In April 2009, in a town of the state of Veracruz in Mexico, an unusual viral event took place making the headlines in every newspaper and establishing a panic scenario worldwide. A reassorted human/swine/bird influenza virus had combined with a Eurasian pig influenza virus (Trifonov et al, 2009) and was responsible for the 2009 pandemic H1N1 which ultimately affected more than 200 countries and caused over 14 000 deaths (World Health Organization, 2010). The threat of influenza epidemics in humans is taken very seriously mostly due to its consistent yearly occurrence and the pandemic ability whenever a major viral variant emerges. Additionally, the influenza virus is continuously and extensively shed airborne through coughing or sneezing and virus transmission can occur even before any symptoms become apparent. The influenza virus is considered to be highly contagious, and therefore viral dissemination is very difficult to control resulting in the prospective death of millions of people — and the world is continually reminded of the 1918 pandemic in which estimates of the number who died reach 50 million people, more than the First World War itself (Taubenberger and Morens, 2006) (Table 1). On August 10 2010, Margaret Chan, the Director General of the World Health Organization, announced to the world the official end of the H1N1 pandemic, the first influenza pandemic of the 21st century (World Health Organization/Europe, 2010). This, however, does not necessarily mean the end of this virus or its toll on the human population. It is now known that the H1N1(2009) is circulating along with seasonal influenza viruses while replacing the former seasonal H1N1 strains, and that acquired immunity resulting from previous exposure to H1N1(2009) attenuates the effects of this virus (Gyles, 2010). The potential for the emergence of new H1N1 strains is well established and is due to antigenic drift (World Health Organization, 2010).
An analysis of the viral reassortment episodes that originated the 2009 pandemic H1N1 (Figure 1) immediately reveals the hidden face of this problem — the influenza virus infection occurs in a variety of animal species and these may shed the virus to the human population in specific, favourable situations especially when in close contact with humans. On the rebound of this latest pandemic time should be taken to reflect on the significant role of animals in the preserving, changing, and spreading of influenza, and on the roles of veterinary professionals in maintaining surveillance and awareness.
Influenza viruses are significant pathogens of animals, but seldom are zoonotic and therefore are not directly transmitted from animals on every occasion a human infection occurs. Instead, the viruses are continuously evolving in host range variants in animals to ultimately become epidemic or even pandemic when they invade humans. This is the fundamental principle behind veterinary and human concerns over influenza, and the reason why they are so tightly connected. Additionally, it is established that reassortment among avian, human and/or swine influenza virus gene segments has occurred in swine and the novel reassortant swine strains have spread to humans (Ma et al, 2008). Therefore, awareness in both human and veterinary research is needed in order to focus on potential zoonotic transmission capacity of influenza viruses.
Animal infuenza
The influenza virus belongs to the family Orthomyxoviridae, and to the genus influenzavirus that comprise s3 types, A, B and C. The influenza virus possesses a segmented negative-strand RNA genome. The influenza A virus infects many mammals and birds, while influenza B virus has been reported in seals and influenza C virus in swine (World Health Organization, 2002).
Influenza A viruses infects a variety of animals, including humans, horses, pigs, sea mammals, and a variety of birds. Interestingly, phylogenetic approaches to influenza A viruses have revealed species-specific lineages of viral genes (Webster et al, 1992). There are now convincing data supporting the view that all 16 haemagglutinin (HA) subtypes of influenza A virus are perpetuated in the aquatic bird populations of the world, especially in ducks, shorebirds and gulls (World Health Organization, 2002). In these animals the viruses are replicated in the intestinal epithelium cell lining and are later excreted in faeces (Daoust et al, 2011). This high concentration viral shedding and proficient faecal–oral transmission pattern allows migrating aquatic birds to efficiently transport viruses between continents playing an important role in influenza virus evolution (Murphy et al, 1999).
