65       Orthomyxoviridae

 

The family Orthomyxoviridae (Greek orthos, proper and myxa, mucus) contains those viruses which cause influenza in humans and animals. Orthomyxoviruses are spherical or pleomorphic, enveloped viruses, 80 to 120 nm in diameter. Long filamentous forms also occur. The envelope, which is derived from host cell membrane lipids, contains glycosylated and non-glycosylated viral proteins. Surface projections of glycoproteins form ‘spikes’ or peplomers which, in influenza A and B viruses, are of two types: a haemagglutinin (H) responsible for virus attachment and envelope fusion, and a neuraminidase (N) capable of cleaving viral receptors thus promoting both entry of virus into cells and release of virions from infected cells.

Influenza viruses haemagglutinate erythrocytes from a wide range of species. Antibodies to the H glycoprotein are mainly responsible for virus neutralization. The nucleocapsid has a helical symmetry. The genome, which is composed of six to eight segments, consists of linear, negative-sense, single-stranded RNA. Replication occurs in cell nuclei with release of virions by budding from plasma membranes. Virions are labile in the environment and are sensitive to heat, lipid solvents, detergents, irradiation and oxidizing agents.

The family contains six genera, namely Influenzavirus A, Influenzavirus B, Influenzavirus C, Thogotovirus, Quaranjavirus and Isavirus. Influenza B and C viruses are pathogens of humans; Thogoto virus and Dhori virus are tick-borne arboviruses isolated from camels, cattle and humans in parts of Africa, Europe and Asia; infectious salmon anaemia virus affects farmed salmon. Influenza A virus, the most important member of the family, is a significant pathogen of animals and humans.

Isolates of influenza A virus are grouped into subtypes on the basis of their H and N antigens. Currently, 18 H antigens and 11 N antigens are recognized and new subtypes of influenza A virus emerge periodically. A number of mechanisms – point mutation and recombination (genetic reassortment) – are responsible for the emergence of new strains and new subtypes respectively. Point mutations give rise to antigenic drift, in which variation occurs within a subtype. Genetic reassortment, a more complex process in which the genome segments of two or more related viruses infecting the same cell are exchanged, results in the development of new subtypes (antigenic shift). To assess the risk posed by the emergence of new variant viruses, a precise classification of isolates has been adopted by the World Health Organization. This system is based on the influenza virus type, host, geographical origin, strain number, year of isolation and subtype. An example of this classification system, influenza virus A/equine/Prague/1/56 (H7N7), indicates that this virus was isolated from a horse in Prague during 1956. Antigenic subtypes of influenza A virus which cause disease in humans and farm animals are presented in Table 65.1.

Table 65.1 Antigenic subtypes of influenza A virus isolated from humans and animals.

Hosts	Antigenic subtypes	Comments
Humans	H1N1 (1918, 1977, 2009)a H2N2 (1957) H3N2 (1968)	Subtypes which have been found in pigs such as H1N1 have been implicated in human pandemics. Sporadic or limited transmission of infections reported with H5N1, H7N2, H7N3, H7N7, H7N9, H9N2 and H10N8 in recent years
Birds	Many antigenic subtypes represented by different combinations of haemagglutinin (H) and neuraminidase (N) peplomers have been recognized	Disease is usually associated with subtypes expressing H5 or H7. Wild birds, especially migrating ducks, act as carriers
Pigs	Predominantly H1N1, H1N2 and H3N2	Severity of disease is determined by the antigenic subtype
Horses	Usually H7N7 or H3N8 (H7N7 has not been detected in horses for more than 20 years. H3N8 has replaced H7N7 as the predominant subtype)	Subtypes associated with disease, which are widely distributed geographically, are absent from Australia, New Zealand and Iceland
Dogs	H3N8 (originated from an equine H3N8 lineage), H3N2	H3N8 first reported in Florida in 2004. Large outbreak of influenza (H3N2) in dogs in USA in 2014

^aYear of recognition.

