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Baricitinib treatment resolves lower airway inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques

View ORCID ProfileTimothy N. Hoang, Maria Pino, Arun K. Boddapati, Elise G. Viox, Carly E. Starke, Amit A. Upadhyay, Sanjeev Gumber, Kathleen Busman-Sahay, Zachary Strongin, Justin L. Harper, Gregory K. Tharp, Kathryn L. Pellegrini, Shannon Kirejczyk, Keivan Zandi, Sijia Tao, Tristan R. Horton, Elizabeth N. Beagle, Ernestine A. Mahar, Michelle YH Lee, Joyce Cohen, Sherrie M. Jean, Jennifer S. Wood, Fawn Connor-Stroud, Rachelle L. Stammen, Olivia M. Delmas, Shelly Wang, Kimberly A. Cooney, Michael N. Sayegh, Lanfang Wang, Daniela Weiskopf, Peter D. Filev, Jesse Waggoner, Anne Piantadosi, Sudhir P. Kasturi, Hilmi Al- Shakhshir, Susan P. Ribeiro, Rafick P. Sekaly, Rebecca D. Levit, Jacob D. Estes, Thomas H. Vanderford, Raymond F. Schinazi, Steven E. Bosinger, Mirko Paiardini
doi: https://doi.org/10.1101/2020.09.16.300277
Timothy N. Hoang
1Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
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  • ORCID record for Timothy N. Hoang
Maria Pino
1Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
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Arun K. Boddapati
2Yerkes Genomics Core Laboratory, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
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Elise G. Viox
1Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
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Carly E. Starke
9Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR, USA
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Amit A. Upadhyay
2Yerkes Genomics Core Laboratory, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
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Sanjeev Gumber
6Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, Atlanta, Georgia, USA
7Division of Pathology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
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Kathleen Busman-Sahay
9Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR, USA
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Zachary Strongin
1Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
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Justin L. Harper
1Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
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Gregory K. Tharp
2Yerkes Genomics Core Laboratory, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
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Kathryn L. Pellegrini
2Yerkes Genomics Core Laboratory, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
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Shannon Kirejczyk
7Division of Pathology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
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Keivan Zandi
8Center for AIDS Research, Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia, USA
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Sijia Tao
8Center for AIDS Research, Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia, USA
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Tristan R. Horton
2Yerkes Genomics Core Laboratory, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
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Elizabeth N. Beagle
2Yerkes Genomics Core Laboratory, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
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Ernestine A. Mahar
1Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
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Michelle YH Lee
1Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
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Joyce Cohen
3Division of Animal Resources, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
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Sherrie M. Jean
3Division of Animal Resources, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
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Jennifer S. Wood
3Division of Animal Resources, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
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Fawn Connor-Stroud
3Division of Animal Resources, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
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Rachelle L. Stammen
3Division of Animal Resources, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
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Olivia M. Delmas
1Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
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Shelly Wang
1Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
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Kimberly A. Cooney
4Department of Medicine, School of Medicine, Emory University, Atlanta, Georgia, USA
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Michael N. Sayegh
4Department of Medicine, School of Medicine, Emory University, Atlanta, Georgia, USA
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Lanfang Wang
4Department of Medicine, School of Medicine, Emory University, Atlanta, Georgia, USA
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Daniela Weiskopf
12Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA, USA
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Peter D. Filev
5Department of Radiology and Imaging Sciences, School of Medicine, Emory University, Atlanta, Georgia, USA
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Jesse Waggoner
4Department of Medicine, School of Medicine, Emory University, Atlanta, Georgia, USA
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Anne Piantadosi
4Department of Medicine, School of Medicine, Emory University, Atlanta, Georgia, USA
6Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, Atlanta, Georgia, USA
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Sudhir P. Kasturi
1Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
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Hilmi Al- Shakhshir
11Department of Pathology, Case Western Reserve University, Cleveland, OH, USA
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Susan P. Ribeiro
11Department of Pathology, Case Western Reserve University, Cleveland, OH, USA
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Rafick P. Sekaly
11Department of Pathology, Case Western Reserve University, Cleveland, OH, USA
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Rebecca D. Levit
4Department of Medicine, School of Medicine, Emory University, Atlanta, Georgia, USA
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Jacob D. Estes
9Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR, USA
10Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA
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Thomas H. Vanderford
1Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
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Raymond F. Schinazi
8Center for AIDS Research, Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia, USA
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Steven E. Bosinger
1Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
2Yerkes Genomics Core Laboratory, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
6Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, Atlanta, Georgia, USA
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Mirko Paiardini
1Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
6Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, Atlanta, Georgia, USA
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  • For correspondence: mirko.paiardini@emory.edu
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Abstract

