{"doi":"10.1101/2020.07.09.196188","title":"SARS-CoV-2 infection in the lungs of human ACE2 transgenic mice causes severe inflammation, immune cell infiltration, and compromised respiratory function","abstract":"Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) emerged in late 2019 and has spread worldwide resulting in the Coronavirus Disease 2019 (COVID-19) pandemic. Although animal models have been evaluated for SARS-CoV-2 infection, none have recapitulated the severe lung disease phenotypes seen in hospitalized human cases. Here, we evaluate heterozygous transgenic mice expressing the human ACE2 receptor driven by the epithelial cell cytokeratin-18 gene promoter (K18-hACE2) as a model of SARS-CoV-2 infection. Intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice results in high levels of viral infection in lung tissues with additional spread to other organs. Remarkably, a decline in pulmonary function, as measured by static and dynamic tests of respiratory capacity, occurs 4 days after peak viral titer and correlates with an inflammatory response marked by infiltration into the lung of monocytes, neutrophils, and activated T cells resulting in pneumonia. Cytokine profiling and RNA sequencing analysis of SARS-CoV-2-infected lung tissues show a massively upregulated innate immune response with prominent signatures of NF-kB-dependent, type I and II interferon signaling, and leukocyte activation pathways. Thus, the K18-hACE2 model of SARS-CoV-2 infection recapitulates many features of severe COVID-19 infection in humans and can be used to define the mechanistic basis of lung disease and test immune and antiviral-based countermeasures.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":118733,"datarank":0.5709993734655481,"base_score":3.8066624897703196,"endowment":3.8066624897703196,"self_citation_contribution":0.5709993734655481,"citation_network_contribution":0.0,"self_endowment_contribution":0.5709993734655481,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":44,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9588,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":107150,"name":"Adam L. Bailey","orcid":"0000-0002-6560-9680","position":1,"is_corresponding":false},{"id":106513,"name":"Natasha M. Kafai","orcid":"0000-0002-3115-3400","position":2,"is_corresponding":false},{"id":107151,"name":"Sharmila Nair","orcid":null,"position":3,"is_corresponding":false},{"id":106524,"name":"Broc T. McCune","orcid":"0000-0002-8342-5316","position":4,"is_corresponding":false},{"id":107152,"name":"Jinsheng Yu","orcid":"0000-0003-3377-4304","position":5,"is_corresponding":false},{"id":106515,"name":"Julie M. Fox","orcid":"0000-0003-0567-738X","position":6,"is_corresponding":false},{"id":106500,"name":"Rita E. Chen","orcid":"0000-0002-5100-7750","position":7,"is_corresponding":false},{"id":107153,"name":"James T. Earnest","orcid":"0000-0002-5904-8733","position":8,"is_corresponding":false},{"id":106525,"name":"Shamus P. Keeler","orcid":"0000-0002-1301-0852","position":9,"is_corresponding":false},{"id":107154,"name":"Jon H. Ritter","orcid":"0009-0003-4514-6935","position":10,"is_corresponding":false},{"id":107155,"name":"Liang‐I Kang","orcid":"0000-0001-7025-3095","position":11,"is_corresponding":false},{"id":107156,"name":"Sarah Dort","orcid":null,"position":12,"is_corresponding":false},{"id":107157,"name":"Annette Robichaud","orcid":null,"position":13,"is_corresponding":false},{"id":107158,"name":"Richard D. Head","orcid":"0000-0002-6865-1542","position":14,"is_corresponding":false},{"id":106526,"name":"Michael J. Holtzman","orcid":"0000-0001-8750-3716","position":15,"is_corresponding":false},{"id":106529,"name":"Michael Diamond","orcid":"0000-0002-8791-3165","position":16,"is_corresponding":false},{"id":106514,"name":"Emma S. Winkler","orcid":"0000-0001-8510-1385","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:14:03.409507Z","pmid":"32676600","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":[]}