Clinical infections

Influenza A viruses cause significant infections in humans, pigs, horses and birds. All known subtypes (except H17N10 and H18N11, which have been found only in bats) can infect birds. Aquatic birds, particularly ducks which are reservoirs of influenza A virus, provide a genetic pool for the generation of the new subtypes capable of infecting mammals. Migratory waterfowl and trade in poultry and poultry products may disseminate avian viruses across international borders. Although isolates of influenza A virus are usually species specific, there are well-documented instances of transfer between species. The viruses replicate in the intestinal tract of birds and transmission of low pathogenic influenza viruses is mainly by the faecal–oral route. Human infection with avian influenza viruses has been attributed to the combined effects of poor hygiene and the close association of concentrated human populations with domestic fowl and pigs. Genetic reassortment in these animal populations can lead to the emergence of novel virulent influenza virus subtypes which are capable of infecting humans, thereby initiating pandemics. Avian influenza viruses usually replicate poorly in humans. However, both human and avian influenza subtypes replicate in pigs, a species in which genetic reassortment readily occurs with the emergence of new subtypes. Such novel subtypes may be implicated in major pandemics which occur at intervals of about 20 years. As there is limited immunity in the human population to new subtypes, spread from country to country tends to occur rapidly.

Subtypes of influenza A virus, which are well established as pathogens in particular animal populations, have also been implicated in crossing species barriers without genetic reassortment. An H1N1 avian subtype appeared in pigs in Europe in 1979. In 1997, following a large epidemic of avian influenza in chickens, a highly pathogenic avian influenza (HPAI) H5N1 subtype (first isolated from a goose in southern China in 1996) was isolated from a fatal case in a young child in Hong Kong. This subtype had not previously been described outside of avian species. Human health fears prompted the destruction of 1.2 million birds in Hong Kong. The virus reappeared in members of a Hong Kong family in 2003 and was subsequently found to be circulating across south-east Asia resulting in spread to the Middle East, Africa and Europe. Fortunately human-to-human transmission has not been demonstrated to any significant extent to date, although human cases (mortality rate approximately 60%) have continued to occur as a result of contact with infected poultry. Other subtypes of avian origin have caused human infections (Table 65.1), particularly in China where factors such as live bird markets appear to be important in disease transmission.

Avian influenza (fowl plague)

Influenza A subtypes occur worldwide. Outbreaks of severe clinical disease, usually caused by subtypes expressing H5 and H7 determinants, occur periodically in chickens and turkeys. In these species, acute infection is often referred to as fowl plague or HPAI and is categorized as a listed disease by the OIE. It is likely that the HPAI viruses in these acute outbreaks arise by mutation from low pathogenic avian influenza viruses. Spread of influenza virus in tissues is dependent on the type of proteases present in a given tissue and the structure of the viral haemagglutinin molecule. The production of infectious virions requires cleavage of the viral haemagglutinin. In the majority of influenza A virus subtypes, haemagglutinin cleavage takes place only in the epithelial cells of the respiratory and digestive tracts. Because of the amino acid composition at their cleavage sites, haemagglutinins of virulent subtypes are susceptible to cleavage in many tissues, facilitating the development of generalized infection. Highly virulent subtypes cause explosive outbreaks of disease with high mortality. Clinical signs are more apparent in birds which survive for a few days. Respiratory distress, diarrhoea, oedema in the cranial region, cyanosis, sinusitis and lacrimation are features of the clinical presentation. In countries free of the disease, test and slaughter policies are implemented. Vaccination is permitted in those countries with recurring outbreaks of disease but is prohibited in countries implementing a slaughter policy.

Equine influenza

Equine influenza is an economically important respiratory disease of horses. Outbreaks of disease are associated with the assembly of horses at shows, sales, racing or training. Affected animals develop a high temperature with nasal discharge and a dry cough. A number of inactivated vaccines are commercially available, but as immunity is short-lived, regular booster injections are required. Vaccinated horses, exposed to field virus, exhibit milder clinical signs than unvaccinated animals.