A humanized mouse model of chronic COVID-19

COVID-19 is an infectious disease; in some it presents 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 SARS-CoV-2 infection up to 28 days post-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 to study two therapeutics on immunopathology: patient-derived antibodies and steroids; We 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.