The ecology of influenza A virus is very peculiar and its study has led to the hypothesis that all mammalian influenza viruses derive from the shedding from an avian influenza reservoir (Gabriel et al, 2005). Phylogenetic analyses of the avian influenza A viruses show that they have evolved into five host-specific lineages: a classical equine lineage (not isolated in over 15 years); a modern equine lineage; a gull lineage; a swine lineage; and a human lineage (Gorman et al, 1990). Genetic studies in avian species reveal separate sub lineages of influenza in Eurasia and the American continent, indicating that migratory birds which move between these continents — called latitudinal migration — have a lesser role in the transmission of influenza, while migratory birds which move longitudinally appear to play a major role in viral evolution (World Health Organization, 2002). This event remains unexplained.
Another discovery has astonished the scientific community — through phylogenetic analyses scientists have discovered that avian influenza strains, unlike the mammalian ones, appear to have low evolutionary rates (Webster, 1998). This is specially highlighted in the case of wild aquatic birds which appear to be in evolutionary stasis, and in which phylogenetic data substantiate that no evolution has occurred over the past 60 years (Webby and Webster, 2001). The asymptomatic nature of the disease in aquatic birds and the apparent evolutionary stasis of viruses in the aquatic bird reservoir are consistent with a stable host–parasite relationship developed during a prolonged period of co-evolution. The evolutionary stasis occurs within a particular species. Only on interspecies transfer, the resulting infection often causes extensive disease and an increased viral mutation rate is observed.
| Pandemic | Date | Deaths | Involved subtype |
|---|---|---|---|
| Spanish Flu | 1918–1920 | 50 million | H1N1 |
| Asian Flu | 1957–1958 | 1.5 to 2 million | H2N2 |
| Hong Kong Flu | 1968–1969 | 1 million | H3N2 |
| Swine Flu | 2009–2010 | >14 000 | H1N1(2009) |
Regardless of the fact that avian influenza viruses are at an evolutionary stasis, nucleotide changes have continued to occur at a similar rate both in avian and mammalian influenza strains. The difference is that the nucleotide changes in the avian influenza virus no longer results in amino acid changes, while all remaining mammalian viral gene segments continue to accumulate changes in the amino acid sequences (Webster, 1998). This high status of genetic conservation is suggestive of an approach or even reaching of an adaptive optimum. However, after transmission to other wild or domestic aquatic avian species, the influenza A viruses once again show a substantial evolutionary rate (World Health Organization, 2002).
From gene mutation to pandemic pandemonium
Antigenic shift and drift are the mechanisms which contribute to the characteristic epidemic pattern and pandemics of influenza A viruses in the human population (Gyles, 2010). Genetic mutations occur frequently often generating changes on the surface proteins, the HA and the neuraminidase (NA) (Figure 2). These alterations in the virus surface allow these viruses to escape existing immunity to previously circulating influenza viruses in an individual and in the population. Through the antigenic drift process, new human strains evolve worldwide, with epidemic capability almost every year (Webby and Webster, 2001). Antigenic drift is less prominent in equine, avian and swine influenza (Murphy et al, 1999). This process does occur but at a reduced rate, unlike in humans, but further studies are clearly needed to understand whether immune mechanisms play a role in emergence of variants. It is the general consensus that influenza transfer between species originates an increase in antigenic drift (Murphy et al, 1999).
During the antigenic shift process viruses emerge which contain surface HA and NA that are not present in the previously circulating viruses. These influenza viruses emerge after viral reassortment in a host con-comitantly infected with two different subtypes of influenza A viruses generating pandemics which are frequently associated with high levels of morbidity and mortality (World Health Organization, 2002).
The pet flu
Viruses that are accountable for most of the respiratory infections in dogs and cats are well studied. In dogs, adenovirus, herpesvirus, reovirus, coronavirus, parainfluenzavirus, or morbillivirus, acting together with bacteria, are usually responsible for the multi-causal genesis of ‘kennel cough’. This acute respiratory syndrome is contagious among dogs housed in groups especially among dogs housed in high density such as in pet shops, breeding and boarding kennels, shelters and veterinary clinics (Harder and Vahlenkamp, 2010).
Dogs often came into contact with sources of influenza virus through direct contact with other animal (mammalian and avian) species, most of which are hosts of endemic influenza A virus infections. Additionally, pets live in intimate contact with their owners, who are frequently susceptible to the seasonal epidemic activity of influenza virus, so exposure to these viruses is constant. This is why influenza has been baffling scientists for decades, as it has long been absent from the list of respiratory infectious agents considered as possibilities in dogs (Beeler, 2009).
