Baricitinib lowers inflammation and pathology in SARS-CoV-2-infected rhesus macaques

Background: The emergence of SARS-CoV-2 and COVID-19 pandemic has placed an excessive burden on public and private healthcare systems with over 1,400,000 deaths worldwide. Thus, therapeutics aimed at mitigating disease severity are urgently needed. Immunological features of COVID-19 progression include an influx of innate and adaptive immune cells to the lung, with severe cases having elevated levels of pro-inflammatory cytokines and chemokines. Baricitinib is an oral, selective inhibitor of JAK 1/2 with potent antiinflammatory activity approved for patients with moderate to severe active rheumatoid arthritis and predicted to have anti-SARS-CoV-2 effects based on in silico modeling. Methods: 8 rhesus macaques (RMs) were infected with 1.1x10 6 PFU SARSCoV- 2;at 2 days post infection (dpi), 4 of the 8 RMs began daily baricitinib treatment (4 mg/day). Nasal and throat swabs were collected daily for viral load;longitudinal blood and bronchoalveolar lavage (BAL) samples were collected for viral load, flow cytometry, cytokines and RNAseq analysis and at 10/11 dpi all RMs were euthanized for pathological analyses. Results: Baricitinib was found in plasma and in the lungs of all treated RMs and was safe and well tolerated. Viral replication dynamics measured from nasal and throat swabs, BAL and lung at necropsy were not reduced with baricitinib. Innate Type-I IFN antiviral responses and adaptive SARS-CoV-2- specific T-cell responses remained similar between the two groups. RMs treated with baricitinib showed reduced inflammation (ferritin, CRP, histology), T cell immune activation and proliferation, neutrophil NETosis activity, and lung pathology, with decreased type 2 pneumocyte hyperplasia, peribronchiolar hyperplasia, and inflammatory cell infiltration. Importantly, baricitinib treated RMs had a rapid and remarkably potent suppression of alveolar macrophage production of cytokines (IL-6, TNFa, IL-10, IL-1b and IFNb1) and chemokines (CCL4L1, CXCL10, CXCL3 and CXCL8) responsible for a pro-inflammatory environment and for the recruitment of neutrophil and pro-inflammatory monocytes. Additionally, we identified that a population of MARCOmacrophages are the primary producers of pro-inflammatory cytokines and are reduced in the lungs of baricitinib treated animals. Conclusion: These data provide rationale and mechanistic insight for the use of baricitinib as a frontline therapeutic to reduce systemic inflammation induced following SARS-CoV-2 infection.