Modeling Filovirus Infection of and Trafficking through Skin

摘要： 细丝病毒，如埃博拉病毒(EBOV)，在感染后期的皮肤表面发现 当病毒血症很严重时。有证据表明，皮肤相关病毒是 传播给他人的病毒。然而，病毒是如何到达表面的还不是很清楚。我们的 初步研究表明，EBOV可以通过感染这两种病毒传播到皮肤表面 皮肤内的真皮和表皮细胞群，这种病毒传播到 在活体中，皮肤的表面很重要。然而，皮肤内的哪些细胞支持丝状病毒复制 以及对病毒载量负有主要责任的人是未知的。在这里，我们试图了解EBOV 当皮肤从体内排出时，与之相互作用。我们还将评估EBOV是否能够 从完好或磨损的皮肤表面进入。我们假设细胞的直接感染 皮肤内是EBOV传播的重要途径。为了检验这一点，我们将测试 目标有以下几点。纯化的原代皮肤细胞(例如角质形成细胞、成纤维细胞和抗原 将检查它们对EBOV感染的支持情况，我们将确定是否 这些相同的群体在皮肤外植体中被感染。此外，我们将确定是否已知细胞 表面受体在允许的皮肤细胞和外植体中表达，如果抑制病毒 与这些受体的相互作用可以阻止EBOV感染。我们还将评估皮肤移植的时机 参与小鼠和猕猴体内的EBOV感染。在完成这些操作后 重要的研究，将发展对EBOV与皮肤相互作用的理解，并开发一种新的 将建立研究高度相关人群丝状病毒感染的模型平台 组织。

Abstract: Filoviruses such as Ebola virus (EBOV) are found on the skin's surface at late times of infection when viremia is high. Evidence indicates that skin-associated virus is an important source of virus transmitted to others. Yet, how virus arrives at the surface is not well understood. Our preliminary studies suggest that EBOV can traffic to the surface of the skin by infecting both dermal and epidermal cell populations within the skin and that this route of virus delivery to the skin's surface is important in vivo. Yet, which cells within the skin support filovirus replication and are principally responsible for virus load are unknown. Here, we seek to understand EBOV interactions with skin as it egresses from the body. We will also evaluate if EBOV is able to enter through the intact or abraded skin surface. We hypothesize that direct infection of cells within the skin serves as an important route of EBOV transmission. To examine this, we will test the following aims. Purified primary skin cells (e.g. keratinocytes, fibroblasts, and antigen presenting cells) will be examined for their support of EBOV infection and we will determine if these same populations are infected in skin explants. Further, we will determine if known cell surface receptors are expressed in permissive skin cells and explants and if inhibition of virus interactions with those receptors blocks EBOV infection. We will also assess the timing of skin involvement in EBOV infection in vivo in mice and in macaques. At the completion of these important studies, an understanding of EBOV interactions with skin will be developed and a new model platform will be established for studying filovirus infections of highly relevant human tissue.