tetano
Editor, Senior Moderator
Commun Biol
. 2024 Oct 1;7(1):1230.
doi: 10.1038/s42003-024-06928-6. Modulation of human-to-swine influenza a virus adaptation by the neuraminidase low-affinity calcium-binding pocket
Matias Cardenas[SUP] 1 [/SUP], Brittany Seibert[SUP] 1 2 [/SUP], Brianna Cowan[SUP] 1 [/SUP], C Joaquin Caceres[SUP] 1 [/SUP], L Claire Gay[SUP] 1 [/SUP], Flavio Cargnin Faccin[SUP] 1 [/SUP], Daniel R Perez[SUP] 1 [/SUP], Amy L Baker[SUP] 3 [/SUP], Tavis K Anderson[SUP] 3 [/SUP], Daniela S Rajao[SUP] 4 [/SUP]
Affiliations
Frequent interspecies transmission of human influenza A viruses (FLUAV) to pigs contrasts with the limited subset that establishes in swine. While hemagglutinin mutations are recognized for their role in cross-species transmission, the contribution of neuraminidase remains understudied. Here, the NA's role in FLUAV adaptation was investigated using a swine-adapted H3N2 reassortant virus with human-derived HA and NA segments. Adaptation in pigs resulted in mutations in both HA (A138S) and NA (D113A). The D113A mutation abolished calcium (Ca[SUP]2+[/SUP]) binding in the low-affinity Ca[SUP]2+[/SUP]-binding pocket of NA, enhancing enzymatic activity and thermostability under Ca[SUP]2+[/SUP]-depleted conditions, mirroring swine-origin FLUAV NA behavior. Structural analysis predicts that swine-adapted H3N2 viruses lack Ca[SUP]2+[/SUP] binding in this pocket. Further, residue 93 in NA (G93 in human, N93 in swine) also influences Ca[SUP]2+[/SUP] binding and impacts NA activity and thermostability, even when D113 is present. These findings demonstrate that mutations in influenza A virus surface proteins alter evolutionary trajectories following interspecies transmission and reveal distinct mechanisms modulating NA activity during FLUAV adaptation, highlighting the importance of Ca[SUP]2+[/SUP] binding in the low-affinity calcium-binding pocket.
. 2024 Oct 1;7(1):1230.
doi: 10.1038/s42003-024-06928-6. Modulation of human-to-swine influenza a virus adaptation by the neuraminidase low-affinity calcium-binding pocket
Matias Cardenas[SUP] 1 [/SUP], Brittany Seibert[SUP] 1 2 [/SUP], Brianna Cowan[SUP] 1 [/SUP], C Joaquin Caceres[SUP] 1 [/SUP], L Claire Gay[SUP] 1 [/SUP], Flavio Cargnin Faccin[SUP] 1 [/SUP], Daniel R Perez[SUP] 1 [/SUP], Amy L Baker[SUP] 3 [/SUP], Tavis K Anderson[SUP] 3 [/SUP], Daniela S Rajao[SUP] 4 [/SUP]
Affiliations
- PMID: 39354058
- PMCID: PMC11445579
- DOI: 10.1038/s42003-024-06928-6
Frequent interspecies transmission of human influenza A viruses (FLUAV) to pigs contrasts with the limited subset that establishes in swine. While hemagglutinin mutations are recognized for their role in cross-species transmission, the contribution of neuraminidase remains understudied. Here, the NA's role in FLUAV adaptation was investigated using a swine-adapted H3N2 reassortant virus with human-derived HA and NA segments. Adaptation in pigs resulted in mutations in both HA (A138S) and NA (D113A). The D113A mutation abolished calcium (Ca[SUP]2+[/SUP]) binding in the low-affinity Ca[SUP]2+[/SUP]-binding pocket of NA, enhancing enzymatic activity and thermostability under Ca[SUP]2+[/SUP]-depleted conditions, mirroring swine-origin FLUAV NA behavior. Structural analysis predicts that swine-adapted H3N2 viruses lack Ca[SUP]2+[/SUP] binding in this pocket. Further, residue 93 in NA (G93 in human, N93 in swine) also influences Ca[SUP]2+[/SUP] binding and impacts NA activity and thermostability, even when D113 is present. These findings demonstrate that mutations in influenza A virus surface proteins alter evolutionary trajectories following interspecies transmission and reveal distinct mechanisms modulating NA activity during FLUAV adaptation, highlighting the importance of Ca[SUP]2+[/SUP] binding in the low-affinity calcium-binding pocket.