{"doi":"10.1038/s42003-024-06928-6","title":"Modulation of human-to-swine influenza a virus adaptation by the neuraminidase low-affinity calcium-binding pocket","abstract":"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 (Ca2+) binding in the low-affinity Ca2+-binding pocket of NA, enhancing enzymatic activity and thermostability under Ca2+-depleted conditions, mirroring swine-origin FLUAV NA behavior. Structural analysis predicts that swine-adapted H3N2 viruses lack Ca2+ binding in this pocket. Further, residue 93 in NA (G93 in human, N93 in swine) also influences Ca2+ 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 Ca2+ binding in the low-affinity calcium-binding pocket. Modulation of calcium binding in the neuraminidase low-affinity calcium-binding pocket suggests a novel role of calcium during cross-species transmission of Influenza A viruses.","journal":"Communications Biology","year":2024,"id":443383,"datarank":0.3472268089834597,"base_score":2.1972245773362196,"endowment":2.1972245773362196,"self_citation_contribution":0.32958368660043297,"citation_network_contribution":0.017643122383026743,"self_endowment_contribution":0.32958368660043297,"citer_contribution":0.017643122383026743,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":5,"citers_with_citation_signal":2,"citers_with_endowment":2,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9552,"is_data_producer":true,"deposit_databanks":{"BioProject":["PRJNA1117070"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":655212,"name":"Brittany Seibert","orcid":"0000-0002-5721-5382","position":1,"is_corresponding":false},{"id":911382,"name":"Brianna Cowan","orcid":"0000-0002-1493-3878","position":2,"is_corresponding":false},{"id":655209,"name":"C. Joaquín Cáceres","orcid":"0000-0001-8508-6592","position":3,"is_corresponding":false},{"id":996229,"name":"L. Claire Gay","orcid":"0000-0003-4360-0519","position":4,"is_corresponding":false},{"id":996228,"name":"Flavio Cargnin Faccin","orcid":"0000-0002-5006-5182","position":5,"is_corresponding":false},{"id":399634,"name":"Daniel R. Pérez","orcid":"0000-0002-6569-5689","position":6,"is_corresponding":false},{"id":896342,"name":"Amy L. Vincent","orcid":"0000-0002-4953-7285","position":7,"is_corresponding":false},{"id":347379,"name":"Tavis K. Anderson","orcid":"0000-0002-3138-5535","position":8,"is_corresponding":false},{"id":655213,"name":"Daniela S. Rajão","orcid":"0000-0002-0772-0065","position":9,"is_corresponding":false},{"id":911381,"name":"Matías Cárdenas","orcid":"0000-0001-8247-3669","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":null,"created_at":"2026-07-19T02:01:24.471942Z","pmid":"39354058","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}