Defective viral genomes in RSV pathogenesis

摘要 对病毒致病机制的不了解限制了我们控制病毒的能力 病毒感染和减少其公共卫生负担。复制型非标准病毒基因组 病毒感染时产生的cbVGs是呼吸道抗病毒免疫的主要诱因。 合胞病毒(RSV)在体外，在小鼠和在人类中。最重要的是，我们最近报道了cbvgs 在RSV复制过程中产生的病毒对儿童和成人感染的临床结局产生重大影响。 这些数据表明，cbVGs是病毒致病的关键决定因素，它们的活性可以 被利用来最大限度地减少病毒相关疾病。 很明显，病毒宿主之间的相互作用是复杂的，解决这种复杂性对于 确定更好的疾病严重程度预测因素以及更好的治疗策略。更好地理解 影响CbVGs生成和活动的因素对于将其作为一种工具加以开发是必要的 减轻呼吸道合胞病毒及相关病毒的公共卫生负担。在原建议资助的研究中，我们 证明cbVG的存在对RSV的致病机制有重要影响。虽然很快就会检测到cbVGs 在感染对严重疾病具有保护作用后，晚期或持续存在的cbVGs与更多 严重的疾病。这里建议的研究，直接跟随这些数据，并专注于调查病毒和宿主 影响cbVG生成和活动的因素。为了做到这一点，我们将描述存在于 我们将研究它们的功能及其与不同临床结果的关系。 这项研究将提供对自然发生的cbvg物种的第一次全面调查，并将 确定确定其保护或潜在致病功能的独特特征(目标1)。我们还将 评估已知RSV风险因素对cbVG产生的影响，以确定cbVG的宿主决定因素 我们将进行概念验证实验，以测试cbVGs是否可以安全地用于 在高危环境中尽量减少病毒引起的疾病(目标2)。最后，我们将测试宿主免疫的作用 迟发或延长cbVGs患者驾驶疾病的偏向，并将确定潜在的治疗靶点 在这些情况下减少疾病(目标3)。

Summary Poor understanding of the mechanisms that modulate virus pathogenesis limits our ability to control viral infections and reduce their public health burden. Non-standard viral genomes of the copy-back type (cbVGs) that are generated during viral infections are the primary inducers of antiviral immunity to respiratory syncytial virus (RSV) in vitro, in mice, and in humans. Most importantly, we recently reported that cbVGs generated during RSV replication significantly impact the clinical outcome of infection in children and adults. These data suggest that cbVGs are key determinants of viral pathogenesis and that their activity can be harnessed to minimize viral-associated disease. It's clear that the virus host-interaction is complex, and it is essential to untangle this complexity to identify better predictors of disease severity as well as better therapeutic strategies. A better understanding of the factors that influence the generation and activity of cbVGs is necessary for exploiting them as a tool for reducing the public health burden of RSV and related viruses. In studies funded in the original proposal, we demonstrated that the presence of cbVG critically impact RSV pathogenesis. While detection of cbVGs soon after infection is protective from severe disease, late or sustained presence of cbVGs associates with more severe disease. Studies proposed here, directly follow these data and focus on investigating viral and host factors that impact cbVG generation and activity. To do this, we will characterize the cbVG species present in human respiratory secretions and we will study their function and association with distinct clinical outcomes. This study will provide the first comprehensive investigation of naturally occurring cbVG species and will identify unique features that determine their protective or potentially pathogenic functions (Aim 1). We will also assess the impact of known RSV risk factors on cbVG generation to identify host determinants of cbVG accumulation, and we will perform proof of concept experiments to test if cbVGs can be safely used to minimize virus-induced disease in high-risk settings (Aim 2). Lastly, we will test the role of the host immune bias in driving disease in patients with late or prolonged cbVGs and will identify potential targets for treatment to reduce disease in these conditions (Aim 3).