The Post-Acute Phase of SARS-CoV-2 Infection in Two Macaque Species Is Associated with Signs of Ongoing Virus Replication and Pathology in Pulmonary and Extrapulmonary Tissues.
Böszörményi, Kinga P; Stammes, Marieke A; Fagrouch, Zahra Cet al.
[en] The post-acute phase of SARS-CoV-2 infection was investigated in rhesus (Macaca mulatta) and cynomolgus macaques (Macaca fascicularis). During the acute phase of infection, SARS-CoV-2 was shed via the 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, computed tomography (CT) and positron emission tomography (PET)-CT revealed 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, such as 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.
Disciplines :
Veterinary medicine & animal health
Author, co-author :
Böszörményi, Kinga P ; Biomedical Primate Research Centre (BPRC), Department of Virology, 2288 GJ Rijswijk, The Netherlands
Stammes, Marieke A ; Department of Parasitology, BPRC, 2288 GJ Rijswijk, The Netherlands
Fagrouch, Zahra C; Biomedical Primate Research Centre (BPRC), Department of Virology, 2288 GJ Rijswijk, The Netherlands
Kiemenyi-Kayere, Gwendoline; Biomedical Primate Research Centre (BPRC), Department of Virology, 2288 GJ Rijswijk, The Netherlands
Niphuis, Henk; Biomedical Primate Research Centre (BPRC), Department of Virology, 2288 GJ Rijswijk, The Netherlands
Mortier, Daniella; Biomedical Primate Research Centre (BPRC), Department of Virology, 2288 GJ Rijswijk, The Netherlands
van Driel, Nikki ; Animal Science Department, BPRC, 2288 GJ Rijswijk, The Netherlands
Nieuwenhuis, Ivonne; Department of Parasitology, BPRC, 2288 GJ Rijswijk, The Netherlands
Vervenne, Richard A W; Department of Parasitology, BPRC, 2288 GJ Rijswijk, The Netherlands
Acar, Roja Fidel; Biomedical Primate Research Centre (BPRC), Department of Virology, 2288 GJ Rijswijk, The Netherlands
Zuiderwijk-Sick, Ella; Alternatives Unit, BPRC, 2288 GJ Rijswijk, The Netherlands
Meijer, Lisette; Department of Parasitology, BPRC, 2288 GJ Rijswijk, The Netherlands
Mooij, Petra ; Biomedical Primate Research Centre (BPRC), Department of Virology, 2288 GJ Rijswijk, The Netherlands
Remarque, Ed J; Biomedical Primate Research Centre (BPRC), Department of Virology, 2288 GJ Rijswijk, The Netherlands
Oostermeijer, Herman; Biomedical Primate Research Centre (BPRC), Department of Virology, 2288 GJ Rijswijk, The Netherlands
Koopman, Gerrit ; Biomedical Primate Research Centre (BPRC), Department of Virology, 2288 GJ Rijswijk, The Netherlands
Hoste, Alexis ; Université de Liège - ULiège > Département GxABT > Microbial technologies ; Eurofins-Inmunología y Genética Aplicada (Eurofins-INGENASA), 28037 Madrid, Spain
Sastre, Patricia; Eurofins-Inmunología y Genética Aplicada (Eurofins-INGENASA), 28037 Madrid, Spain
Haagmans, Bart L ; Department of Viroscience, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
Bontrop, Ronald E; Department of Comparative Genetics and Refinement, BPRC, 2288 GJ Rijswijk, The Netherlands ; Department of Biology, Theoretical Biology and Bioinformatics, Utrecht University, 3584 CH Utrecht, The Netherlands
Langermans, Jan A M ; Animal Science Department, BPRC, 2288 GJ Rijswijk, The Netherlands ; Unit Animals in Science and Society, Department of Population Health Sciences, Veterinary Faculty, Utrecht University, 3584 CL Utrecht, The Netherlands
Bogers, Willy M ; Biomedical Primate Research Centre (BPRC), Department of Virology, 2288 GJ Rijswijk, The Netherlands
The Post-Acute Phase of SARS-CoV-2 Infection in Two Macaque Species Is Associated with Signs of Ongoing Virus Replication and Pathology in Pulmonary and Extrapulmonary Tissues.
