Baricitinib treatment resolves lower-airway macrophage 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, Michael Nekorchuk, 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 Y H 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, Peter D Filev, Daniela Weiskopf, Guido Silvestri, 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
Author Information
Timothy N Hoang: Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Maria Pino: Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Arun K Boddapati: Yerkes Genomics Core Laboratory, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Elise G Viox: Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Carly E Starke: Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006, USA.
Amit A Upadhyay: Yerkes Genomics Core Laboratory, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Sanjeev Gumber: Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, Atlanta, GA 30322, USA; Division of Pathology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Michael Nekorchuk: Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006, USA.
Kathleen Busman-Sahay: Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006, USA.
Zachary Strongin: Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Justin L Harper: Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Gregory K Tharp: Yerkes Genomics Core Laboratory, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Kathryn L Pellegrini: Yerkes Genomics Core Laboratory, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Shannon Kirejczyk: Division of Pathology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Keivan Zandi: Center for AIDS Research, Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322, USA.
Sijia Tao: Center for AIDS Research, Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322, USA.
Tristan R Horton: Yerkes Genomics Core Laboratory, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Elizabeth N Beagle: Yerkes Genomics Core Laboratory, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Ernestine A Mahar: Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Michelle Y H Lee: Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Joyce Cohen: Division of Animal Resources, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Sherrie M Jean: Division of Animal Resources, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Jennifer S Wood: Division of Animal Resources, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Fawn Connor-Stroud: Division of Animal Resources, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Rachelle L Stammen: Division of Animal Resources, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Olivia M Delmas: Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Shelly Wang: Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Kimberly A Cooney: Department of Medicine, School of Medicine, Emory University, Atlanta, GA 30322, USA.
Michael N Sayegh: Department of Medicine, School of Medicine, Emory University, Atlanta, GA 30322, USA.
Lanfang Wang: Department of Medicine, School of Medicine, Emory University, Atlanta, GA 30322, USA.
Peter D Filev: Department of Radiology and Imaging Sciences, School of Medicine, Emory University, Atlanta, GA 30322, USA.
Daniela Weiskopf: Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
Guido Silvestri: Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA; Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, Atlanta, GA 30322, USA.
Jesse Waggoner: Department of Medicine, School of Medicine, Emory University, Atlanta, GA 30322, USA.
Anne Piantadosi: Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, Atlanta, GA 30322, USA; Department of Medicine, School of Medicine, Emory University, Atlanta, GA 30322, USA.
Sudhir P Kasturi: Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Hilmi Al-Shakhshir: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
Susan P Ribeiro: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
Rafick P Sekaly: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
Rebecca D Levit: Department of Medicine, School of Medicine, Emory University, Atlanta, GA 30322, USA.
Jacob D Estes: Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006, USA; Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006, USA.
Thomas H Vanderford: Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Raymond F Schinazi: Center for AIDS Research, Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322, USA. Electronic address: rschina@emory.edu.
Steven E Bosinger: Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA; Yerkes Genomics Core Laboratory, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA; Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, Atlanta, GA 30322, USA. Electronic address: steven.bosinger@emory.edu.
Mirko Paiardini: Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA; Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, Atlanta, GA 30322, USA. Electronic address: mirko.paiardini@emory.edu.
SARS-CoV-2-induced hypercytokinemia and inflammation are critically associated with COVID-19 severity. Baricitinib, a clinically approved JAK1/JAK2 inhibitor, is currently being investigated in COVID-19 clinical trials. 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 interferon (IFN) antiviral responses and SARS-CoV-2-specific T cell responses remained similar between the two groups. Animals treated with baricitinib showed reduced inflammation, decreased lung infiltration of inflammatory cells, reduced NETosis activity, and more limited lung pathology. Importantly, baricitinib-treated animals had a rapid and remarkably potent suppression of lung macrophage 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 inflammation induced by SARS-CoV-2 infection.
