biostudies-literatureRobertson SJIntramural NIH HHSDivision of Intramural Research, National Institute of Allergy and Infectious Diseases4481https://www.ebi.ac.uk/biostudies/studies/S-EPMC10368652biostudies-literatureUnknown14(1)Inflammation in response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection drives severity of coronavirus disease 2019 (COVID-19) and is influenced by host genetics. To understand mechanisms of inflammation, animal models that reflect genetic diversity and clinical outcomes observed in humans are needed. We report a mouse panel comprising the genetically diverse Collaborative Cross (CC) founder strains crossed to human ACE2 transgenic mice (K18-hACE2) that confers susceptibility to SARS-CoV-2. Infection of CC x K18-hACE2 resulted in a spectrum of survival, viral replication kinetics, and immune profiles. Importantly, in contrast to the K18-hACE2 model, early type I interferon (IFN-I) and regulated proinflammatory responses were required for control of SARS-CoV-2 repNature communicationsGenetically diverse mouse models of SARS-CoV-2 infection reproduce clinical variation in type I interferon and cytokine responses in COVID-19.PMC103686521ZIAAI001125-04ZIA AI001125Shamsaddini ABest SMBedard OGardina PHarder JMRobertson SJBruno DPSturdevant GLHolland SMLeung JMSun JClancy CSShaia CChiramel AIBrunton CMunger SLewis MForte EMcNally KLBroeckel RMPreuss CShannon JGMartens CBaker CNRosenthal NALack JBRosenke RAnzick SLSturdevant DEfalseGenetically diverse mouse models of SARS-CoV-2 infection reproduce clinical variation in type I interferon and cytokine responses in COVID-19.Inflammation in response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection drives severity of coronavirus disease 2019 (COVID-19) and is influenced by host genetics. To understand mechanisms of inflammation, animal models that reflect genetic diversity and clinical outcomes observed in humans are needed. We report a mouse panel comprising the genetically diverse Collaborative Cross (CC) founder strains crossed to human ACE2 transgenic mice (K18-hACE2) that confers susceptibility to SARS-CoV-2. Infection of CC x K18-hACE2 resulted in a spectrum of survival, viral replication kinetics, and immune profiles. Importantly, in contrast to the K18-hACE2 model, early type I interferon (IFN-I) and regulated proinflammatory responses were required for control of SARS-CoV-2 rep2023-01-01T00:00:00Z2023 Jul2025-04-04T20:33:03.812Z2025-02-19T00:26:33.272ZS-EPMC103686523749135210.1038/s41467-023-40076-5