H2020 - 721367 - HONOURs - Host switching pathogens, infectious outbreaks and zoonosis; a Marie Sklodowska-Curie Training Network
Funders :
EU - European Union
Funding text :
Funding: This study was supported by funding from the Biomedical Primate Research Centre. K.P.B. was supported by the European Union’s Marie Skłodowska-Curie Innovative Training Network HONOURs; grant agreement no. 721367. This publication was also supported by the European Virus Archive GLOBAL (EVA-GLOBAL) project that has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement no. 871029.This study was supported by funding from the Biomedical Primate Research Centre. K.P.B. was supported by the European Union?s Marie Sk?odowska-Curie Innovative Training Network HONOURs; grant agreement no. 721367. This publication was also supported by the European Virus Archive GLOBAL (EVA-GLOBAL) project that has received funding from the European Union?s Horizon 2020 research and innovation program under grant agreement no. 871029.
Whetton, A.D.; Preston, G.W.; Abubeker, S.; Geifman, N. Proteomics and Informatics for Understanding Phases and Identifying Biomarkers in COVID-19 Disease. J. Proteome Res. 2020, 19, 4219–4232. [CrossRef]
Polak, S.B.; Van Gool, I.C.; Cohen, D.; von der Thusen, J.H.; van Paassen, J. A systematic review of pathological findings in COVID-19: A pathophysiological timeline and possible mechanisms of disease progression. Mod. Pathol. 2020, 33, 2128–2138. [CrossRef]
Kwee, T.C.; Kwee, R.M. Chest CT in COVID-19: What the Radiologist Needs to Know. Radiographics 2020, 40, 1848–1865. [CrossRef] [PubMed]
Lin, L.; Lu, L.; Cao, W.; Li, T. Hypothesis for potential pathogenesis of SARS-CoV-2 infection-a review of immune changes in patients with viral pneumonia. Emerg. Microbes Infect. 2020, 9, 727–732. [CrossRef] [PubMed]
Oronsky, B.; Larson, C.; Hammond, T.C.; Oronsky, A.; Kesari, S.; Lybeck, M.; Reid, T.R. A Review of Persistent Post-COVID Syndrome (PPCS). Clin. Rev. Allergy Immunol. 2021, 3, 1–9. [CrossRef]
Sollini, M.; Morbelli, S.; Ciccarelli, M.; Cecconi, M.; Aghemo, A.; Morelli, P.; Chiola, S.; Gelardi, F.; Chiti, A. Long COVID hallmarks on [18F]FDG-PET/CT: A case-control study. Eur. J. Nucl. Med. Mol. Imaging 2021, 7, 1–11. [CrossRef]
Sudre, C.H.; Murray, B.; Varsavsky, T.; Graham, M.S.; Penfold, R.S.; Bowyer, R.C.; Pujol, J.C.; Klaser, K.; Antonelli, M.; Canas, L.S.; et al. Attributes and predictors of long COVID. Nat. Med. 2021, 27, 626–4631. [CrossRef]
Boudewijns, R.; Thibaut, H.J.; Kaptein, S.J.F.; Li, R.; Vergote, V.; Seldeslachts, L.; Van Weyenbergh, J.; De Keyzer, C.; Bervoets, L.; Sharma, S.; et al. STAT2 signaling restricts viral dissemination but drives severe pneumonia in SARS-CoV-2 infected hamsters. Nat. Commun. 2020, 11, 5838. [CrossRef]
