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The post-acute phase of SARS-CoV-2 infection in two macaques species is associated with signs of ongoing virus replication and pathology in pulmonary and extrapulmonary tissues

View ORCID ProfileKinga P. Böszörményi, Marieke A. Stammes, Zahra C. Fagrouch, Gwendoline Kiemenyi-Kayere, Henk Niphuis, Daniella Mortier, Nikki van Driel, Ivonne Nieuwenhuis, Richard A. W. Vervenne, Tom Haaksma, Boudewijn Ouwerling, Deborah Adema, Roja Fidel Acar, Ella Zuiderwijk-Sick, Lisette Meijer, Petra Mooij, Ed J. Remarque, Herman Oostermeijer, Gerrit Koopman, Alexis C. R. Hoste, Patricia Sastre, Bart L. Haagmans, Ronald E. Bontrop, Jan A.M. Langermans, Willy M. Bogers, Ivanela Kondova, Ernst J. Verschoor, Babs E. Verstrepen
doi: https://doi.org/10.1101/2020.11.05.369413
Kinga P. Böszörményi
1Department of Virology, Biomedical Primate Research Centre (BPRC), Rijswijk, Netherlands
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  • ORCID record for Kinga P. Böszörményi
Marieke A. Stammes
2Department of Parasitology, BPRC, Rijswijk, Netherlands
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Zahra C. Fagrouch
1Department of Virology, Biomedical Primate Research Centre (BPRC), Rijswijk, Netherlands
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Gwendoline Kiemenyi-Kayere
1Department of Virology, Biomedical Primate Research Centre (BPRC), Rijswijk, Netherlands
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Henk Niphuis
1Department of Virology, Biomedical Primate Research Centre (BPRC), Rijswijk, Netherlands
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Daniella Mortier
1Department of Virology, Biomedical Primate Research Centre (BPRC), Rijswijk, Netherlands
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Nikki van Driel
3Animal Science Department, BPRC, Rijswijk, Netherlands
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Ivonne Nieuwenhuis
2Department of Parasitology, BPRC, Rijswijk, Netherlands
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Richard A. W. Vervenne
2Department of Parasitology, BPRC, Rijswijk, Netherlands
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Tom Haaksma
3Animal Science Department, BPRC, Rijswijk, Netherlands
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Boudewijn Ouwerling
3Animal Science Department, BPRC, Rijswijk, Netherlands
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Deborah Adema
3Animal Science Department, BPRC, Rijswijk, Netherlands
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Roja Fidel Acar
1Department of Virology, Biomedical Primate Research Centre (BPRC), Rijswijk, Netherlands
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Ella Zuiderwijk-Sick
4Alternatives unit, BPRC, Rijswijk, Netherlands
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Lisette Meijer
2Department of Parasitology, BPRC, Rijswijk, Netherlands
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Petra Mooij
1Department of Virology, Biomedical Primate Research Centre (BPRC), Rijswijk, Netherlands
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Ed J. Remarque
1Department of Virology, Biomedical Primate Research Centre (BPRC), Rijswijk, Netherlands
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Herman Oostermeijer
1Department of Virology, Biomedical Primate Research Centre (BPRC), Rijswijk, Netherlands
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Gerrit Koopman
1Department of Virology, Biomedical Primate Research Centre (BPRC), Rijswijk, Netherlands
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Alexis C. R. Hoste
5Eurofins-Inmunología y Genética Aplicada (Eurofins-INGENASA), Madrid, Spain
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Patricia Sastre
5Eurofins-Inmunología y Genética Aplicada (Eurofins-INGENASA), Madrid, Spain
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Bart L. Haagmans
6Department of Viroscience, Erasmus University Medical Center, Rotterdam, Netherlands
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Ronald E. Bontrop
7Department of Comparative Genetics and Refinement, BPRC, Rijswijk, Netherlands
8Department of Biology, Theoretical Biology and Bioinformatics, Utrecht University, Utrecht, Netherlands
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Jan A.M. Langermans
3Animal Science Department, BPRC, Rijswijk, Netherlands
9Department of Population Health Sciences, Unit Animals in Science and Society, Veterinary Faculty, Utrecht University, Utrecht, Netherlands
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Willy M. Bogers
1Department of Virology, Biomedical Primate Research Centre (BPRC), Rijswijk, Netherlands
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Ivanela Kondova
3Animal Science Department, BPRC, Rijswijk, Netherlands
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Ernst J. Verschoor
1Department of Virology, Biomedical Primate Research Centre (BPRC), Rijswijk, Netherlands
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  • For correspondence: verschoor@bprc.nl
Babs E. Verstrepen
1Department of Virology, Biomedical Primate Research Centre (BPRC), Rijswijk, Netherlands
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Abstract

