PMID- 35073750 OWN - NLM STAT- MEDLINE DCOM- 20230228 LR - 20230307 IS - 2150-7511 (Electronic) VI - 13 IP - 1 DP - 2022 Feb 22 TI - Hamsters Expressing Human Angiotensin-Converting Enzyme 2 Develop Severe Disease following Exposure to SARS-CoV-2. PG - e0290621 LID - 10.1128/mbio.02906-21 [doi] LID - e02906-21 AB - The rapid emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created a global health emergency. While most human disease is mild to moderate, some infections lead to a severe disease characterized by acute respiratory distress, hypoxia, anosmia, ageusia, and, in some instances, neurological involvement. Small-animal models reproducing severe disease, including neurological sequela, are needed to characterize the pathophysiological mechanism(s) of disease and to identify medical countermeasures. Transgenic mice expressing the human angiotensin-converting enzyme 2 (hACE2) viral receptor under the control of the K18 promoter develop severe and lethal respiratory disease subsequent to SARS-CoV-2 intranasal challenge when high viral doses are used. Here, we report on SARS-CoV-2 infection of hamsters engineered to express the hACE2 receptor under the control of the K18 promoter. K18-hACE2 hamsters infected with a relatively low dose of 100 or 1,000 PFU of SARS-CoV-2 developed a severe and lethal disease, with most animals succumbing by day 5 postinfection. Hamsters developed severe lesions and inflammation within the upper and lower respiratory system, including infection of the nasal cavities causing marked destruction of the olfactory epithelium as well as severe bronchopneumonia that extended deep into the alveoli. Additionally, SARS-CoV-2 infection spread to the central nervous system (CNS), including the brain stem and spinal cord. Wild-type (WT) hamsters naturally support SARS-CoV-2 infection, with the primary lesions present in the respiratory tract and nasal cavity. Overall, infection in the K18-hACE2 hamsters is more extensive than that in WT hamsters, with more CNS involvement and a lethal outcome. These findings demonstrate the K18-hACE2 hamster model will be valuable for studying SARS-CoV-2. IMPORTANCE The rapid emergence of SARS-CoV-2 has created a global health emergency. While most human SARS-CoV-2 disease is mild, some people develop severe, life-threatening disease. Small-animal models mimicking the severe aspects of human disease are needed to more clearly understand the pathophysiological processes driving this progression. Here, we studied SARS-CoV-2 infection in hamsters engineered to express the human angiotensin-converting enzyme 2 viral receptor under the control of the K18 promoter. SARS-CoV-2 produces a severe and lethal infection in transgenic hamsters that mirrors the most severe aspects of COVID-19 in humans, including respiratory and neurological injury. In contrast to other animal systems, hamsters manifest disease with levels of input virus more consistent with natural human infection. This system will be useful for the study of SARS-CoV-2 disease and the development of drugs targeting this virus. FAU - Golden, Joseph W AU - Golden JW AD - Virology Division, United States Army Medical Research Institute of Infectious Diseasesgrid.416900.a, Fort Detrick, Maryland, USA. FAU - Li, Rong AU - Li R AD - Department of Animal, Dairy, and Veterinary Sciences, Utah State Universitygrid.53857.3c, Logan, Utah, USA. FAU - Cline, Curtis R AU - Cline CR AD - Pathology, United States Army Medical Research Institute of Infectious Diseasesgrid.416900.a, Fort Detrick, Maryland, USA. FAU - Zeng, Xiankun AU - Zeng X AD - Pathology, United States Army Medical Research Institute of Infectious Diseasesgrid.416900.a, Fort Detrick, Maryland, USA. FAU - Mucker, Eric M AU - Mucker EM AUID- ORCID: 0000-0002-4656-5379 AD - Virology