The first cases of clinically apparent influenza virus infection associated with sustained transmission in canine populations were sparked by trans-species transmission of equine H3N8 influenza viruses in racing greyhounds in Florida in January 2004. Respiratory disease outbreaks were continuously identified in greyhounds from nine North American States from 2004 through 2006 (Crawford et al, 2005; Yoon et al, 2005). Most of the affected dogs presented typical clinical signs of the upper respiratory tract such as cough for 10 to 30 days, nasal discharge and fever (Payungporn et al, 2008). These animals usually recovered; nevertheless some infections were fatal, associated with extensive lung, pleural and mediastinum haemorrhages. The gross examination showed the presence of lesions of bronchitis, bronchiolitis, tracheitis and bronchopneumonia, mainly of suppurative characteristics. Microscopic examination revealed extensive erosion of epithelial cells and infammatory infiltrate, rich in neutrophils. Interestingly, serologic studies and molecular epidemiology studies on infected greyhound dogs strongly suggests sustained influenza virus circulation by dog-to-dog transmission (Crawford et al, 2005; Yoon et al, 2005).
In South Korea a subtype H3N2 canine influenza A virus of avian origin was identified in 2007 as being responsible for severe respiratory disease outbreaks among pet dogs (Song et al, 2008). Experimental infection with an H3N2 isolate provided conclusive data on the pathogenic responsibility of this virus (Song et al, 2009; Harder and Vahlenkamp, 2010).
Highly pathogenic avian influenza virus (HPAIV) H5N1, the well-known ‘bird flu’ virus which is highly virulent for humans, was found to be responsible for the fatal infection of a dog following contact with HPAIV H5N1 positive chicken carcasses in Thailand (Songserm et al, 2006). In addition in Thailand, 25% of a dog population (629 dogs) were found to be positive for H5-specific antibodies (Butler, 2006).
In an effort to further study the role of H5N1 in dogs and the possibility of dogs acting as reservoirs for this highly virulent virus which could ultimately infect humans, experimental infection with two H5N1 strains was performed (Giese et al, 2008); conjunctivitis and temporary elevated temperatures were observed in dogs. Despite the swift seroconversion, short-term shedding from the nasal cavity was observed with low viral titres (Maas et al, 2007; Giese et al, 2008; Harder and Vahlenkamp, 2010).
Influenza virus vaccines
To date, there is no evidence of transmission of influenza virus from dogs to people. While canine influenza virus (influenza A H3N8) infects dogs and spreads among them, there is no evidence that this virus infects humans (Centers for Disease Control and Prevention, 2011). Nevertheless, infections in humans with novel influenza viruses and for which the human population have little immunity would be a reason for concern if they occurred. In America, in order to prevent canine influenza virus transmission between dogs, and therefore reduce the possibility of influenza virus spillover to humans, a vaccine has been approved and recommended for use in healthy dogs 6 weeks of age or older. This vaccine contains inactivated virus (influenza A H3N8) and has been shown to reduce the incidence and severity of lung lesions in dogs (Deshpande et al, 2009).
Conclusions
Influenza viruses are important pathogens of humans and many animals. Despite influenza viruses’ toll on public health, due mainly to its high morbidity/mortality and fast community spread, only recently several scientific findings have changed the comprehension of the role of this virus in dogs. With several influenza strains associated with infection in dogs, veterinary professionals should have a key role to play in the vigilance of potentially zoonotic influenza infections by paying close attention to idiopathic infection-like respiratory diseases. These professionals can pose as the first barrier to infection spread and can prevent unreasonable fears that usually arise from major influenza epidemics, by alerting personnel and owners about influenza infection. Veterinary professionals have the knowledge to explain to owners about the scarce possibility of dogs posing as reservoirs for influenza virus. Nevertheless, an influenza infection should always take part in the algorithm of a respiratory distress. While there is no evidence that this virus infects humans, any suspicion of zoonotic transmission to humans should trigger an alert for the health authorities.