Kim, Y.I.; Kim, S.G.; Kim, S.M.; Kim, E.H.; Park, S.J.; Yu, K.M.; Chang, J.H.; Kim, E.J.; Lee, S.; Casel, M.A.B.; et al. Infection and Rapid Transmission of SARS-CoV-2 in Ferrets. Cell Host Microbe 2020, 27, 704–709.e2. [CrossRef]
Richard, M.; Kok, A.; de Meulder, D.; Bestebroer, T.M.; Lamers, M.M.; Okba, N.M.A.; van Fentener Vlissingen, M.; Rockx, B.; Haagmans, B.L.; Koopmans, M.P.G.; et al. SARS-CoV-2 is transmitted via contact and via the air between ferrets. Nat. Commun. 2020, 11, 3496. [CrossRef]
Estes, J.D.; Wong, S.W.; Brenchley, J.M. Nonhuman primate models of human viral infections. Nat. Rev. Immunol. 2018, 18, 390–404. [CrossRef]
Gong, S.R.; Bao, L.L. The battle against SARS and MERS coronaviruses: Reservoirs and Animal Models. Anim. Model Exp. Med. 2018, 1, 125–133. [CrossRef]
Sutton, T.C.; Subbarao, K. Development of animal models against emerging coronaviruses: From SARS to MERS coronavirus. Virology 2015, 479–480, 247–258. [CrossRef]
Lu, S.; Zhao, Y.; Yu, W.; Yang, Y.; Gao, J.; Wang, J.; Kuang, D.; Yang, M.; Yang, J.; Ma, C.; et al. Comparison of nonhuman primates identified the suitable model for COVID-19. Signal Transduct. Target. Ther. 2020, 5, 157. [CrossRef] [PubMed]
Singh, A.; Singh, R.S.; Sarma, P.; Batra, G.; Joshi, R.; Kaur, H.; Sharma, A.R.; Prakash, A.; Medhi, B. A Comprehensive Review of Animal Models for Coronaviruses: SARS-CoV-2, SARS-CoV, and MERS-CoV. Virol. Sin. 2020, 35, 290–304. [CrossRef]
Johnston, S.C.; Ricks, K.M.; Jay, A.; Raymond, J.L.; Rossi, F.; Zeng, X.; Scruggs, J.; Dyer, D.; Frick, O.; Koehler, J.W.; et al. Development of a coronavirus disease 2019 nonhuman primate model using airborne exposure. PLoS ONE 2021, 16, e0246366. [CrossRef]
Woolsey, C.; Borisevich, V.; Prasad, A.N.; Agans, K.N.; Deer, D.J.; Dobias, N.S.; Heymann, J.C.; Foster, S.L.; Levine, C.B.; Medina, L.; et al. Establishment of an African green monkey model for COVID-19 and protection against re-infection. Nat. Immunol. 2021, 22, 86–98. [CrossRef]
Munster, V.J.; Feldmann, F.; Williamson, B.N.; van Doremalen, N.; Perez-Perez, L.; Schulz, J.; Meade-White, K.; Okumura, A.; Callison, J.; Brumbaugh, B.; et al. Respiratory disease in rhesus macaques inoculated with SARS-CoV-2. Nature 2020, 585, 268–272. [CrossRef]
Rockx, B.; Kuiken, T.; Herfst, S.; Bestebroer, T.; Lamers, M.M.; Oude Munnink, B.B.; de Meulder, D.; van Amerongen, G.; van den Brand, J.; Okba, N.M.A.; et al. Comparative pathogenesis of COVID-19, MERS, and SARS in a nonhuman primate model. Science 2020, 368, 1012–1015. [CrossRef]
Brining, D.L.; Mattoon, J.S.; Kercher, L.; LaCasse, R.A.; Safronetz, D.; Feldmann, H.; Parnell, M.J. Thoracic radiography as a refinement methodology for the study of H1N1 influenza in cynomologus macaques (Macaca fascicularis). Comp. Med. 2010, 60, 389–395.
