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

SARS-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).

SARS-CoV-2诱导的细胞因子风暴与炎症反应与COVID-19疾病严重程度密切相关。巴瑞替尼（baricitinib）是一款临床获批的JAK1/2抑制剂，目前正处于COVID-19临床试验阶段。本研究在SARS-CoV-2感染的恒河猴模型中，探究了巴瑞替尼的免疫学与病毒学疗效。通过鼻拭子、咽拭子、支气管肺泡灌洗液（bronchoalveolar lavages，以下简称BAL）及组织样本检测的病毒脱落水平，在巴瑞替尼给药组中未出现显著降低。两组的I型干扰素（Type-I IFN）抗病毒应答以及SARS-CoV-2特异性T细胞应答水平均无明显差异。值得注意的是，巴瑞替尼处理的动物表现出炎症反应减轻、肺部中性粒细胞浸润减少、中性粒细胞胞外陷阱形成（NETosis）活性降低，以及更局限的肺部病理损伤。此外，巴瑞替尼处理组动物的肺部巨噬细胞所产生的促炎细胞因子与招募中性粒细胞的趋化因子的分泌，被快速且显著抑制。本研究数据支持巴瑞替尼作为SARS-CoV-2感染所致重症炎症的一线治疗方案的有益作用，并阐明了其背后的免疫学机制。
整体实验设计：共5只恒河猴（Macaca mulatta）经SARS-CoV-2感染。其中2只恒河猴于感染后第2天（post-infection day，以下简称DPI）开始给予4 mg巴瑞替尼，连续给药8-9天。分别在SARS-CoV-2接种前（-5 DPI；基线）、感染后第4天，以及开始巴瑞替尼给药后48小时（4 DPI），对从BAL中分离的细胞进行单细胞RNA测序（single-cell RNA sequencing，以下简称scRNA-Seq）转录组分析。