely non-structural protein 1 (NS1) and non-structural protein 2 (NS2), which is also known as the nuclear export protein (NEP) [97]. The NS1 protein is considered to be a true non-structural protein that is not found in the virus particle, but is produced in large amounts in the host cell [14, 172]. The NS2 protein is primarily found in host cells, but some protein can be found in the virion [130]. Several additional accessory proteins have been described that result from transcription from alternative open reading frames, although the function of many of them is poorly understood [177]. The PB1-F2 protein, an 87-amino-acid protein that is transcribed from a different reading frame from the PB1 protein, is a potential virulence factor thought to be involved in apoptosis in host cells, but it is not found in all IAVs [21]. The PA-X protein, a product of a ribosomal frame shift, has been shown to modulate the mouse immune response [51]. The role and importance of these accessory proteins are still being studied, and their importance to the pathogenesis of the virus is unknown.

The HA protein is categorized into 18 different subtypes, originally based on the hemagglutination inhibition (HI) assay, but now confirmed by gene sequencing and analysis (Table 1.1). The different subtypes are not uniformly distributed among the various bird and mammal species, but the greatest diversity of IAVs occurs in the class Aves, principally in two orders of wild birds, namely the Anseriformes and Charadriiformes. The subtype distribution is more limited in mammals, with restriction of a few HA subtypes to endemic or sporadic infections of mammals.

Table 1.1 Hemagglutinin subtype distributiona of influenza A viruses between different birds (class: Aves) and mammals (class: Mammalia)

a ± = sporadic, + = multiple reports, ++ = most common.

b ( ) = Previously common but now not reported.

c Both LP and HP viruses.

d Rare subtypes.

e Primarily swine influenza virus infections of domestic turkeys.

Modified from Swayne, D. E. and M. Pantin-Jackwood. 2008. Pathobiology of avian influenza virus infections in birds and mammals. In: Avian Influenza, D. E. Swayne, ed. Blackwell Publishing: Ames, IA....