Younan Patrick, Ramanathan Palaniappan, Graber Jessica, Gusovsky Fabian, Bukreyev Alexander
Department of Pathology, The University of Texas Medical Branch, Galveston, Texas, USA.
Galveston National Laboratory, The University of Texas Medical Branch, Galveston, Texas, USA.
mBio. 2017 Apr 25;8(2):e00226-17. doi: 10.1128/mBio.00226-17.
The 2013-2016 outbreak of Ebola virus (EBOV) in West Africa, which has seen intermittent reemergence since it was officially declared over in February of 2016, has demonstrated the need for the rapid development of therapeutic intervention strategies. Indirect evidence has suggested that the EBOV infection shares several commonalities associated with the onset of bacterial sepsis, including the development of a "cytokine storm." Eritoran, a Toll-like receptor 4 (TLR4) antagonist, was previously shown to result in protection of mice against lethal influenza virus infection. Here, we report that eritoran protects against the lethality caused by EBOV and the closely related Marburg virus (MARV) in mice. Daily administration of eritoran reduced clinical signs of the disease and, unexpectedly, resulted in reduced viral titers. Analysis of peripheral blood indicated that eritoran reduced granulocytosis despite an apparent increase in the percentage of activated neutrophils. Surprisingly, the increased survival rate and reduced viremia were not accompanied by increased CD3 T lymphocytes, as lymphopenia was more pronounced in eritoran-treated mice. Overall, a global reduction in the levels of multiple cytokines, chemokines, and free radicals was detected in serum, suggesting that eritoran treatment may alleviate the severity of the "cytokine storm." Last, we provide compelling preliminary evidence suggesting that eritoran treatment may alter the kinetics of cytokine responses. Hence, these studies are the first to demonstrate the role of TLR4 in the pathogenesis of EBOV disease and indicate that eritoran is a prime candidate for further evaluation as a clinically viable therapeutic intervention strategy for EBOV and MARV infections. A hallmark of bacterial sepsis is the uncontrolled activation of the TLR4 pathway, which is the primary cause of the pathological features associated with this disease. Considering the importance of TLR4 signaling in bacterial sepsis and the remarkable pathological similarities associated with infections caused by filoviruses Ebola virus (EBOV) and Marburg virus (MARV), we assessed the ability of eritoran, a TLR4 antagonist, to protect mice against these viruses. Here, we show that eritoran effectively promotes survival of mice of filovirus infection, as 70% and 90% of mice receiving daily eritoran treatment survived lethal EBOV and MARV infections, respectively. Eritoran treatment resulted in a remarkable global reduction of inflammatory mediators, which is suggestive of the mechanism of action of this therapeutic treatment. These studies are the first to show the critical importance of the TLR4 pathway in the pathogenesis of filovirus infection and may provide a new avenue for therapeutic interventions.
2013 - 2016年埃博拉病毒（EBOV）在西非爆发，自2016年2月正式宣布疫情结束后仍有间歇性复发，这表明需要迅速制定治疗干预策略。间接证据表明，埃博拉病毒感染与细菌性败血症的发病有若干共同特征，包括“细胞因子风暴”的发生。脂多糖拮抗剂依替膦（Eritoran）此前已被证明可保护小鼠免受致死性流感病毒感染。在此，我们报告依替膦可保护小鼠免受埃博拉病毒和密切相关的马尔堡病毒（MARV）致死性感染。每日给予依替膦可减轻疾病的临床症状，出乎意料的是，还可降低病毒滴度。外周血分析表明，尽管活化中性粒细胞百分比明显增加，但依替膦可减轻粒细胞增多症。令人惊讶的是，存活率提高和病毒血症降低并未伴随CD3 T淋巴细胞增加，因为在接受依替膦治疗的小鼠中淋巴细胞减少更为明显。总体而言，在血清中检测到多种细胞因子、趋化因子和自由基水平全面降低，这表明依替膦治疗可能减轻“细胞因子风暴”的严重程度。最后，我们提供了令人信服的初步证据表明依替膦治疗可能改变细胞因子反应的动力学。因此，这些研究首次证明了Toll样受体4（TLR4）在埃博拉病毒病发病机制中的作用，并表明依替膦是作为埃博拉病毒和马尔堡病毒感染的临床可行治疗干预策略进行进一步评估的主要候选药物。细菌性败血症的一个标志是TLR4途径的失控激活，这是与该疾病相关的病理特征的主要原因。考虑到TLR4信号传导在细菌性败血症中的重要性以及与丝状病毒埃博拉病毒（EBOV）和马尔堡病毒（MARV）感染相关的显著病理相似性，我们评估了TLR4拮抗剂依替膦保护小鼠免受这些病毒感染的能力。在此，我们表明依替膦可有效提高感染丝状病毒小鼠的存活率，因为每日接受依替膦治疗的小鼠分别有70%和90%在致死性埃博拉病毒和马尔堡病毒感染中存活。依替膦治疗导致炎症介质显著全面减少，这提示了这种治疗方法的作用机制。这些研究首次表明TLR4途径在丝状病毒感染发病机制中的关键重要性，并可能为治疗干预提供新途径。
