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Baricitinib treatment resolves lower-airway macrophage inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques.
Cell. 2021 01 21; 184(2):460-475.e21.Cell

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.

Authors+Show Affiliations

Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.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.Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006, 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; Division of Pathology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006, USA.Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006, USA.Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.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.Yerkes Genomics Core Laboratory, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.Division of Pathology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.Center for AIDS Research, Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322, USA.Center for AIDS Research, Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322, USA.Yerkes Genomics Core Laboratory, 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.Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.Division of Animal Resources, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.Division of Animal Resources, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.Division of Animal Resources, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.Division of Animal Resources, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.Division of Animal Resources, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.Department of Medicine, School of Medicine, Emory University, Atlanta, GA 30322, USA.Department of Medicine, School of Medicine, Emory University, Atlanta, GA 30322, USA.Department of Medicine, School of Medicine, Emory University, Atlanta, GA 30322, USA.Department of Radiology and Imaging Sciences, School of Medicine, Emory University, Atlanta, GA 30322, USA.Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.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.Department of Medicine, School of Medicine, Emory University, Atlanta, GA 30322, USA.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.Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.Department of Medicine, School of Medicine, Emory University, Atlanta, GA 30322, USA.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.Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.Center for AIDS Research, Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322, USA. Electronic address: rschina@emory.edu.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.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.

Pub Type(s)

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

Language

eng

PubMed ID

33278358

Citation

Hoang, Timothy N., et al. "Baricitinib Treatment Resolves Lower-airway Macrophage Inflammation and Neutrophil Recruitment in SARS-CoV-2-infected Rhesus Macaques." Cell, vol. 184, no. 2, 2021, pp. 460-475.e21.
Hoang TN, Pino M, Boddapati AK, et al. Baricitinib treatment resolves lower-airway macrophage inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques. Cell. 2021;184(2):460-475.e21.
Hoang, T. N., Pino, M., Boddapati, A. K., Viox, E. G., Starke, C. E., Upadhyay, A. A., Gumber, S., Nekorchuk, M., Busman-Sahay, K., Strongin, Z., Harper, J. L., Tharp, G. K., Pellegrini, K. L., Kirejczyk, S., Zandi, K., Tao, S., Horton, T. R., Beagle, E. N., Mahar, E. A., ... Paiardini, M. (2021). Baricitinib treatment resolves lower-airway macrophage inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques. Cell, 184(2), 460-e21. https://doi.org/10.1016/j.cell.2020.11.007
Hoang TN, et al. Baricitinib Treatment Resolves Lower-airway Macrophage Inflammation and Neutrophil Recruitment in SARS-CoV-2-infected Rhesus Macaques. Cell. 2021 01 21;184(2):460-475.e21. PubMed PMID: 33278358.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Baricitinib treatment resolves lower-airway macrophage inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques. AU - Hoang,Timothy N, AU - Pino,Maria, AU - Boddapati,Arun K, AU - Viox,Elise G, AU - Starke,Carly E, AU - Upadhyay,Amit A, AU - Gumber,Sanjeev, AU - Nekorchuk,Michael, AU - Busman-Sahay,Kathleen, AU - Strongin,Zachary, AU - Harper,Justin L, AU - Tharp,Gregory K, AU - Pellegrini,Kathryn L, AU - Kirejczyk,Shannon, AU - Zandi,Keivan, AU - Tao,Sijia, AU - Horton,Tristan R, AU - Beagle,Elizabeth N, AU - Mahar,Ernestine A, AU - Lee,Michelle Y H, AU - Cohen,Joyce, AU - Jean,Sherrie M, AU - Wood,Jennifer S, AU - Connor-Stroud,Fawn, AU - Stammen,Rachelle L, AU - Delmas,Olivia M, AU - Wang,Shelly, AU - Cooney,Kimberly A, AU - Sayegh,Michael N, AU - Wang,Lanfang, AU - Filev,Peter D, AU - Weiskopf,Daniela, AU - Silvestri,Guido, AU - Waggoner,Jesse, AU - Piantadosi,Anne, AU - Kasturi,Sudhir P, AU - Al-Shakhshir,Hilmi, AU - Ribeiro,Susan P, AU - Sekaly,Rafick P, AU - Levit,Rebecca D, AU - Estes,Jacob D, AU - Vanderford,Thomas H, AU - Schinazi,Raymond F, AU - Bosinger,Steven E, AU - Paiardini,Mirko, Y1 - 2020/11/10/ PY - 2020/08/28/received PY - 2020/10/08/revised PY - 2020/11/04/accepted PY - 2020/12/6/pubmed PY - 2021/1/30/medline PY - 2020/12/5/entrez KW - COVID-19 KW - SARS-CoV-2 KW - baricitinib KW - immune activation KW - immunology KW - inflammation KW - nonhuman primate KW - pathogenesis SP - 460 EP - 475.e21 JF - Cell JO - Cell VL - 184 IS - 2 N2 - 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. SN - 1097-4172 UR - https://www.unboundmedicine.com/medline/citation/33278358/Baricitinib_treatment_resolves_lower_airway_macrophage_inflammation_and_neutrophil_recruitment_in_SARS_CoV_2_infected_rhesus_macaques_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0092-8674(20)31466-5 DB - PRIME DP - Unbound Medicine ER -