show Abstracthide AbstractSARS-CoV-2 induced hypercytokinemia and inflammation are critically associated with COVID-19 disease severity. Baricitinib, a clinically approved JAK1/2 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 IFN antiviral responses and SARS-CoV-2-specific T-cell responses remained similar between the two groups. Importantly, animals treated with baricitinib showed reduced inflammation, decreased lung infiltration of neutrophils, reduced NETosis activity, and more limited lung pathology. Moreover, baricitinib treated animals had a rapid and remarkably potent suppression of lung macrophages 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. Overall design: Five rhesus macaques (Macaca mulatta) were infected with SARS-CoV-2. Two RMs were administered 4 mg Baricitinib starting at day 2 post-infection (DPI) for 8-9 consecutive days. scRNA-Seq profiling of cells isolated from BAL (bronchoalveolar lavages) prior to SARS-CoV-2 inoculation (-5 DPI; Baseline); and 4 days after infection, and 48 hours after beginning baricitinib (4 DPI).