Division, United States Army Medical Research Institute of Infectious Diseasesgrid.416900.a, Fort Detrick, Maryland, USA. FAU - Fuentes-Lao, Amadeo J AU - Fuentes-Lao AJ AD - Virology Division, United States Army Medical Research Institute of Infectious Diseasesgrid.416900.a, Fort Detrick, Maryland, USA. FAU - Spik, Kristin W AU - Spik KW AD - Virology Division, United States Army Medical Research Institute of Infectious Diseasesgrid.416900.a, Fort Detrick, Maryland, USA. FAU - Williams, Janice A AU - Williams JA AD - Pathology, United States Army Medical Research Institute of Infectious Diseasesgrid.416900.a, Fort Detrick, Maryland, USA. FAU - Twenhafel, Nancy AU - Twenhafel N AD - Pathology, United States Army Medical Research Institute of Infectious Diseasesgrid.416900.a, Fort Detrick, Maryland, USA. FAU - Davis, Neil AU - Davis N AD - Pathology, United States Army Medical Research Institute of Infectious Diseasesgrid.416900.a, Fort Detrick, Maryland, USA. FAU - Moore, Joshua L AU - Moore JL AD - Veterinary Medicine Division, United States Army Medical Research Institute of Infectious Diseasesgrid.416900.a, Fort Detrick, Maryland, USA. FAU - Stevens, Stephen AU - Stevens S AD - Veterinary Medicine Division, United States Army Medical Research Institute of Infectious Diseasesgrid.416900.a, Fort Detrick, Maryland, USA. FAU - Blue, Eugene AU - Blue E AD - Veterinary Medicine Division, United States Army Medical Research Institute of Infectious Diseasesgrid.416900.a, Fort Detrick, Maryland, USA. FAU - Garrison, Aura R AU - Garrison AR AD - Virology Division, United States Army Medical Research Institute of Infectious Diseasesgrid.416900.a, Fort Detrick, Maryland, USA. FAU - Larson, Deanna D AU - Larson DD AD - Department of Animal, Dairy, and Veterinary Sciences, Utah State Universitygrid.53857.3c, Logan, Utah, USA. FAU - Stewart, Rebekah AU - Stewart R AD - Department of Animal, Dairy, and Veterinary Sciences, Utah State Universitygrid.53857.3c, Logan, Utah, USA. FAU - Kunzler, Madelyn AU - Kunzler M AD - Department of Animal, Dairy, and Veterinary Sciences, Utah State Universitygrid.53857.3c, Logan, Utah, USA. FAU - Liu, Yanan AU - Liu Y AD - Department of Animal, Dairy, and Veterinary Sciences, Utah State Universitygrid.53857.3c, Logan, Utah, USA. FAU - Wang, Zhongde AU - Wang Z AD - Department of Animal, Dairy, and Veterinary Sciences, Utah State Universitygrid.53857.3c, Logan, Utah, USA. FAU - Hooper, Jay W AU - Hooper JW AUID- ORCID: 0000-0002-4475-0415 AD - Virology Division, United States Army Medical Research Institute of Infectious Diseasesgrid.416900.a, Fort Detrick, Maryland, USA. LA - eng GR - HHSN272201700041I/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20220125 PL - United States TA - mBio JT - mBio JID - 101519231 RN - EC 3.4.17.23 (Angiotensin-Converting Enzyme 2) RN - 0 (K-18 conjugate) RN - EC 3.4.15.1 (Peptidyl-Dipeptidase A) SB - IM MH - Mice MH - Animals MH - Cricetinae MH - Humans MH - *SARS-CoV-2 MH - *COVID-19/pathology MH - Angiotensin-Converting Enzyme 2 MH - Peptidyl-Dipeptidase A MH - Lung/pathology MH - Mice, Transgenic MH - Disease Models, Animal PMC - PMC8787465 OTO - NOTNLM OT - K18-hACE2 OT - SARS-CoV-2 OT - angiotensin-converting enzyme 2 OT - cardiac lesions OT - nasal cavity OT - neuropathology OT - olfactory bulb OT - transgenic hamsters COIS- The authors declare no conflict of interest. We have no conflicts of interest. EDAT- 2022/01/26 06:00 MHDA- 2023/03/03 06:00 PMCR- 2022/01/25 CRDT- 2022/01/25 05:36 PHST- 2022/01/25 05:36 [entrez] PHST- 2022/01/26 06:00 [pubmed] PHST- 2023/03/03 06:00 [medline] PHST- 2022/01/25 00:00 [pmc-release] AID - 02906-21 [pii] AID - mbio.02906-21 [pii] AID - 10.1128/mbio.02906-21 [doi] PST - ppublish SO - mBio. 2022 Feb 22;13(1):e0290621. doi: 10.1128/mbio.02906-21. Epub 2022 Jan 25.