Comparative pathogenesis of COVID-19, MERS, and SARS in a nonhuman primate model

Barry Rockx, Thijs Kuiken, Sander Herfst, Theo Bestebroer, Mart M Lamers, Bas B Oude Munnink, Dennis de Meulder, Geert van Amerongen, Judith van den Brand, Nisreen M A Okba, Debby Schipper, Peter van Run, Lonneke Leijten, Reina Sikkema, Ernst Verschoor, Babs Verstrepen, Willy Bogers, Jan Langermans, Christian Drosten, Martje Fentener van Vlissingen, Ron Fouchier, Rik de Swart, Marion Koopmans, Bart L Haagmans, Barry Rockx, Thijs Kuiken, Sander Herfst, Theo Bestebroer, Mart M Lamers, Bas B Oude Munnink, Dennis de Meulder, Geert van Amerongen, Judith van den Brand, Nisreen M A Okba, Debby Schipper, Peter van Run, Lonneke Leijten, Reina Sikkema, Ernst Verschoor, Babs Verstrepen, Willy Bogers, Jan Langermans, Christian Drosten, Martje Fentener van Vlissingen, Ron Fouchier, Rik de Swart, Marion Koopmans, Bart L Haagmans

Abstract

The current pandemic coronavirus, severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), was recently identified in patients with an acute respiratory syndrome, coronavirus disease 2019 (COVID-19). To compare its pathogenesis with that of previously emerging coronaviruses, we inoculated cynomolgus macaques with SARS-CoV-2 or Middle East respiratory syndrome (MERS)-CoV and compared the pathology and virology with historical reports of SARS-CoV infections. In SARS-CoV-2-infected macaques, virus was excreted from nose and throat in the absence of clinical signs and detected in type I and II pneumocytes in foci of diffuse alveolar damage and in ciliated epithelial cells of nasal, bronchial, and bronchiolar mucosae. In SARS-CoV infection, lung lesions were typically more severe, whereas they were milder in MERS-CoV infection, where virus was detected mainly in type II pneumocytes. These data show that SARS-CoV-2 causes COVID-19-like disease in macaques and provides a new model to test preventive and therapeutic strategies.

Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Figures

Fig. 1. Virus shedding and virus detection…
Fig. 1. Virus shedding and virus detection in organs of SARS-CoV-2–inoculated cynomolgus macaques.
Viral RNA was detected in nasal (A) and throat (B) swabs and in tissues (C) of SARS-CoV-2–infected animals by RT-qPCR. Samples from four animals (days 1 to 4) or two animals (days >4) per group were tested. The error bars represent the SEM. Virus was detected in tissues from two young and two aged animals on day 4 by RT-qPCR. Asterisk (*) indicates that infectious virus was isolated.
Fig. 2. Characteristic pathological changes and virus…
Fig. 2. Characteristic pathological changes and virus antigen expression in the lungs of SARS-CoV-2–inoculated cynomolgus macaques.
(A) Two foci of pulmonary consolidation in the left lower lung lobe (arrowheads). (B) Area of pneumonia [staining with hematoxylin and eosin (H&E); bar, 0.5 cm). (C) Edema fluid in alveolar lumina (H&E; bar, 25 μm). (D) Neutrophils, as well as erythrocytes, fibrin, and cell debris, in an alveolar lumen flooded by edema fluid (H&E; bar, 10 μm). (E) Mononuclear cells, either type II pneumocytes or alveolar macrophages, in an alveolar lumen flooded by edema fluid (H&E; bar, 10 μm). (F) Syncytium in an alveolar lumen (H&E; 100× objective). Inset: Syncytium expresses keratin, indicating epithelial cell origin [immunohistochemistry (IHC) for pankeratin AE1/AE3; bar, 10 μm]. (G) SARS-CoV-2 antigen expression is colocalized with areas of diffuse alveolar damage (IHC for SARS-CoV-nucleocapsid; bar, 50 μm). (H) Type I (flat) and type II (cuboidal) pneumocytes in affected lung tissue express SARS-CoV-2 antigen (IHC for SARS-CoV-nucleocapsid; bar, 25 μm). (I) Ciliated columnar epithelial cells of respiratory mucosa in nasal cavity express SARS-CoV-2 antigen (IHC for SARS-CoV-nucleocapsid; bar, 25 μm).
Fig. 3. Virus shedding and virus detection…
Fig. 3. Virus shedding and virus detection in organs of MERS-CoV–inoculated cynomolgus macaques.
Viral RNA was detected in nasal (A) and throat (B) swabs and tissues (C) of MERS-CoV–infected animals by RT-qPCR. Samples from four animals per group were tested. The error bars represent the SEM. Virus was detected in tissues on day 4 by RT-qPCR. Histopathological changes (D) (left) with hypertrophic and hyperplastic type II pneumocytes in the alveolar septa and increased numbers of alveolar macrophages in the alveolar lumina and virus antigen expression (right) in type II pneumocytes. Bar, 50 μm.

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