Genetically engineered chickens (partially) resist influenza

Avian influenza outbreaks regularly devastate the poultry industry and potentially threaten people, so scientists have long sought ways to alter the genes of birds to protect them from influenza viruses. Now, researchers have taken an impressive step forward: their genetically edited chickens resisted direct infection with influenza viruses[1]. But not quite.

The researchers focused on a gene that is key to enabling avian influenza viruses to grow in chicken but not, typically, human cells. The gene codes for a protein, ANP32A, that normally plays a role in transcribing DNA into messenger RNA. The chicken ANP32A has 33 more amino acids than the human version, and an avian influenza enzyme called polymerase can co-opt it to make new virions.

The researchers also found chickens have a second gene for the same protein, ANP32B, that lacks this vulnerability. The virus can’t exploit its protein because it differs in two amino acids from ANP32A. So for the new work, they used CRISPR to introduce those mutations into the ANP32A gene in chicken primordial germ cells—the precursors of eggs and sperm—paving the way to breed chicks with the desired mutations. The altered birds appeared healthy.

To see whether they could resist infection, the researchers put an avian influenza virus into the nostrils of 20 2-week-old chicks, only half of which had the modified gene. All the wild-type birds became infected, but only one of the 10 genetically edited ones. That infected bird did not transmit to other birds with the resistance gene, further work showed. However, when the researchers inoculated them with 1000-fold higher doses of the virus, all became infected.

An analysis of the viruses that grew in the 'modified' birds revealed something more disturbing: mutations in their polymerase genes. The mutations allowed the enzyme to still get some help from the edited ANP32A protein and also from ANP32B and a third member of the same family, ANP32E, which like ANP32B typically plays no role in influenza replication.

Scientist now are worried that there is a 'high probability' that, if mutant viruses arise because of gene edits in chickens, they will be better adapted to mammals as well.

[1] Idoko-Akoh et al: Creating resistance to avian influenza infection through genome editing of the ANP32 gene family in Nature Communications - 2023. See here.