Effective therapeutics aimed at mitigating COVID-19 symptoms are urgently needed. SARS-CoV-2 induced hypercytokinemia and systemic inflammation are associated with disease severity. Baricitinib, a clinically approved JAK1/2 inhibitor with potent anti-inflammatory properties is currently being investigated in COVID-19 human clinical trials. Recent reports suggest that baricitinib may also have antiviral activity in limiting viral endocytosis. Here, we investigated the immunologic and virologic efficacy of baricitinib in a rhesus macaque model of SARS-CoV-2 infection. Viral shedding measured from nasal and throat swabs, bronchoalveolar lavages and tissues was not reduced with baricitinib. Type I IFN antiviral responses and SARS-CoV-2 specific T cell responses remained similar between the two groups. Importantly, however, animals treated with baricitinib showed reduced immune activation, decreased infiltration of neutrophils into the lung, reduced NETosis activity, and more limited lung pathology. Moreover, baricitinib treated animals had a rapid and remarkably potent suppression of alveolar macrophage derived production of cytokines and chemokines responsible for inflammation and neutrophil recruitment. These data support a beneficial role for, and elucidate the immunological mechanisms underlying, the use of baricitinib as a frontline treatment for severe inflammation induced by SARS-CoV-2 infection.

Competing Interest Statement

Dr. Raymond Schinazi served as an unpaid consultant for Eli Lilly whose drugs are being evaluated in the research described in this paper. In addition, Dr. Schinazi owns shares in Eli Lilly. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policies. All other authors do not have any conflicts to declare.

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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Baricitinib treatment resolves lower airway inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques
Timothy N. Hoang, Maria Pino, Arun K. Boddapati, Elise G. Viox, Carly E. Starke, Amit A. Upadhyay, Sanjeev Gumber, Kathleen Busman-Sahay, Zachary Strongin, Justin L. Harper, Gregory K. Tharp, Kathryn L. Pellegrini, Shannon Kirejczyk, Keivan Zandi, Sijia Tao, Tristan R. Horton, Elizabeth N. Beagle, Ernestine A. Mahar, Michelle YH Lee, Joyce Cohen, Sherrie M. Jean, Jennifer S. Wood, Fawn Connor-Stroud, Rachelle L. Stammen, Olivia M. Delmas, Shelly Wang, Kimberly A. Cooney, Michael N. Sayegh, Lanfang Wang, Daniela Weiskopf, Peter D. Filev, Jesse Waggoner, Anne Piantadosi, Sudhir P. Kasturi, Hilmi Al- Shakhshir, Susan P. Ribeiro, Rafick P. Sekaly, Rebecca D. Levit, Jacob D. Estes, Thomas H. Vanderford, Raymond F. Schinazi, Steven E. Bosinger, Mirko Paiardini
bioRxiv 2020.09.16.300277; doi: https://doi.org/10.1101/2020.09.16.300277
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Baricitinib treatment resolves lower airway inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques
Timothy N. Hoang, Maria Pino, Arun K. Boddapati, Elise G. Viox, Carly E. Starke, Amit A. Upadhyay, Sanjeev Gumber, Kathleen Busman-Sahay, Zachary Strongin, Justin L. Harper, Gregory K. Tharp, Kathryn L. Pellegrini, Shannon Kirejczyk, Keivan Zandi, Sijia Tao, Tristan R. Horton, Elizabeth N. Beagle, Ernestine A. Mahar, Michelle YH Lee, Joyce Cohen, Sherrie M. Jean, Jennifer S. Wood, Fawn Connor-Stroud, Rachelle L. Stammen, Olivia M. Delmas, Shelly Wang, Kimberly A. Cooney, Michael N. Sayegh, Lanfang Wang, Daniela Weiskopf, Peter D. Filev, Jesse Waggoner, Anne Piantadosi, Sudhir P. Kasturi, Hilmi Al- Shakhshir, Susan P. Ribeiro, Rafick P. Sekaly, Rebecca D. Levit, Jacob D. Estes, Thomas H. Vanderford, Raymond F. Schinazi, Steven E. Bosinger, Mirko Paiardini
bioRxiv 2020.09.16.300277; doi: https://doi.org/10.1101/2020.09.16.300277

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