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mirko.paiardini@emory.edu

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We kindly thank the Yerkes National Primate Research Center (YNPRC) Division of Animal Resources, especially Stephanie Ehnert, Stacey Weissman, Denise Bonenberger, John M. Wambua, Dominic M. D’Urso, Racquel Sampson-Harley and Kalpana Patel in Research Resources and Joyce Cohen in Veterinary Medicine, for providing support in animal care. Pharmaceutical-grade Baricitinib was commercially obtained, provided free of charge by Dr. Schinazi, and it was found to be > 99% pure by LC-MS-MS.

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.

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Research Funding:

This study was primarily supported by an Emory University COVID-19 Molecules and Pathogens to Populations and Pandemics (MP3) Initiative Seed Grant to M.Pa., A.P., and R.F.S., and by YNPRC Coronavirus Pilot Research Project Program grant to M.Pa. under award P51 OD11132. This work was supported by the NIAID, NIH, under awards R37AI141258, R01AI116379 to M.Pa. and R01MH116695 to R.F.S and U24 AI120134 to S.E.B. Support for this work was also provided by award NIH Office of Research Infrastructure Programs (ORIP) P51 OD11132 to YNPRC, P51OD011092 to ONPRC, 1S10OD025002-01 to the Integrated Pathology Core/ONPRC, and NIH National Institute of Allergy and Infectious Diseases (NIAID) award P30 AI050409 to the Center for AIDS Research (CFAR) at Emory University. Next generation sequencing services were provided by the Yerkes NHP Genomics Core which is supported in part by NIH P51 OD011132. Sequencing data was acquired on an Illumina NovaSeq6000 funded by NIH S10 OD026799 to S.E.B. This work was additionally funded by grants from the National Institutes of Health/National Institutes of Allergy and Infectious Diseases R01 AI143411-01A1 and R01 AI149672 to J.D.E.

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

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bioRxiv

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Type of Work:

Article | Preprint: Prior to Peer Review

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.

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This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/).
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