A humanized mouse model of chronic COVID-19
- 17 December 2021
- journal article
- research article
- Published by Springer Nature in Nature Biotechnology
- Vol. 40 (6) , 906-920
Abstract
Coronavirus disease 2019 (COVID-19) is an infectious disease that can present as an uncontrolled, hyperactive immune response, causing severe immunological injury. Existing rodent models do not recapitulate the sustained immunopathology of patients with severe disease. Here we describe a humanized mouse model of COVID-19 that uses adeno-associated virus to deliver human ACE2 to the lungs of humanized MISTRG6 mice. This model recapitulates innate and adaptive human immune responses to severe acute respiratory syndrome coronavirus 2 infection up to 28 days after infection, with key features of chronic COVID-19, including weight loss, persistent viral RNA, lung pathology with fibrosis, a human inflammatory macrophage response, a persistent interferon-stimulated gene signature and T cell lymphopenia. We used this model to study two therapeutics on immunopathology, patient-derived antibodies and steroids and found that the same inflammatory macrophages crucial to containing early infection later drove immunopathology. This model will enable evaluation of COVID-19 disease mechanisms and treatments.Keywords
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Funding Information
- Howard Hughes Medical Institute
- Damon Runyon Cancer Research Foundation (DRG-2316-18)
- U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (2T32AI007517, AI061093, AI118855, K08AI128043, R01AI157488)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (F30CA239444, U01CA260507, CA016359)
- https://www.mercatus.org/emergent-ventures
- G. Harold and Leila Y. Mathers Foundation
- G. Harold and Leila Y. Mathers Foundation
- Burroughs Wellcome Fund
- Robert E. Leet and Clara Guthrie Patterson Trust
- G. Harold and Leila Y. Mathers Foundation
- https://www.mercatus.org/emergent-ventures http://www.ludwick.org/
- G. Harold and Leila Y. Mathers Foundation
- Bill and Melinda Gates Foundation
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