PMID- 33257679 OWN - NLM STAT- MEDLINE DCOM- 20201218 LR - 20231112 IS - 2041-1723 (Electronic) IS - 2041-1723 (Linking) VI - 11 IP - 1 DP - 2020 Nov 30 TI - Lethality of SARS-CoV-2 infection in K18 human angiotensin-converting enzyme 2 transgenic mice. PG - 6122 LID - 10.1038/s41467-020-19891-7 [doi] LID - 6122 AB - Vaccine and antiviral development against SARS-CoV-2 infection or COVID-19 disease would benefit from validated small animal models. Here, we show that transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) by the human cytokeratin 18 promoter (K18 hACE2) represent a susceptible rodent model. K18 hACE2 transgenic mice succumbed to SARS-CoV-2 infection by day 6, with virus detected in lung airway epithelium and brain. K18 ACE2 transgenic mice produced a modest TH1/2/17 cytokine storm in the lung and spleen that peaked by day 2, and an extended chemokine storm that was detected in both lungs and brain. This chemokine storm was also detected in the brain at day 6. K18 hACE2 transgenic mice are, therefore, highly susceptible to SARS-CoV-2 infection and represent a suitable animal model for the study of viral pathogenesis, and for identification and characterization of vaccines (prophylactic) and antivirals (therapeutics) for SARS-CoV-2 infection and associated severe COVID-19 disease. FAU - Oladunni, Fatai S AU - Oladunni FS AUID- ORCID: 0000-0001-5050-0183 AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Park, Jun-Gyu AU - Park JG AUID- ORCID: 0000-0001-7163-3591 AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Pino, Paula A AU - Pino PA AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Gonzalez, Olga AU - Gonzalez O AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Akhter, Anwari AU - Akhter A AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Allue-Guardia, Anna AU - Allue-Guardia A AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Olmo-Fontanez, Angelica AU - Olmo-Fontanez A AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. AD - Integrated Biomedical Sciences Program, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA. FAU - Gautam, Shalini AU - Gautam S AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Garcia-Vilanova, Andreu AU - Garcia-Vilanova A AUID- ORCID: 0000-0002-2385-8718 AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Ye, Chengjin AU - Ye C AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Chiem, Kevin AU - Chiem K AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. AD - Integrated Biomedical Sciences Program, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA. FAU - Headley, Colwyn AU - Headley C AUID- ORCID: 0000-0001-6041-7615 AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Dwivedi, Varun AU - Dwivedi V AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Parodi, Laura M AU - Parodi LM AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Alfson, Kendra J AU - Alfson KJ AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Staples, Hilary M AU - Staples HM AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Schami, Alyssa AU - Schami A AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. AD - Integrated Biomedical Sciences Program, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA. FAU - Garcia, Juan I AU - Garcia JI AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Whigham, Alison AU - Whigham A AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Platt, Roy Neal 2nd AU - Platt RN 2nd AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Gazi, Michal AU - Gazi M AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Martinez, Jesse AU - Martinez J AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Chuba, Colin AU - Chuba C AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Earley, Stephanie AU - Earley S AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Rodriguez, Oscar H AU - Rodriguez OH AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Mdaki, Stephanie Davis AU - Mdaki SD AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Kavelish, Katrina N AU - Kavelish KN AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Escalona, Renee AU - Escalona R AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Hallam, Cory R A AU - Hallam CRA AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Christie, Corbett AU - Christie C AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Patterson, Jean L AU - Patterson JL AUID- ORCID: 0000-0001-8069-8098 AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Anderson, Tim J C AU - Anderson TJC AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Carrion, Ricardo Jr AU - Carrion R Jr AUID- ORCID: 0000-0001-7046-7683 AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Dick, Edward J Jr AU - Dick EJ Jr AUID- ORCID: 0000-0003-2373-7921 AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Hall-Ursone, Shannan AU - Hall-Ursone S AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Schlesinger, Larry S AU - Schlesinger LS AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Alvarez, Xavier AU - Alvarez X AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Kaushal, Deepak AU - Kaushal D AUID- ORCID: 0000-0003-3521-1257 AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Giavedoni, Luis D AU - Giavedoni LD AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. FAU - Turner, Joanne AU - Turner J AUID- ORCID: 0000-0002-0840-7484 AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. joanneturner@txbiomed.org. FAU - Martinez-Sobrido, Luis AU - Martinez-Sobrido L AUID- ORCID: 0000-0001-7084-0804 AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. lmartinez@txbiomed.org. FAU - Torrelles, Jordi B AU - Torrelles JB AUID- ORCID: 0000-0001-7702-5941 AD - Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. jtorrelles@txbiomed.org. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20201130 PL - England TA - Nat Commun JT - Nature communications JID - 101528555 RN - 0 (KRT18 protein, human) RN - 0 (Keratin-18) RN - EC 3.4.17.23 (Angiotensin-Converting Enzyme 2) SB - IM MH - *Angiotensin-Converting Enzyme 2/genetics/immunology MH - Animals MH - Brain/immunology/pathology/virology MH - *COVID-19/immunology/pathology MH - Cytokine Release Syndrome/immunology/pathology MH - *Disease Models, Animal MH - Disease Susceptibility MH - Genetic Predisposition to Disease MH - Keratin-18/genetics MH - Lung/immunology/pathology/virology MH - Mice MH - Mice, Transgenic MH - Mortality MH - Promoter Regions, Genetic/genetics MH - Respiratory Mucosa/immunology/pathology/virology MH - Virus Diseases/immunology/pathology PMC - PMC7705712 COIS- The authors declare no competing interests. EDAT- 2020/12/02 06:00 MHDA- 2020/12/19 06:00 PMCR- 2020/11/30 CRDT- 2020/12/01 05:56 PHST- 2020/07/18 00:00 [received] PHST- 2020/11/05 00:00 [accepted] PHST- 2020/12/01 05:56 [entrez] PHST- 2020/12/02 06:00 [pubmed] PHST- 2020/12/19 06:00 [medline] PHST- 2020/11/30 00:00 [pmc-release] AID - 10.1038/s41467-020-19891-7 [pii] AID - 19891 [pii] AID - 10.1038/s41467-020-19891-7 [doi] PST - epublish SO - Nat Commun. 2020 Nov 30;11(1):6122. doi: 10.1038/s41467-020-19891-7.