Hoang Timothy N, Pino Maria, Boddapati Arun K, Viox Elise G, Starke Carly E, Upadhyay Amit A, Gumber Sanjeev, Busman-Sahay Kathleen, Strongin Zachary, Harper Justin L, Tharp Gregory K, Pellegrini Kathryn L, Kirejczyk Shannon, Zandi Keivan, Tao Sijia, Horton Tristan R, Beagle Elizabeth N, Mahar Ernestine A, Lee Michelle Yh, Cohen Joyce, Jean Sherrie M, Wood Jennifer S, Connor-Stroud Fawn, Stammen Rachelle L, Delmas Olivia M, Wang Shelly, Cooney Kimberly A, Sayegh Michael N, Wang Lanfang, Weiskopf Daniela, Filev Peter D, Waggoner Jesse, Piantadosi Anne, Kasturi Sudhir P, Al-Shakhshir Hilmi, Ribeiro Susan P, Sekaly Rafick P, Levit Rebecca D, Estes Jacob D, Vanderford Thomas H, Schinazi Raymond F, Bosinger Steven E, Paiardini Mirko
Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
Yerkes Genomics Core Laboratory, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
bioRxiv. 2020 Sep 16:2020.09.16.300277. doi: 10.1101/2020.09.16.300277.
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.
迫切需要有效的疗法来减轻新冠病毒疾病（COVID-19）的症状。严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引发的高细胞因子血症和全身炎症与疾病严重程度相关。巴瑞替尼是一种临床批准的具有强效抗炎特性的Janus激酶1/2（JAK1/2）抑制剂，目前正在COVID-19人体临床试验中进行研究。最近的报告表明，巴瑞替尼在限制病毒内吞作用方面可能也具有抗病毒活性。在此，我们在SARS-CoV-2感染的恒河猴模型中研究了巴瑞替尼的免疫学和病毒学疗效。通过鼻腔和咽喉拭子、支气管肺泡灌洗和组织检测的病毒脱落情况，使用巴瑞替尼后并未减少。两组之间的I型干扰素抗病毒反应和SARS-CoV-2特异性T细胞反应仍相似。然而，重要的是，接受巴瑞替尼治疗的动物免疫激活减少，肺内中性粒细胞浸润减少，中性粒细胞胞外诱捕作用活性降低，肺部病理变化也更有限。此外，接受巴瑞替尼治疗的动物对肺泡巨噬细胞产生的负责炎症和中性粒细胞募集的细胞因子和趋化因子有快速且显著有效的抑制作用。这些数据支持了巴瑞替尼作为SARS-CoV-2感染所致严重炎症的一线治疗方法的有益作用，并阐明了其潜在的免疫机制。
