Two monoclonal antibodies against glycoprotein Gn protect mice from Rift Valley Fever challenge by cooperative effects
Two monoclonal antibodies against glycoprotein Gn protect mice from Rift Valley Fever challenge by cooperative effects
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DOI：
10.1371/journal.pntd.0008143
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发表时间：
2020-03-01
影响因子：
3.8
通讯作者：
Eiden, Martin
中科院分区：
文献类型：
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作者：
Gutjahr, Benjamin;Keller, Markus;Eiden, Martin
裂谷热病毒是一种急性病毒性疾病，影响动物，特别是牲畜和人类，是造成整个非洲和阿拉伯半岛广泛暴发的原因。该病毒导致流产和高死亡率，特别是在年幼的动物中，而人类的症状从轻微的流感样疾病到可能致命的严重出血表现不等。到目前为止，还没有用于动物和人类的抗病毒治疗方法。因此，我们评估了两种单克隆抗体-一种中和抗体和一种非中和抗体-在小鼠模型中用于针对裂谷热的治疗性治疗。我们选择这些抗体，因为它们在体外表现出协同作用。在裂谷热病毒感染小鼠期间，单独应用的中和抗体仅显示部分保护。相比之下，两种抗体的联合应用在一个治疗组中导致完全保护（100%存活）。详细的病理学和分子分析清楚地表明，治疗小鼠的靶组织中的病毒复制大幅减少。两者合计，这些结果确定了两个单克隆抗体具有较强的抗裂谷热感染，这是有前途的候选人对RVFV的治疗干预。裂谷热病毒（RVFV）是一种人畜共患虫媒病毒，导致严重的疾病，在人类和反刍动物。感染的特征是怀孕动物流产，新生儿死亡率高，以及人类发热性疾病，1%的病例发生脑炎或出血热。目前尚无针对RVFV感染的特异性抗病毒治疗。在这项研究中，两个单克隆抗体（mAb），提出了对糖蛋白Gn，在治疗研究中应用。在两个不同的时间点（病毒攻击前30分钟或病毒攻击后30分钟）用单独的中和mAb Gn 3治疗RVFV感染的小鼠仅显示出在两种应用中约58.3%存活的中等功效。然而，当在致死攻击剂量后30分钟施用时，与非中和mAb Gn 32一起的组合疗法显示出完全保护（100%存活）。mAb效力的增加可能是基于协同中和效应。这些数据表明，与单克隆抗体Gn 3和Gn 32的联合治疗可能是针对RVFV感染的有效治疗选择。
Author summaryRift Valley fever virus represents an acute viral disease affecting animals especially livestock and humans and is responsible for widespread outbreaks throughout Africa and on the Arabian Peninsula. The virus causes abortions and high mortality especially in young animals, whereas the symptoms in humans range from mild flu-like illness to severe hemorrhagic manifestations that can be lethal. So far, no antiviral therapeutics for animals nor humans were available yet. Therefore, we evaluated two monoclonal antibodies-one neutralizing and one non-neutralizing-in a mouse model for therapeutic treatment against Rift Valley fever. We selected these antibodies since they exhibited cooperative effects in vitro. During Rift Valley fever virus infection in mice, the applied neutralizing antibody alone showed only partial protection. In contrast, a combined application with both antibodies, lead to a complete protection in one treatment group (100% survival). A detailed pathological and molecular analysis clearly indicated a strong reduction of virus replication in target tissues of treated mice. Taken together, these results identified two monoclonal antibodies with strong antiviral effects against Rift Valley fever infection, which are promising candidates for therapeutic interventions against RVFV.Rift Valley fever virus (RVFV) is a zoonotic arbovirus that causes severe disease in humans and ruminants. The infection is characterized by abortions in pregnant animals, high mortality in neonates as well as febrile illness in humans that develop in 1% of cases encephalitis or hemorrhagic fever. There is presently no specific antiviral treatment for RVFV infection available. In this study, two monoclonal antibodies (mAbs), raised against glycoprotein Gn, were applied in a therapeutic study. Treatment of RVFV infected mice with neutralizing mAb Gn3 alone at two different time points (30 minutes before or 30 minutes after virus challenge) showed only moderate efficacy of about 58.3% survival in both applications. However, a combination therapy together with non-neutralizing mAb Gn32 demonstrated complete protection (100% survival) when applied 30 minutes after the lethal challenge dose. The increase of mAb efficacy is probably based on cooperative neutralization effects. These data suggest that a combination therapy with mAbs Gn3 and Gn32 could be an effective treatment option against RVFV infection.