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

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 bei...

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Published in:bioRxiv 2020-09
Main Authors: Hoang, Timothy N, Pino, Maria, Boddapati, Arun K, Viox, Elise G, Starke, Carly E, Upadhyay, Amit A, Gumber, Sanjeev, Busman-Sahay, Kathleen, Strongin, Zachary, Harper, Justin L, Tharp, Gregory K, Pellegrini, Kathryn L, Kirejczyk, Shannon, Zandi, Keivan, Tao, Sijia, Horton, Tristan R, Beagle, Elizabeth N, Mahar, Ernestine A, Lee, Michelle Yh, Cohen, Joyce, Jean, Sherrie M, Wood, Jennifer S, Connor-Stroud, Fawn, Stammen, Rachelle L, Delmas, Olivia M, Wang, Shelly, Cooney, Kimberly A, Sayegh, Michael N, Wang, Lanfang, Weiskopf, Daniela, Filev, Peter D, Waggoner, Jesse, Piantadosi, Anne, Kasturi, Sudhir P, Al- Shakhshir, Hilmi, Ribeiro, Susan P, Sekaly, Rafick P, Levit, Rebecca D, Estes, Jacob D, Vanderford, Thomas H, Schinazi, Raymond F, Bosinger, Steven E, Paiardini, Mirko
Format: Article
Language:English
Subjects:
Alveoli
Anti-inflammatory agents
Antiviral activity
Antiviral agents
Bronchus
Cell activation
Chemokines
Clinical trials
Coronaviruses
COVID-19
Cytokines
Drug development
Endocytosis
Immunosuppressive agents
Inflammation
Interferon
Janus kinase
Leukocytes (neutrophilic)
Lymphocytes T
Macrophages
Neutrophils
Respiratory tract diseases
Severe acute respiratory syndrome coronavirus 2
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Summary: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.
DOI:10.1101/2020.09.16.300277