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.

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 / drug therapy*
  • COVID-19 / immunology*
  • COVID-19 / physiopathology
  • 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