The post-acute phase of SARS-CoV-2 infection was investigated in rhesus macaques (Macaca mulatta) and cynomolgus macaques (Macaca fascicularis). During the acute phase of infection, SARS-CoV-2 was shed via nose and throat, and viral RNA was occasionally detected in feces. This phase coincided with a transient change in systemic immune activation. Even after the alleged resolution of the infection, as suggested by the absence of viral RNA in nasal and tracheal swabs, computed tomography (CT) and positron emission tomography (PET)-CT were able to reveal pulmonary lesions and activated tracheobronchial lymph nodes in all animals. Post-mortem histological examination of the lung tissue revealed mostly marginal or resolving minimal lesions that were indicative of SARS-CoV-2 infection. Evidence for SARS-CoV-2-induced histopathology was also found in extrapulmonary tissue samples, like conjunctiva, cervical and mesenteric lymph nodes.

However, 5-6 weeks after SARS-CoV-2 exposure, upon necropsy, viral RNA was still detectable in a wide range of tissue samples in 50% of the macaques and included amongst others the heart, the respiratory tract and surrounding lymph nodes, salivary gland, and conjunctiva. Subgenomic messenger RNA was detected in the lungs and tracheobronchial lymph nodes, indicative of ongoing virus replication during the post-acute phase. These results could be relevant for understanding the long-term consequences of COVID-19 in humans.

Author summary More than a year after the start of the pandemic, the long-term consequences of SARS-CoV-2 infection start to surface. The variety of clinical manifestations associated with post-acute COVID-19 suggests the involvement of multiple biological mechanisms. In this study, we show that rhesus and cynomolgus macaques shed virus from their respiratory tract, generate virus-specific humoral immune responses, and show signs of SARS-CoV-2-induced lung pathology. PET-CT revealed that both species showed ongoing mild to moderate pulmonary disease, even after the virus was no longer detectable in nasal and tracheal swabs. Five to six weeks after infection, necropsy confirmed minimal to mild histopathological manifestations in various tissues, like the lungs, heart, lymph nodes, and conjunctiva. We detected Viral RNA in the heart, respiratory tract, and tracheobronchial lymph nodes, and subgenomic messenger RNA in the lungs and surrounding lymph nodes, indicative of ongoing virus replication. We show widespread tissue dissemination of SARS-CoV-2 in infected macaques and the presence of replicating virus in lungs and surrounding lymph nodes after alleged convalescence of infection. This finding is intriguing in the light of long-COVID disease symptoms seen in humans as it has been hypothesized that persistent infection may contribute to this phenomenon.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 04, 2021.
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The post-acute phase of SARS-CoV-2 infection in two macaques species is associated with signs of ongoing virus replication and pathology in pulmonary and extrapulmonary tissues
Kinga P. Böszörményi, Marieke A. Stammes, Zahra C. Fagrouch, Gwendoline Kiemenyi-Kayere, Henk Niphuis, Daniella Mortier, Nikki van Driel, Ivonne Nieuwenhuis, Richard A. W. Vervenne, Tom Haaksma, Boudewijn Ouwerling, Deborah Adema, Roja Fidel Acar, Ella Zuiderwijk-Sick, Lisette Meijer, Petra Mooij, Ed J. Remarque, Herman Oostermeijer, Gerrit Koopman, Alexis C. R. Hoste, Patricia Sastre, Bart L. Haagmans, Ronald E. Bontrop, Jan A.M. Langermans, Willy M. Bogers, Ivanela Kondova, Ernst J. Verschoor, Babs E. Verstrepen
bioRxiv 2020.11.05.369413; doi: https://doi.org/10.1101/2020.11.05.369413
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The post-acute phase of SARS-CoV-2 infection in two macaques species is associated with signs of ongoing virus replication and pathology in pulmonary and extrapulmonary tissues
Kinga P. Böszörményi, Marieke A. Stammes, Zahra C. Fagrouch, Gwendoline Kiemenyi-Kayere, Henk Niphuis, Daniella Mortier, Nikki van Driel, Ivonne Nieuwenhuis, Richard A. W. Vervenne, Tom Haaksma, Boudewijn Ouwerling, Deborah Adema, Roja Fidel Acar, Ella Zuiderwijk-Sick, Lisette Meijer, Petra Mooij, Ed J. Remarque, Herman Oostermeijer, Gerrit Koopman, Alexis C. R. Hoste, Patricia Sastre, Bart L. Haagmans, Ronald E. Bontrop, Jan A.M. Langermans, Willy M. Bogers, Ivanela Kondova, Ernst J. Verschoor, Babs E. Verstrepen
bioRxiv 2020.11.05.369413; doi: https://doi.org/10.1101/2020.11.05.369413

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