Influenza A viruses are a common concern among many animal species, including birds, horses, pigs, and humans and the effects can range from asymptomatic to severe respiratory injury leading to death.
The low fidelity of the genome-replication machinery – together with the segmented nature of the influenza virus genome – allows the rapid emergence of various pathogenic variants of these viruses, as well as their transmission to new hosts. During the 20th and 21st-centuries, humans have experienced four pandemics caused by new influenza viruses:
- Spanish influenza in 1918, in which the causative agent was an avian-origin virus of the H1N1 subtype;
- Asian influenza in 1957, where the pandemic virus was a mixture of human and avian viruses
- Hong Kong influenza in 1968, where again the hemagglutinin and other genes were of avian origin; and
- the 2009–2010 swine flu pandemic, which began in April 2009, with outbreaks in Mexico and the US, before spreading globally. Again this pandemic virus was a reassortment between the classical swine and avian viruses.
So, the viruses responsible for each of these pandemics were derived from avian or swine influenza viruses that mutated to allow human-to-human transmission. Therefore, looking ahead, an improved understanding of how avian influenza viruses can be transmitted to cohabitating species can enhance our ability to develop accurate models for disease spread and develop control strategies.
What stops viruses from jumping between species all of the time?
There are multiple obstacles that a virus must overcome to jump species. For example, polymerases from avian strains are considerably less active in mammalian cells than their counterparts from mammalian-adapted strains in humans. Also, there are differences in the receptor-binding specificities of human and avian influenza viruses; therefore, the hemagglutinin of avian influenza viruses must adapt to human receptors to achieve efficient human-to-human transmissibility. These barriers (also known as host range determinants) make it difficult for an avian influenza virus to infect and propagate in human cells. However, the molecular basis of the avian-human species barrier is incompletely understood.
M segment splicing as a host range determinant
In their recent work, Bogdanow et al. describe a novel mechanism that makes the leap from bird to humans much less likely. The researchers infected human pulmonary epithelial cells with either bird-adapted or human-adapted flu viruses and compared what happened. By mass spectrometry, the authors measured the quantity of all newly produced proteins in the virus infected cells and found that the bird-adapted strain produced much less of the matrix protein M1 compared to the human-adapted strain.
What’s the role of M1?
M1 protein binds to the viral RNA via a peptide sequence rich in basic amino acids. Among other fundamental roles in virus morphology and assembly, M1 is involved in the export of the replicated viral RNA from the host cell nucleus of the infected cells. At this point, M1 can then combine this viral RNA with other viral proteins to form flu virus offspring.
Why does bird-adapted flu produce less M1 in human cells?
Bogdanow et al. investigated the mechanism underlying this impaired M1 production and, as the culprit, identified increased splicing of the M segment RNA by the bird-adapted strains in the human cells. They found that the cis-regulatory secondary structure in the avian M segment causes excessive splicing. This leads to the underproduction of M1 mRNA and protein in human cells infected with avian-adapted IAVs. This poor availability of the M1 protein likely contributes to an impaired nuclear export of viral ribonucleoproteins. Indeed, when the team transferred the cis-regulatory element from the bird virus to the human virus, this resulted in the human-adapted flu virus replicating less effectively in human lung cells.
Next, comparing chicken to human lung cells, the authors report that the level of M1 was much higher in chicken. This result suggests that the reduced M1 production of avian viruses in human cells reflects poor adaptation to the mammalian splicing environment.
What does all this mean?
Basically, the genetic material of the bird-adapted flu virus was far less capable of breaking out of the cell nucleus than the RNA of the human flu virus. The viral RNA of bird flu viruses in human cells remains trapped in the cell’s nucleus because there is too little M1 protein present.
The importance of understanding the avian origins of pandemic influenza
Bogdanow et al. underline the importance of their contribution to the literature by reminding us that we continue to live through a pandemic era of IAV infections. This began ~1918 when an avian virus acquired the ability to spread among humans. To this day, this pioneer avian flu continues to contribute genetic material to pandemic flues.
Any insights into how bird flus manage to jump to humans are certain to be extremely useful as we encounter future pandemics.
