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SARS-CoV-2 infection leads to acute infection with dynamic cellular and inflammatory flux in the lung that varies across nonhuman primate species

Dhiraj Kumar Singh, Shashank R. Ganatra, Bindu Singh, Journey Cole, Kendra J. Alfson, Elizabeth Clemmons, Michal Gazi, Olga Gonzalez, Ruby Escobedo, Tae-Hyung Lee, Ayan Chatterjee, Yenny Goez-Gazi, Riti Sharan, Rajesh Thippeshappa, Maya Gough, Cynthia Alvarez, Alyssa Blakley, Justin Ferdin, Carmen Bartley, Hilary Staples, Laura Parodi, Jessica Callery, Amanda Mannino, Benjamin Klaffke, Priscilla Escareno, Roy N. Platt II, Vida Hodara, Julia Scordo, Adelekan Oyejide, Dharani K. Ajithdoss, Richard Copin, Alina Baum, Christos Kyratsous, Xavier Alvarez, Bruce Rosas, Mushtaq Ahmed, Anna Goodroe, John Dutton, Shannan Hall-Ursone, Patrice A. Frost, Andra K. Voges, Corinna N. Ross, Ken Sayers, Christopher Chen, Cory Hallam, Shabaana A. Khader, Makedonka Mitreva, View ORCID ProfileTimothy J. C. Anderson, Luis Martinez-Sobrido, Jean L. Patterson, Joanne Turner, Jordi B. Torrelles, Edward J. Dick Jr., Kathleen Brasky, Larry S. Schlesinger, Luis D. Giavedoni, Ricardo Carrion Jr., View ORCID ProfileDeepak Kaushal
doi: https://doi.org/10.1101/2020.06.05.136481
Dhiraj Kumar Singh
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Shashank R. Ganatra
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Bindu Singh
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Journey Cole
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Kendra J. Alfson
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Elizabeth Clemmons
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Michal Gazi
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Olga Gonzalez
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Ruby Escobedo
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Tae-Hyung Lee
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Ayan Chatterjee
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Yenny Goez-Gazi
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Riti Sharan
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Rajesh Thippeshappa
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Maya Gough
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Cynthia Alvarez
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Alyssa Blakley
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Justin Ferdin
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Carmen Bartley
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Hilary Staples
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Laura Parodi
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Jessica Callery
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Amanda Mannino
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Benjamin Klaffke
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Priscilla Escareno
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Roy N. Platt II
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Vida Hodara
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Julia Scordo
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Adelekan Oyejide
3Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591
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Dharani K. Ajithdoss
3Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591
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Richard Copin
3Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591
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Alina Baum
3Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591
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Christos Kyratsous
3Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591
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Xavier Alvarez
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Bruce Rosas
4Washington University in St Louis School of Medicine, St Louis, MO
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Mushtaq Ahmed
4Washington University in St Louis School of Medicine, St Louis, MO
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Anna Goodroe
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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John Dutton
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Shannan Hall-Ursone
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Patrice A. Frost
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Andra K. Voges
5Veterinary Imaging Consulting of South Texas, San Antonio, TX, 78258
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Corinna N. Ross
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Ken Sayers
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Christopher Chen
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Cory Hallam
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Shabaana A. Khader
4Washington University in St Louis School of Medicine, St Louis, MO
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Makedonka Mitreva
4Washington University in St Louis School of Medicine, St Louis, MO
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Timothy J. C. Anderson
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Luis Martinez-Sobrido
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Jean L. Patterson
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Joanne Turner
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Jordi B. Torrelles
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Edward J. Dick Jr.
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Kathleen Brasky
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Larry S. Schlesinger
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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Luis D. Giavedoni
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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  • For correspondence: dkaushal@txbiomed.org rcarrion@txbiomed.org lgiavedoni@txbiomed.org
Ricardo Carrion Jr.
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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  • For correspondence: dkaushal@txbiomed.org rcarrion@txbiomed.org lgiavedoni@txbiomed.org
Deepak Kaushal
1Southwest National Primate Research Center
2Texas Biomedical Research Institute, San Antonio, TX, 78227
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  • ORCID record for Deepak Kaushal
  • For correspondence: dkaushal@txbiomed.org rcarrion@txbiomed.org lgiavedoni@txbiomed.org
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Summary

There are no known cures or vaccines for COVID-19, the defining pandemic of this era. Animal models are essential to fast track new interventions and nonhuman primate (NHP) models of other infectious diseases have proven extremely valuable. Here we compare SARS-CoV-2 infection in three species of experimentally infected NHPs (rhesus macaques, baboons, and marmosets). During the first 3 days, macaques developed clinical signatures of viral infection and systemic inflammation, coupled with early evidence of viral replication and mild-to-moderate interstitial and alveolar pneumonitis, as well as extra-pulmonary pathologies. Cone-beam CT scans showed evidence of moderate pneumonia, which progressed over 3 days. Longitudinal studies showed that while both young and old macaques developed early signs of COVID-19, both groups recovered within a two-week period. Recovery was characterized by low-levels of viral persistence in the lung, suggesting mechanisms by which individuals with compromised immune systems may be susceptible to prolonged and progressive COVID-19. The lung compartment contained a complex early inflammatory milieu with an influx of innate and adaptive immune cells, particularly interstitial macrophages, neutrophils and plasmacytoid dendritic cells, and a prominent Type I-interferon response. While macaques developed moderate disease, baboons exhibited prolonged shedding of virus and extensive pathology following infection; and marmosets demonstrated a milder form of infection. These results showcase in critical detail, the robust early cellular immune responses to SARS-CoV-2 infection, which are not sterilizing and likely impact development of antibody responses. Thus, various NHP genera recapitulate heterogeneous progression of COVID-19. Rhesus macaques and baboons develop different, quantifiable disease attributes making them immediately available essential models to test new vaccines and therapies.