Corman, V.M.; Landt, O.; Kaiser, M.; Molenkamp, R.; Meijer, A.; Chu, D.K.; Bleicker, T.; Brunink, S.; Schneider, J.; Schmidt, M.L.; et al. Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR. Eurosurveillance 2020, 25, 2001483. [CrossRef]
Wolfel, R.; Corman, V.M.; Guggemos, W.; Seilmaier, M.; Zange, S.; Muller, M.A.; Niemeyer, D.; Jones, T.C.; Vollmar, P.; Rothe, C.; et al. Virological assessment of hospitalized patients with COVID-2019. Nature 2020, 581, 465–469. [CrossRef]
Stammes, M.A.; Bakker, J.; Vervenne, R.A.W.; Zijlmans, D.G.M.; van Geest, L.; Vierboom, M.P.M.; Langermans, J.A.M.; Verreck, F.A.W. Recommendations for Standardizing Thorax PET–CT in Non-Human Primates by Recent Experience from Macaque Studies. Animals 2021, 11, 204. [CrossRef]
Finch, C.L.; Crozier, I.; Lee, J.H.; Byrum, R.; Cooper, T.K.; Liang, J.; Sharer, K.; Solomon, J.; Sayre, P.J.; Kocher, G.; et al. Characteristic and quantifiable COVID-19-like abnormalities in CT-and PET/CT-imaged lungs of SARS-CoV-2-infected crabeating macaques (Macaca fascicularis). bioRxiv 2020. [CrossRef]
Pan, F.; Ye, T.; Sun, P.; Gui, S.; Liang, B.; Li, L.; Zheng, D.; Wang, J.; Hesketh, R.L.; Yang, L.; et al. Time Course of Lung Changes at Chest CT during Recovery from Coronavirus Disease 2019 (COVID-19). Radiology 2020, 295, 715–721. [CrossRef]
Maaskant, A.; Meijer, L.; Bakker, J.; van Geest, L.; Zijlmans, D.G.M.; Langermans, J.A.M.; Verschoor, E.J.; Stammes, M.A. Bronchoalveolar lavage affects thorax computed tomography of healthy and SARS-CoV-2 infected rhesus macaques bioRxiv. PloS ONE 2021, 16, e0252941. [CrossRef]
Hoste, A.C.R.; Venteo, A.; Fresco-Taboada, A.; Tapia, I.; Monedero, A.; Lopez, L.; Jebbink, M.F.; Perez-Ramirez, E.; Jimenez Clavero, M.A.; Almonacid, M.; et al. Two serological approaches for detection of antibodies to SARS-CoV-2 in different scenarios: A screening tool and a point-of-care test. Diagn. Microbiol. Infect. Dis. 2020, 98, 115167. [CrossRef]
Dagotto, G.; Mercado, N.B.; Martinez, D.R.; Hou, Y.J.; Nkolola, J.P.; Carnahan, R.H.; Crowe, J.E., Jr.; Baric, R.S.; Barouch, D.H. Comparison of Subgenomic and Total RNA in SARS-CoV-2 Challenged Rhesus Macaques. J. Virol. 2021, 95, e02370-20. [CrossRef]
Wang, L. C-reactive protein levels in the early stage of COVID-19. Med. Mal. Infect. 2020, 50, 332–334. [CrossRef] [PubMed]
Ronco, C.; Reis, T. Kidney involvement in COVID-19 and rationale for extracorporeal therapies. Nat. Rev. Nephrol. 2020, 16, 308–310. [CrossRef] [PubMed]
Ronco, C.; Reis, T.; Husain-Syed, F. Management of acute kidney injury in patients with COVID-19. Lancet Respir. Med. 2020, 8, 738–742. [CrossRef]
Cheng, Y.; Luo, R.; Wang, K.; Zhang, M.; Wang, Z.; Dong, L.; Li, J.; Yao, Y.; Ge, S.; Xu, G. Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney Int. 2020, 97, 829–838. [CrossRef]
Spiezia, L.; Boscolo, A.; Poletto, F.; Cerruti, L.; Tiberio, I.; Campello, E.; Navalesi, P.; Simioni, P. COVID-19-Related Severe Hypercoagulability in Patients Admitted to Intensive Care Unit for Acute Respiratory Failure. Thromb. Haemost. 2020, 120, 998–1000. [CrossRef]
Connors, J.M.; Levy, J.H. COVID-19 and its implications for thrombosis and anticoagulation. Blood 2020, 135, 2033–2040. [CrossRef]
Kovacs, A.; Palasti, P.; Vereb, D.; Bozsik, B.; Palko, A.; Kincses, Z.T. The sensitivity and specificity of chest CT in the diagnosis of COVID-19. Eur. Radiol. 2021, 31, 2819–2824. [CrossRef]
