Avian Influenza Virus (AIV) has evolved to a point where it has a strikingly successful relationship with wild waterfowl. The waterfowl allow replication of vast quantities of AIV in their intestinal tract with no adverse effects to the waterfowl. The AIV becomes widely travelled as waterfowl migrate and profuse fecal shedding of the virus serves to spread the AIV to other susceptible waterfowl. No harm: no foul up to that point. ( No pun intended )
The ability of AIV to cause disease is governed primarily by the hemagglutinin (HA) glycoprotein. Highly pathogenic avian influenza viruses (HPAI) contain a highly cleavable HA molecule susceptible to ubiquitous host proteases, such as furin, and as a result they are capable of more severe systemic infections. In contrast, low-pathogenic avian influenza viruses have HAs that require activation by trypsin-like proteases and are therefore restricted to specific organs, causing localized and mild infections.
These Japanese researchers were able to generate highly pathogenic virus variants from low-pathogenic avian influenza (LPAI) waterfowl isolates that originally replicated poorly in domestic poultry. The increased ability of these “passaged” strains from one generation of host to the next was correlated with a genetic change at the HA cleavage site. This involved 24 generations of passage through air sacs and then 5 more generations through chick brains. The researchers were able to show what was initially a benign virus maintained in wild waterfowl in nature was capable of evolving into having the ability to spread systemically in domestic chickens with up to 100 % mortality. Highly pathogenic indeed! The researchers also point out that the circulation of LPAI in domestic poultry can also mutate into HPAI with as little as a single amino acid substitution at a cleavage site.
Why is it That AIV replicate better in some hosts and not others? The host specificity of AIV is also primarily determined by the HA glycoprotein. AIVs usually replicate much less efficiently in humans. Human influenza viruses usually replicate much less efficiently in birds. This host restriction and replication ability largely reflects differences in receptor-binding specificity of the HA protein. Most AIVs preferentially bind to sialic acid receptors with α2,3-linked galactose (SAα2,3Gal), while human viruses prefer the SAα2,6Gal linkage. Where do the pigs come into this sad story you ask? Well as it turns out, both of these receptor types are expressed in the respiratory tissue lining the airways of pigs. Swine are not the only species that has the potential serve as “mixing vessels” that facilitate viral reassortment. Their ability to more easily host avian, human and pig adapted influenza viruses at the same time allows pigs to have greater potential as a mixing vessel and recombination events. Avian viruses that are successfully propagated in pigs slowly over many generations can also acquire the ability to bind more efficiently to human cell surface receptors even without genetic reassortment events. A process of “viral drift” facilitated by RNA replication mistakes.
Take Home Messages:
- These results provide a molecular basis for the key mechanisms underlying the emergence of novel influenza viruses with pandemic potential in humans.
- The researchers go on to point out that the recent increase in mammalian adaptive mutations of H5 HPAIVs , including the H5N1 epidemic in dairy cattle in the United States , is an issue to watch for the potential emergence of a human pandemic virus.
- Given the importance of pigs as mixing vessels it will be important to continue to maintain sustained surveillance of swine populations for avian-like and other host adapted influenza viruses.
Reference: Toshihiro Ito Pathogenicity and host range of avian influenza viruses: molecular determinants and virological perspectives J Vet Med Sci . 2025 Sep 16. doi: 10.1292/jvms.25-0313. Online ahead of print.
