{"doi":"10.1016/j.ebiom.2024.105361","title":"Influence of Th1 versus Th2 immune bias on viral, pathological, and immunological dynamics in SARS-CoV-2 variant-infected human ACE2 knock-in mice","abstract":"BACKGROUND: Mouse models that recapitulate key features of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection are important tools for understanding complex interactions between host genetics, immune responses, and SARS-CoV-2 pathogenesis. Little is known about how predominantly cellular (Th1 type) versus humoral (Th2 type) immune responses influence SARS-CoV-2 dynamics, including infectivity and disease course. METHODS: We generated knock-in (KI) mice expressing human ACE2 (hACE2) and/or human TMPRSS2 (hTMPRSS2) on Th1-biased (C57BL/6; B6) and Th2-biased (BALB/c) genetic backgrounds. Mice were infected intranasally with SARS-CoV-2 Delta (B.1.617.2) or Omicron BA.1 (B.1.1.529) variants, followed by assessment of disease course, respiratory tract infection, lung histopathology, and humoral and cellular immune responses. FINDINGS: In both B6 and BALB/c mice, hACE2 expression was required for infection of the lungs with Delta, but not Omicron BA.1. Disease severity was greater in Omicron BA.1-infected hTMPRSS2-KI and double-KI BALB/c mice compared with B6 mice, and in Delta-infected double-KI B6 and BALB/c mice compared with hACE2-KI mice. hACE2-KI B6 mice developed more severe lung pathology and more robust SARS-CoV-2-specific splenic CD8 T cell responses compared with hACE2-KI BALB/c mice. There were no notable differences between the two genetic backgrounds in plasma cell, germinal center B cell, or antibody responses to SARS-CoV-2. INTERPRETATION: SARS-CoV-2 Delta and Omicron BA.1 infection, disease course, and CD8 T cell response are influenced by the host genetic background. These humanized mice hold promise as important tools for investigating the mechanisms underlying the heterogeneity of SARS-CoV-2-induced pathogenesis and immune response. FUNDING: This work was funded by NIH U19 AI142790-02S1, the GHR Foundation, the Arvin Gottleib Foundation, and the Overton family (to SS and EOS); Prebys Foundation (to SS); NIH R44 AI157900 (to KJ); and by an American Association of Immunologists Career Reentry Fellowship (FASB).","journal":"EBioMedicine","year":2024,"id":439120,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9569,"is_data_producer":false,"deposit_databanks":null,"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":869397,"name":"Fernanda Ana‐Sosa‐Batiz","orcid":null,"position":1,"is_corresponding":false},{"id":1133059,"name":"Julia Timis","orcid":null,"position":2,"is_corresponding":false},{"id":868862,"name":"Norazizah Shafee","orcid":"0000-0002-6877-7612","position":3,"is_corresponding":false},{"id":458039,"name":"Erin Maule","orcid":null,"position":4,"is_corresponding":false},{"id":1214302,"name":"Paolla Beatriz Almeida Pinto","orcid":null,"position":5,"is_corresponding":false},{"id":1250380,"name":"Chris Conner","orcid":null,"position":6,"is_corresponding":false},{"id":353877,"name":"Kristen Valentine","orcid":"0000-0003-0662-3076","position":7,"is_corresponding":false},{"id":373874,"name":"Dale O. Cowley","orcid":"0000-0001-5697-5817","position":8,"is_corresponding":false},{"id":280469,"name":"Robyn L. Miller","orcid":"0000-0002-4679-7567","position":9,"is_corresponding":false},{"id":353880,"name":"Annie Elong Ngono","orcid":"0000-0002-6741-3518","position":10,"is_corresponding":false},{"id":1146845,"name":"Linda Tran","orcid":"0000-0002-7356-2878","position":11,"is_corresponding":false},{"id":1250381,"name":"Krithik Varghese","orcid":null,"position":12,"is_corresponding":false},{"id":353878,"name":"Rúbens Prince dos Santos Alves","orcid":"0000-0001-5538-6025","position":13,"is_corresponding":false},{"id":103730,"name":"Kathryn M. Hastie","orcid":"0000-0002-3406-1210","position":14,"is_corresponding":false},{"id":104945,"name":"Erica Ollmann Saphire","orcid":"0000-0002-1206-7451","position":15,"is_corresponding":false},{"id":1250382,"name":"David R. Webb","orcid":null,"position":16,"is_corresponding":false},{"id":1250383,"name":"Kurt Jarnagin","orcid":null,"position":17,"is_corresponding":false},{"id":325228,"name":"Kenneth Kim","orcid":"0000-0002-5993-4575","position":18,"is_corresponding":false},{"id":290791,"name":"Sujan Shresta","orcid":"0000-0003-2906-8474","position":19,"is_corresponding":false},{"id":859278,"name":"Shailendra Kumar Verma","orcid":"0000-0001-9142-3022","position":0,"is_corresponding":true}],"reference_count":67,"raw_metadata":null,"created_at":"2026-07-19T02:00:47.992543Z","pmid":"39353281","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":[]}