Glazer, G.M.; Gross, B.H.; Quint, L.E.; Francis, I.R.; Bookstein, F.L.; Orringer, M.B. Normal mediastinal lymph nodes: Number and size according to American Thoracic Society mapping. AJR Am. J. Roentgenol. 1985, 144, 261–265. [CrossRef]
Walitt, B.; Bartrum, E. A clinical primer for the expected and potential post-COVID-19 syndromes. Pain Rep. 2021, 6, e887. [CrossRef]
Chandrashekar, A.; Liu, J.; Martinot, A.J.; McMahan, K.; Mercado, N.B.; Peter, L.; Tostanoski, L.H.; Yu, J.; Maliga, Z.; Nekorchuk, M.; et al. SARS-CoV-2 infection protects against rechallenge in rhesus macaques. Science 2020, 369, 812–817. [CrossRef]
Williamson, B.N.; Feldmann, F.; Schwarz, B.; Meade-White, K.; Porter, D.P.; Schulz, J.; van Doremalen, N.; Leighton, I.; Yinda, C.K.; Perez-Perez, L.; et al. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. Nature 2020, 585, 273–276. [CrossRef]
De Wit, E.; Rasmussen, A.L.; Falzarano, D.; Bushmaker, T.; Feldmann, F.; Brining, D.L.; Fischer, E.R.; Martellaro, C.; Okumura, A.; Chang, J.; et al. Middle East respiratory syndrome coronavirus (MERS-CoV) causes transient lower respiratory tract infection in rhesus macaques. Proc. Natl. Acad. Sci. USA 2013, 110, 16598–16603. [CrossRef]
Coperchini, F.; Chiovato, L.; Croce, L.; Magri, F.; Rotondi, M. The cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system. Cytokine Growth Factor Rev. 2020, 53, 25–32. [CrossRef]
Huang, C.; Wang, Y.; Li, X.; Ren, L.; Zhao, J.; Hu, Y.; Zhang, L.; Fan, G.; Xu, J.; Gu, X.; et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020, 395, 497–506. [CrossRef]
Lu, R.; Zhao, X.; Li, J.; Niu, P.; Yang, B.; Wu, H.; Wang, W.; Song, H.; Huang, B.; Zhu, N.; et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. Lancet 2020, 395, 565–574. [CrossRef]
Hartman, A.L.; Nambulli, S.; McMillen, C.M.; White, A.G.; Tilston-Lunel, N.L.; Albe, J.R.; Cottle, E.; Dunn, M.D.; Frye, L.J.; Gilliland, T.H.; et al. SARS-CoV-2 infection of African green monkeys results in mild respiratory disease discernible by PET/CT imaging and shedding of infectious virus from both respiratory and gastrointestinal tracts. PLoS Pathog 2020, 16, e1008903. [CrossRef]
Simpson, S.; Kay, F.U.; Abbara, S.; Bhalla, S.; Chung, J.H.; Chung, M.; Henry, T.S.; Kanne, J.P.; Kligerman, S.; Ko, J.P.; et al. Radiological Society of North America Expert Consensus Statement on Reporting Chest CT Findings Related to COVID-19. Endorsed by the Society of Thoracic Radiology, the American College of Radiology, and RSNA-Secondary Publication. J. Thorac. Imaging 2020, 35, 219–227. [CrossRef]
Fan, L.; Liu, S. CT and COVID-19: Chinese experience and recommendations concerning detection, staging and follow-up. Eur. Radiol. 2020, 30, 5214–5216. [CrossRef]
Blair, R.V.; Vaccari, M.; Doyle-Meyers, L.A.; Roy, C.J.; Russell-Lodrigue, K.; Fahlberg, M.; Monjure, C.J.; Beddingfield, B.; Plante, K.S.; Plante, J.A.; et al. Acute Respiratory Distress in Aged, SARS-CoV-2-Infected African Green Monkeys but Not Rhesus Macaques. Am. J. Pathol. 2021, 191, 274–282. [CrossRef]
Singh, D.K.; Singh, B.; Ganatra, S.R.; Gazi, M.; Cole, J.; Thippeshappa, R.; Alfson, K.J.; Clemmons, E.; Gonzalez, O.; Escobedo, R.; et al. Responses to acute infection with SARS-CoV-2 in the lungs of rhesus macaques, baboons and marmosets. Nat. Microbiol. 2021, 6, 73–86. [CrossRef] [PubMed]
Yu, J.; Tostanoski, L.H.; Peter, L.; Mercado, N.B.; McMahan, K.; Mahrokhian, S.H.; Nkolola, J.P.; Liu, J.; Li, Z.; Chandrashekar, A.; et al. DNA vaccine protection against SARS-CoV-2 in rhesus macaques. Science 2020, 369, 806–811. [CrossRef]
