{"doi":"10.1101/2020.08.11.246314","title":"K18-hACE2 mice develop respiratory disease resembling severe COVID-19","abstract":"Abstract SARS-CoV-2 emerged in late 2019 and resulted in the ongoing COVID-19 pandemic. Several animal models have been rapidly developed that recapitulate the asymptomatic to moderate disease spectrum. Now, there is a direct need for additional small animal models to study the pathogenesis of severe COVID-19 and for fast-tracked medical countermeasure development. Here, we show that transgenic mice expressing the human SARS-CoV-2 receptor (angiotensin-converting enzyme 2 [hACE2]) under a cytokeratin 18 promoter (K18) are susceptible to SARS-CoV-2 and that infection resulted in a dose-dependent lethal disease course. After inoculation with either 10 4 TCID 50 or 10 5 TCID 50 , the SARS-CoV-2 infection resulted in rapid weight loss in both groups and uniform lethality in the 10 5 TCID 50 group. High levels of viral RNA shedding were observed from the upper and lower respiratory tract and intermittent shedding was observed from the intestinal tract. Inoculation with SARS-CoV-2 resulted in upper and lower respiratory tract infection with high infectious virus titers in nasal turbinates, trachea and lungs. The observed interstitial pneumonia and pulmonary pathology, with SARS-CoV-2 replication evident in pneumocytes, were similar to that reported in severe cases of COVID-19. SARS-CoV-2 infection resulted in macrophage and lymphocyte infiltration in the lungs and upregulation of Th1 and proinflammatory cytokines/chemokines. Extrapulmonary replication of SARS-CoV-2 was observed in the cerebral cortex and hippocampus of several animals at 7 DPI but not at 3 DPI. The rapid inflammatory response and observed pathology bears resemblance to COVID-19. Taken together, this suggests that this mouse model can be useful for studies of pathogenesis and medical countermeasure development. Authors Summary The disease manifestation of COVID-19 in humans range from asymptomatic to severe. While several mild to moderate disease models have been developed, there is still a need for animal models that recapitulate the severe and fatal progression observed in a subset of patients. Here, we show that humanized transgenic mice developed dose-dependent disease when inoculated with SARS-CoV-2, the etiological agent of COVID-19. The mice developed upper and lower respiratory tract infection, with virus replication also in the brain after day 3 post inoculation. The pathological and immunological diseases manifestation observed in these mice bears resemblance to human COVID-19, suggesting increased usefulness of this model for elucidating COVID-19 pathogenesis further and testing of countermeasures, both of which are urgently needed.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":118771,"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":42,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9509,"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":107164,"name":"Julia R. Port","orcid":"0000-0002-0489-6591","position":1,"is_corresponding":false},{"id":107166,"name":"Trenton Bushmaker","orcid":"0000-0002-2161-4808","position":2,"is_corresponding":false},{"id":552055,"name":"Irene Owusu Donkor","orcid":"0000-0002-8523-955X","position":3,"is_corresponding":false},{"id":107165,"name":"Victoria A. Avanzato","orcid":"0000-0001-5758-8624","position":4,"is_corresponding":false},{"id":237180,"name":"Robert J. Fischer","orcid":"0000-0002-1816-472X","position":5,"is_corresponding":false},{"id":107172,"name":"Jonathan E. Schulz","orcid":"0000-0001-5462-5952","position":6,"is_corresponding":false},{"id":107173,"name":"Myndi G. Holbrook","orcid":"0000-0003-2376-2633","position":7,"is_corresponding":false},{"id":552056,"name":"Madison J. Hebner","orcid":"0000-0002-4415-762X","position":8,"is_corresponding":false},{"id":107182,"name":"Rebecca Rosenke","orcid":"0000-0003-3779-7423","position":9,"is_corresponding":false},{"id":339483,"name":"Tina Thomas","orcid":"0000-0001-6417-8076","position":10,"is_corresponding":false},{"id":329012,"name":"Andrea Marzi","orcid":"0000-0003-0186-9587","position":11,"is_corresponding":false},{"id":254592,"name":"Sonja M. Best","orcid":"0000-0003-0206-297X","position":12,"is_corresponding":false},{"id":106696,"name":"Emmie de Wit","orcid":"0000-0002-9763-7758","position":13,"is_corresponding":false},{"id":552057,"name":"Carl Shaia","orcid":"0000-0001-8907-8821","position":14,"is_corresponding":false},{"id":107159,"name":"Neeltje van Doremalen","orcid":"0000-0003-4368-6359","position":15,"is_corresponding":false},{"id":107194,"name":"Vincent J. Munster","orcid":"0000-0002-2288-3196","position":16,"is_corresponding":false},{"id":108653,"name":"Claude Kwe Yinda","orcid":"0000-0002-5195-5478","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-18T23:14:03.409507Z","pmid":"32803199","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":[]}