Competing Interest Statement

RC, Jr is funded by Regeneron, Inc. This funder had no role, however, in the design and execution of the experiments and the interpretation of data. The authors declare that no other financial conflict of interest exists. This work was primarily supported by a philanthropic award to Texas Biomed Coronavirus Working Group; a SNPRC Pilot study award to LDG, RC, JP, LM and JBT; an award to RC, Jr from Regeneron Pharmaceuticals, (contract # 2020_004110) in part with federal funds from the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority, under Contract No. HHSO100201700020C; and institutional NIH awards P51OD111033 and U42OD010442. Some members of the Regeneron team provided direct scientific help and are thus coauthors on this paper. However, the views expressed here are those of the authors and do not necessarily represent the views or official position of the funding agencies.

Footnotes

  • Abbreviations: COVID-19, Coronavirus disease 2019; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus-2; BAL, bronchoalveolar lavage; PFU, Plaque Forming Unit; CRP, C-reactive protein; CXR, thoracic radiograph; NHP, nonhuman primate; PBMC, peripheral blood mononuclear cell; dpi, days post-infection.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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SARS-CoV-2 infection leads to acute infection with dynamic cellular and inflammatory flux in the lung that varies across nonhuman primate species
Dhiraj Kumar Singh, Shashank R. Ganatra, Bindu Singh, Journey Cole, Kendra J. Alfson, Elizabeth Clemmons, Michal Gazi, Olga Gonzalez, Ruby Escobedo, Tae-Hyung Lee, Ayan Chatterjee, Yenny Goez-Gazi, Riti Sharan, Rajesh Thippeshappa, Maya Gough, Cynthia Alvarez, Alyssa Blakley, Justin Ferdin, Carmen Bartley, Hilary Staples, Laura Parodi, Jessica Callery, Amanda Mannino, Benjamin Klaffke, Priscilla Escareno, Roy N. Platt II, Vida Hodara, Julia Scordo, Adelekan Oyejide, Dharani K. Ajithdoss, Richard Copin, Alina Baum, Christos Kyratsous, Xavier Alvarez, Bruce Rosas, Mushtaq Ahmed, Anna Goodroe, John Dutton, Shannan Hall-Ursone, Patrice A. Frost, Andra K. Voges, Corinna N. Ross, Ken Sayers, Christopher Chen, Cory Hallam, Shabaana A. Khader, Makedonka Mitreva, Timothy J. C. Anderson, Luis Martinez-Sobrido, Jean L. Patterson, Joanne Turner, Jordi B. Torrelles, Edward J. Dick Jr., Kathleen Brasky, Larry S. Schlesinger, Luis D. Giavedoni, Ricardo Carrion Jr., Deepak Kaushal
bioRxiv 2020.06.05.136481; doi: https://doi.org/10.1101/2020.06.05.136481
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SARS-CoV-2 infection leads to acute infection with dynamic cellular and inflammatory flux in the lung that varies across nonhuman primate species
Dhiraj Kumar Singh, Shashank R. Ganatra, Bindu Singh, Journey Cole, Kendra J. Alfson, Elizabeth Clemmons, Michal Gazi, Olga Gonzalez, Ruby Escobedo, Tae-Hyung Lee, Ayan Chatterjee, Yenny Goez-Gazi, Riti Sharan, Rajesh Thippeshappa, Maya Gough, Cynthia Alvarez, Alyssa Blakley, Justin Ferdin, Carmen Bartley, Hilary Staples, Laura Parodi, Jessica Callery, Amanda Mannino, Benjamin Klaffke, Priscilla Escareno, Roy N. Platt II, Vida Hodara, Julia Scordo, Adelekan Oyejide, Dharani K. Ajithdoss, Richard Copin, Alina Baum, Christos Kyratsous, Xavier Alvarez, Bruce Rosas, Mushtaq Ahmed, Anna Goodroe, John Dutton, Shannan Hall-Ursone, Patrice A. Frost, Andra K. Voges, Corinna N. Ross, Ken Sayers, Christopher Chen, Cory Hallam, Shabaana A. Khader, Makedonka Mitreva, Timothy J. C. Anderson, Luis Martinez-Sobrido, Jean L. Patterson, Joanne Turner, Jordi B. Torrelles, Edward J. Dick Jr., Kathleen Brasky, Larry S. Schlesinger, Luis D. Giavedoni, Ricardo Carrion Jr., Deepak Kaushal
bioRxiv 2020.06.05.136481; doi: https://doi.org/10.1101/2020.06.05.136481

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