Influenza: Fear triggers renewed interest in interspecies transmission

Q: Please review influenza in animals

A: At the 2007 American College of Veterinary Internal Medicine Forum in Seattle, Dr. Gabriele A. Landolt gave a lecture titled "Up to New Tricks: Interspecies Transmission of Influenza." Here are some relevant points:

Recently, the need to understand influenza host range has taken on increased significance. Specifically, the re-emergence of highly pathogenic avian H5N1 influenza A viruses in poultry, cats and humans throughout large parts of Asia, Europe and North Africa have triggered fears of an impending influenza pandemic.

Yet these viruses' apparent inability to efficiently spread from person-to-person, a requirement for full-scale emergence and maintenance of a new pathogen in a population, is an important reason why these avian H5N1 viruses have not yet sparked a full-blown pandemic. It has long been recognized that barriers exist that limit direct transmission of influenza viruses among species.

Moreover, the prevalence of influenza virus interspecies transmission appears to be dependent on the animal species involved.

For example, horses often have been regarded as isolated hosts for influenza viruses, although recent events clearly indicate that the species barrier for viruses jumping to or from horses is not absolute.

Avian reservoirs

Historically, only a limited number of influenza virus subtypes have circulated widely in mammalian populations. For example, in humans, only viruses of H1, H2, H3, N1 and N2 subtypes have been associated with widespread infection. In horses, influenza infections have been restricted largely to viruses of H7N7 and H3N8 subtypes, and only H1, H3, N1 and N2 subtypes have consistently been isolated from pigs.

In contrast, viruses of all 16 HA and nine NA subtypes have been recovered from wild waterfowl and seabirds. In these birds, influenza viruses are highly host-adapted, as evidenced in the low evolutionary rate of the viral genome (evolutionary stasis). Infection typically results in subclinical disease.

As the viruses preferentially replicate in the duck's intestinal tract, they are shed in high concentration in the feces, thereby contaminating lakes and ponds visited by these animals. As such, aquatic birds, particularly migrating waterfowl, represent a global reservoir of all subtypes of influenza viruses in nature from which novel viruses can emerge to infect mammalian species.

Indeed, viruses of avian origin have been the source of outbreaks of influenza in animals, such as seals, whales, mink, pigs and horses. The importance of the avian reservoir is further highlighted by the fact that the virus that caused the 1918 Spanish influenza pandemic, undoubtedly the most devastating pandemic known to man, derived all of its genes from an avian virus. Moreover, the pandemic strains of the 1957 Asian pandemic, as well as the 1968 Hong Kong pandemic, arose from genetic reassortment of contemporary human and avian influenza viruses.

Lastly, phylogenetic analyses demonstrate that viruses from aquatic birds were the ancestral precursors of all contemporary influenza viruses present in other species.

Evidence supports that barriers exist, limiting the direct transmission of influenza viruses from birds to mammals. For example, despite the fairly high prevalence of H5N1 viruses in birds in parts of Asia, transmission of the virus to humans remains sporadic. In addition, these viruses still do not appear to have developed the ability to transmit efficiently from person-to-person — a feature considered the chief prerequisite for pandemic emergence of influenza. Given this limited capacity for transmission and spread of avian viruses in humans, it is hypothesized that the emergence of an avian virus with pandemic potential requires prior adaptation of the virus in an intermediate host.

Role of intermediate host

As avian viruses of virtually all HA subtypes were able to infect and replicate in pigs, it has been postulated that these animals are logical intermediate hosts. As pigs are susceptible to infection with human lineage viruses, pigs may serve as mixing-vessel hosts for genetic reassortment between human and avian viruses. In fact, there are several well-documented examples of direct avian-to-pig transmission of influenza as well as instances where genetic reassortment of human and avian viruses was shown to have occurred in pigs.

While the pig has been considered the leading candidate for the role as intermediate host for virus adaptation, recent information suggests that terrestrial poultry, such as quail and chickens, also may play a central role in the emergence of viruses with pandemic potential. Yet, as human and swine lineage viruses appear to replicate inefficiently in land-based poultry, the pig remains the most likely domestic animal species in which genetic reassortment between human and avian viruses may occur.

Direct virus transmission between mammals

Influenza viruses of different genotypes and subtypes occasionally can be transmitted between two mammalian species. For instance, direct swine-to-human transmission of influenza viruses has been documented on several occasions. Other examples include the occasional human-to-equine transmission of H1N1, H2N2 and H3N2 viruses. The potential for interspecies transmission among mammals is further highlighted by the recent transmission of an equine-like H3N8 influenza virus to dogs. The equine-to-canine transmission event is particularly intriguing in light of the fact that dogs were not commonly regarded as hosts for influenza A viruses.

