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

doi:10.1016/j.cell.2020.11.007

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

Cell. 2021 Jan 21;184(2):460-475.e21. doi: 10.1016/j.cell.2020.11.007. Epub 2020 Nov 10.

Authors

Timothy N Hoang¹, Maria Pino¹, Arun K Boddapati², Elise G Viox¹, Carly E Starke³, Amit A Upadhyay², Sanjeev Gumber⁴, Michael Nekorchuk³, Kathleen Busman-Sahay³, Zachary Strongin¹, Justin L Harper¹, Gregory K Tharp², Kathryn L Pellegrini², Shannon Kirejczyk⁵, Keivan Zandi⁶, Sijia Tao⁶, Tristan R Horton², Elizabeth N Beagle², Ernestine A Mahar¹, Michelle Y H Lee¹, Joyce Cohen⁷, Sherrie M Jean⁷, Jennifer S Wood⁷, Fawn Connor-Stroud⁷, Rachelle L Stammen⁷, Olivia M Delmas¹, Shelly Wang¹, Kimberly A Cooney⁸, Michael N Sayegh⁸, Lanfang Wang⁸, Peter D Filev⁹, Daniela Weiskopf¹⁰, Guido Silvestri¹¹, Jesse Waggoner⁸, Anne Piantadosi¹², Sudhir P Kasturi¹, Hilmi Al-Shakhshir¹³, Susan P Ribeiro¹³, Rafick P Sekaly¹³, Rebecca D Levit⁸, Jacob D Estes¹⁴, Thomas H Vanderford¹, Raymond F Schinazi¹⁵, Steven E Bosinger¹⁶, Mirko Paiardini¹⁷

Affiliations

¹ Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
² Yerkes Genomics Core Laboratory, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
³ Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006, USA.
⁴ 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.
⁵ Division of Pathology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
⁶ Center for AIDS Research, Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322, USA.
⁷ Division of Animal Resources, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
⁸ Department of Medicine, School of Medicine, Emory University, Atlanta, GA 30322, USA.
⁹ Department of Radiology and Imaging Sciences, School of Medicine, Emory University, Atlanta, GA 30322, USA.
¹⁰ Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
¹¹ 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.
¹² 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.
¹³ Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
¹⁴ 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.
¹⁵ Center for AIDS Research, Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322, USA. Electronic address: rschina@emory.edu.
¹⁶ 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.
¹⁷ 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.

Abstract

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.

Keywords: COVID-19; SARS-CoV-2; baricitinib; immune activation; immunology; inflammation; nonhuman primate; pathogenesis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Inflammatory Agents / administration & dosage*
Azetidines / administration & dosage*
COVID-19 / immunology*
COVID-19 / physiopathology
COVID-19 Drug Treatment*
Cell Death / drug effects
Cell Degranulation / drug effects
Disease Models, Animal
Inflammation / drug therapy
Inflammation / genetics
Inflammation / immunology
Janus Kinases / antagonists & inhibitors
Lung / drug effects
Lung / immunology
Lung / pathology
Lymphocyte Activation / drug effects
Macaca mulatta*
Macrophages, Alveolar / immunology
Neutrophil Infiltration / drug effects*
Purines / administration & dosage*
Pyrazoles / administration & dosage*
SARS-CoV-2 / physiology
Severity of Illness Index
Sulfonamides / administration & dosage*
T-Lymphocytes / immunology
Virus Replication / drug effects

Substances

Anti-Inflammatory Agents
Azetidines
Purines
Pyrazoles
Sulfonamides
Janus Kinases
baricitinib

Abstract

Publication types

MeSH terms

Substances

Grants and funding