The recent spillover and spread of H5N1 clade 2.3.4.4b avian influenza viruses (AIVs) in dairycattle is unprecedented and marks a concerning expansion of the virus’s mammalian hostrange. AIVs typically replicate poorly in mammals, in part due to host antiviral defences suchas type I and III interferon (IFN) responses and the induction of interferon-stimulated genes(ISGs). Understanding how H5N1 genotypes interact with bovine antiviral defences isimportant for assessing their replication potential in cattle and risk of onward transmissionto other mammalian species. Using a panel of recombinant IAVs bearing internal geneconstellations from diverse clade 2.3.4.4b genotypes, we assessed viral sensitivity to thebovine IFN-ISG response. We confirmed MX1 induction in bovine udder tissue followinginfection with recombinant A/Texas/37/2024 and demonstrated that all 2.3.4.4breassortants were restricted by bovine MX1 and human MxA. Bovine-adapted virusesexhibited enhanced modulation of the IFN response, characterised by stronger host cellshutoff and reduced activation of IFN signalling compared to their avian ancestors. Segmentswap experiments revealed that the PB2, NP and NS segments of bovine-derived B3.13 allcontribute to this phenotype. Interestingly, genotype EA-2022-BB, which has infected furfarm animals, showed similar IFN modulation to the bovine-adapted viruses. Furthermore,most 2.3.4.4b viruses tested escaped human BTN3A3 restriction, one of the human geneticbarriers to avian IAVs. Together these findings reveal that clade 2.3.4.4b viruses, includingthose that spilled into cattle, are evolving stronger suppression of host antiviral defences,increasing the pool of IAVs with zoonotic potential.
Influence of H5N1 2.3.4.4b Internal Gene Constellations in Modulationof Host Antiviral Defences in Bovine Cells
Muhammad Ahsan Yaseen;
2026-01-01
Abstract
The recent spillover and spread of H5N1 clade 2.3.4.4b avian influenza viruses (AIVs) in dairycattle is unprecedented and marks a concerning expansion of the virus’s mammalian hostrange. AIVs typically replicate poorly in mammals, in part due to host antiviral defences suchas type I and III interferon (IFN) responses and the induction of interferon-stimulated genes(ISGs). Understanding how H5N1 genotypes interact with bovine antiviral defences isimportant for assessing their replication potential in cattle and risk of onward transmissionto other mammalian species. Using a panel of recombinant IAVs bearing internal geneconstellations from diverse clade 2.3.4.4b genotypes, we assessed viral sensitivity to thebovine IFN-ISG response. We confirmed MX1 induction in bovine udder tissue followinginfection with recombinant A/Texas/37/2024 and demonstrated that all 2.3.4.4breassortants were restricted by bovine MX1 and human MxA. Bovine-adapted virusesexhibited enhanced modulation of the IFN response, characterised by stronger host cellshutoff and reduced activation of IFN signalling compared to their avian ancestors. Segmentswap experiments revealed that the PB2, NP and NS segments of bovine-derived B3.13 allcontribute to this phenotype. Interestingly, genotype EA-2022-BB, which has infected furfarm animals, showed similar IFN modulation to the bovine-adapted viruses. Furthermore,most 2.3.4.4b viruses tested escaped human BTN3A3 restriction, one of the human geneticbarriers to avian IAVs. Together these findings reveal that clade 2.3.4.4b viruses, includingthose that spilled into cattle, are evolving stronger suppression of host antiviral defences,increasing the pool of IAVs with zoonotic potential.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