Although circumstantial evidence from surveillance studies indicates that dogs are susceptible to infection with human-lineage viruses, infection did not result in clinical disease and the viruses did not spread efficiently among dogs.

In contrast, the equine H3N8 strain that caused the canine influenza outbreak in the United States spread quickly among dogs. Given that influenza A viruses do not establish persistent infections, the apparent maintenance of the H3N8 virus in the canine population implies that this particular strain infects and replicates efficiently in dogs.

Molecular determinants

To date, the viral and host factors that determine influenza virus species specificity and the mechanism by which host-range barriers are overcome are not completely understood. Nevertheless, evidence has accumulated over the years indicating potential contributions by the products of all eight gene segments. Despite this, several virus genes appear to play dominant roles in controlling influenza host range. Due to its role as the viral receptor binding protein, many investigators have focused their attention on the HA as the primary determinant of host range. Over the years, a large body of evidence has accumulated indicating that the HA is a key player in influenza virus species specificity.

Concluding remarks

Infections caused by influenza A viruses have burdened humans and animals since ancient times. Yet, due to the existence of a global avian reservoir of all subtypes of influenza viruses, influenza's inherent ability to infect a broad range of animal hosts, as well as the viruses' continued genetic evolution, influenza continues to represent a serious infectious disease threat. Recent examples of interspecies transmission of viruses include the spread of equine H3N8 virus to dogs in the United States as well as the resurgence of H5N1 avian influenza viruses in poultry, cats and humans throughout large parts of Asia, North Africa and Europe. Although there has been an explosion of information on the molecular determinants of influenza virus species specificity, much has remained unclear. The realization of the importance of interspecies transmission in the ecology of influenza has importance for influenza control, since commercially available vaccines may not provide protection against infection with viruses stemming from other species. Thus, virus surveillance in animal species must remain a priority. Surveillance and genomic sequencing of large numbers of influenza viruses will help us comprehend the genetic basis of host adaptation and will enhance our understanding regarding the extent and impact of the animal reservoir of influenza A viruses.

Dr. Hoskins is owner of DocuTech Services. He is a diplomate of the American College of Veterinary Internal Medicine with specialities in small animal pediatrics. He can be reached at (225) 955-3252, fax: (214) 242-2200 or e-mail: jdhoskins@mindspring.com.

Johnny Hoskins

Research abstract

Serological Evidence for Canine Influenza Virus Circulation in Racing Greyhounds from 1999 to 2003:

T.C. Anderson; L. Grimes; J. Pompey; C. Osborne; W.J. Dodds; J.M. Katz; C.H. Courtney; P.C. Crawford University of Florida College of Veterinary Medicine, Gainesville, FL, USA; Immunology and Viral Pathogenesis Section, Influenza Branch, Centers for Disease Control and Prevention, Atlanta, GA, USA; Hemopet/Pet Life-Line, Garden Grove, CA, USA.

Influenza H3N8 virus was first isolated from racing greyhounds that died from hemorrhagic pneumonia during multiple respiratory-disease outbreaks at tracks in 2004 and 2005. In addition to virus isolation, substantial serological evidence indicated that CIV was associated with these respiratory-disease outbreaks. Limited testing of archived tissue and serum samples from racing greyhounds has suggested that CIV may have circulated in this population prior to 2004. To further investigate this possibility, serum samples collected from racing greyhounds during the period from 1984 to 2004 were tested for CIV antibodies.

Archived serum samples collected from 702 racing greyhounds were tested for CIV antibodies using the hemagglutination inhibition (HI) assay. One set of samples was collected from greyhounds in Florida in 1984 and 1985 (n=153 dogs). Another set of samples was collected from dogs in multiple states from 1999 to 2004 (n=549 dogs).

In these dogs, prior racing history was traced using unique ear tattoos carried by all racing greyhounds and a corresponding database housed at www.greyhound-data.com/. For comparison, serum samples from non-greyhound dogs collected upon entry into a Florida animal shelter from 1999 to 2004 (n=288) were tested for CIV antibody.

None of the samples from greyhounds in Florida in 1984 and 1985 were positive for CIV antibody. For samples from greyhounds collected from 1999 to 2004, 20 percent were seropositive in 1999; 18 percent in 2000; 9 percent in 2001; 44 percent in 2003; and 28 percent were seropositive in 2004. Most of the CIV- seropositive dogs were at tracks or farms in AR, AZ, CO, FL, IA, KS, OK, TX and WI during respiratory-disease outbreaks in 1998, 1999 and 2003. None of the shelter dogs was seropositive for CIV except for one dog that entered the shelter in 2004.

Based on the serological evidence, we conclude that CIV was circulating in the racing-greyhound population as early as 1999. The seropositive dogs were located at tracks involved in respiratory-disease outbreaks of unknown etiology that involved thousands of dogs across the United States. This suggests that CIV may have been the causative agent of those outbreaks.