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

Hoang, T. N.; Pino, M.; Boddapati, A. K.; Viox, E. G.; Starke, C. E.; Upadhyay, A. A.; Gumber, S.; Busman-Sahay, K.; Strongin, Z.; Harper, J. L.; Tharp, G. K.; Pellegrini, K. L.; Kirejczyk, S.; Zandi, K.; Tao, S.; Horton, T. R.; Beagle, E. N.; Mahar, E. A.; Lee, M. Y.; Cohen, J.; Jean, S.; Wood, J. S.; Connor-Stroud, F.; Stammen, R. L.; Delmas, O. M.; Wang, S.; Cooney, K. A.; Sayegh, M. N.; Wang, L.; Weiskopf, D.; Filev, P. D.; Waggoner, J.; Piantadosi, A.; Kasturi, S. P.; Al-Shakhshir, H.; Ribeiro, S. P.; Sekaly, R. P.; Levit, R. D.; Estes, J. D.; Vanderford, T. H.; Schinazi, R. F.; Bosinger,

doi:10.1101/2020.09.16.300277

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bioRxiv · 10.1101/2020.09.16.300277

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

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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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Hoang, T. N., Pino, M., Boddapati, A. K., Viox, E. G., Starke, C. E., Upadhyay, A. A., Gumber, S., Busman-Sahay, K., Strongin, Z., Harper, J. L., Tharp, G. K., Pellegrini, K. L., Kirejczyk, S., Zandi, K., Tao, S., Horton, T. R., Beagle, E. N., Mahar, E. A., Lee, M. Y., Cohen, J., Jean, S., Wood, J. S., Connor-Stroud, F., Stammen, R. L., Delmas, O. M., Wang, S., Cooney, K. A., Sayegh, M. N., Wang, L., Weiskopf, D., Filev, P. D., Waggoner, J., Piantadosi, A., Kasturi, S. P., Al-Shakhshir, H., Ribeiro, S. P., Sekaly, R. P., Levit, R. D., Estes, J. D., Vanderford, T. H., Schinazi, R. F., Bosinger,. 2020-09-16. Baricitinib treatment resolves lower airway inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques. https://doi.org/10.1101/2020.09.16.300277

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