#14,524
Influenza A viruses, being negative-sense single-stranded segmented RNA viruses, are prolific but notoriously sloppy replicators. They make millions of copies of themselves when they infect a host, but in the process, often make small transcription errors.
Most of these `errors' do little to help the virus, and many can be detrimental to its survival.Given the massive number of viruses generated, occasionally these errors can accidentally favor replication in the host, and enable the virus to go on to produce more progeny. If they are biologically `fit' enough, they can even drown out the earlier `wild type’ virus in the host.
This process is called host adaptation, and while it can (and does) happen in the wild, it can be easily simulated in the laboratory as well via a classic serial passage study (see graphic at top of blog).
Essentially, you inoculate a host (mouse, ferret, guinea pig, etc.) with a `wild type’ strain of a virus - let it replicate for awhile - then take the virus from the first host and inoculate a second, and then repeat the process five, ten, fifteen times or more.Over time, the virus tends to adapt to the new host (assuming there are no species barriers to prevent it), often increasing replication, virulence, and/or transmissibility.
This is one of the reasons why - when dealing with a spillover of a novel virus into a new species (including humans) - we look for signs of clusters or chains of infection. The more times a novel virus successfully jumps from one host to the next, the more likely it is to accrue host adaptations.
As we've discussed often (and most recently just 2 days ago in Viruses: Characterization of the H9N2 Avian Influenza Viruses Currently Circulating in South China), LPAI H9N2 continues to show worrisome signs of mammalian adaptation.While its relatively low severity in humans doesn't put H9N2 at the very top of our pandemic threats list, it is still regarded as having at least some pandemic potential (see CDC IRAT SCORE), and several candidate vaccines have been developed.
And if we've learned anything about novel viruses over the past 20 years or so, it is that little genetic changes can bring about large changes in viral behavior. A small number of amino acid substitutions can turn a relatively docile virus into a deadly one.All of which brings us to a new, open-access report published in the Virology Journal that looks at the host adaptations that occur in two different (G1 & ZB) LPAI H9N2 viruses after being serially passaged through mice.
While the wild-type G1 & ZB viruses were practically avirulent in mice, by the 9th passage, all of the G1 infected mice died at 6 dpi (days post infection), while after 14 passages, all of the ZB infected mice died at 5 dpi.I've only posted excerpts from the Abstract below, so you'll want to follow the link to read the report in full. I'll have a brief postscript when you return.
Mouse-adapted H9N2 avian influenza virus causes systemic infection in mice
Zhe Hu, Yiran Zhang, Zhen Wang, Jingjing Wang, Qi Tong, Mingyang Wang, Honglei Sun, Juan Pu, Changqing Liu, Jinhua Liu & Yipeng Sun
Virology Journal volume 16, Article number: 135 (2019)
Abstract
Background
H9N2 influenza viruses continuously circulate in multiple avian species and are repeatedly transmitted to humans, posing a significant threat to public health. To investigate the adaptation ability of H9N2 avian influenza viruses (AIVs) to mammals and the mutations related to the host switch events, we serially passaged in mice two H9N2 viruses of different HA lineages — A/Quail/Hong Kong/G1/97 (G1) of the G1-like lineage and A/chicken/Shandong/ZB/2007 (ZB) of the BJ/94-like lineage —and generated two mouse-adapted H9N2 viruses (G1-MA and ZB-MA) that possessed significantly higher virulence than the wide-type viruses.
Finding
ZB-MA replicated systemically in mice. Genomic sequence alignment revealed 10 amino acid mutations coded by 4 different gene segments (PB2, PA, HA, and M) in G1-MA compared with the G1 virus and 23 amino acid mutations in 5 gene segments (PB1, PA, HA, M, and NS) in ZB-MA compared to ZB virus, indicating that the mutations in the polymerase, HA, M, and NS genes play critical roles in the adaptation of H9N2 AIVs to mammals, especially, the mutations of M1-Q198H and M1-A239T were shared in G1-MA and ZB-MA viruses. Additionally, several substitutions showed a higher frequency in human influenza viruses compared with avian viruses.
ConclusionsThe saving grace of LPAI H9N2 has been that it rarely produces severe illness in humans, and it is believed that any pandemic it might spark would likely be moderate in severity.
Different lineages of H9N2 could adapt well in mice and some viruses could gain the ability to replicate systemically and become neurovirulent. Thus, it is essential to pay attention to the mammalian adaptive evolution of the H9N2 virus.
And despite these findings (which are, after all, only in mice), that may still hold true.But this study does show the H9N2 subtype is capable of gaining in virulence as it adapts to a mammalian host, and that should give us pause. Add in the fact that H9N2 reassorts easily (and often) with other flu viruses, and its adaptability to mammalian hosts becomes even more of a concern.
Given these serial passage experiments were performed on two older lineages (G1 & BJ/94) of the H9N2 virus, and this week's other H9N2 study looked at a newer (Y280) lineage currently circulating in China, it would be very interesting to see this experiment repeated with newer Y280-like viruses.
