The Bird Flu game

Wild animals harbor many diseases, and it is common for them to be infected with multiple types of influenza A viruses. In fact, birds are endemic to bird flu in many areas in the world. And every now and then, a variant is able to jump to our farmed poultry. Since the beginning of this year, over 36.28 million poultry in the US needed to be culled due to an infection with H5N1 bird flu (1). That’s roughly equivalent to the entire population of Canada. But even more surprising, bird flu has found its way into cows in 2023. A recent preprint shows 90% seroprevalence in a dairy herd where only a subset showed signs of disease (2). This cattle outbreak came as a surprise to many and it remains largely a mystery how a traditionally avian pathogen acquired the capacity to infect mammals with increasing efficiency.

Reassortment: the very high stakes trading card game of viruses

Imagine influenza viruses as players in a high-stakes trading card game. In this game, players build customized decks from different types of cards - Energy cards, Trainer cards, and various other cards with unique abilities. Success often depends on finding powerful card combinations that work well together.

Similarly, the influenza virus has eight mRNA strands (PB1, PB2, PA, NP, HA, NA, and M and NS) that come together in a carefully constructed deck.

  • HA (Hemagglutinin) - an Attack card with a powerful attack move, this segment allows the virus to attach to and enter host cells
  • NA (Neuraminidase) - a card with a special ability that allows escape, this helps newly formed viruses break free from infected cells
  • PB2, PB1, PA - an Energy card, powering the virus’s replication machinery
  • NP, M, NS - Trainer cards and Support cards, providing structural elements and interfering with host defenses

Just these eight pieces (cards) make up all of the virus’ genetic information, encoding for proteins that facilitate infection, replication, and transmission.

So, while at its molecular foundation, the influenza virus is quite simple, this segmented genomic architecture harbors the key to avian influenza’s remarkable evolutionary potential. When multiple influenza viruses co-infect an animal, they engage in ‘reassortment’- essentially a viral version of trading cards. Just as Pokemon or Magic players might trade cards to create more powerful decks with new combinations of abilities, viruses can exchange genetic segments, although more so by accident than by intent. This can create functioning viruses with novel combinations with the potential of increased transmissibility, host range expansion, and immune evasion.

Understanding the game

Bird Flu (Avian Influenza) is caused by an Influenza A subtype. There are 4 major Influenza viruses (types), A,B,C,D. Influenza A are further classified into subtypes based on hemagglutinin (H) and neuraminidase (N) genes, then into clades (e.g. 2.4.4b) and genotypes (e.g. B3.13). The H5N1 2.3.4b clade is particularly concerning, as it kept the H5 ‘Attack card’ which most human immune systems have never encountered before. The virus is classified as a highly pathogenic avian influenza - death of infected poultry is inevitable, which is driving the culling. The current US bird flu outbreak is caused by Influenza A H5N1 (A/H5N1), and the longer it continues, the longer ‘blind trades’ continue to occur, increasing the chance of acquiring the ultimate deck.

In order to stop this game, it is quite important to understand this game better.

  • First, It is important to study host range - who is playing the game? H5N1 has a host range broader than ever seen before: cats, mink, seals, zoo animals, cattle and … humans. Transmission - ie trading activity - is still difficult to observe, and we continue to struggle identifying major reservoirs. Because of this, the H5N1 virus is regarded as the world’s strongest pandemic threat.
  • Second it is important to trace the card deck trades. The current (April 2025) genotypes D1.1 and B3.13 that circulate in mammals are genetically different and evolved both separately to somehow end up in the same hosts. What drives this?

Building the ultimate deck

By visualizing what we know of the game, we can trace H5N1’s remarkable evolutionary trajectory from its origins through multiple reassortment events that eventually led to strains capable of sustained transmission in dairy cattle and marine mammals.

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Sources

https://www.cdc.gov/bird-flu/avian-timeline/2010-2019.html https://journals.asm.org/doi/10.1128/jvi.01401-23 http://doi.org/10.1016/j.virol.2023.109860 https://doi.org/10.3201/eid2304.161668 https://www.aphis.usda.gov/sites/default/files/dairy-cattle-hpai-tech-brief.pdf