Anti-viral Mechanisms of Defensins

项目摘要 先天免疫反应是宿主抵御感染的重要组成部分。阿尔法-防御素，一 抗菌肽家族，是一类进化上保守的天然免疫效应物，具有良好的 被描述的抗细菌活性；然而，它们在病毒免疫中的作用还不是很清楚。强大的 在体外和细胞培养中，已经描述了α-防御素中和各种病毒的情况。通过聚焦 关于人腺病毒和乳头状瘤病毒，我们已经确定了阿尔法防御素 结合到病毒衣壳上，并在细胞进入时改变涂层，以阻止感染。最近我们发现， 通过口服/粪便途径传播的病毒(如轮状病毒和肠道腺病毒)对 来自宿主物种的α-防御素的抗病毒活性，同时对非宿主α-防御素保持敏感。 防御素。在某些情况下，宿主α-防御素甚至会增加或加强这些病毒的感染， 这使我们假设肠道病毒已经进化为或者逃避或劫持了这些宿主防御 增加感染和传播的多肽。为了验证这一假设，我们将研究增强和 宿主和非宿主α-防御素中和轮状病毒。轮状病毒是人类重要的病原体。 而更深入地理解决定它们取向的宿主因素对于理解 变速箱。这些研究将结合生化和遗传方法来识别α-防御素 结合病毒衣壳上的决定因素并鉴定区分中和作用的α-防御素特性 和加强活动。我们还将确定轮状病毒中和和增强的机制。 最后，我们将确定这些机制是否会改变体内的病毒感染。 为了确定我们在对腺病毒和HPV的研究中发现的抗病毒机制 一般情况下，我们还将对细小病毒的抑制机制进行剖析。细小病毒，特别是腺病毒- 相关病毒是重要的病毒载体。此外，还有众所周知的(例如B19)和新兴的(例如， 博卡病毒)细小病毒是人类重要的病原体。这些研究将由HIGH提供帮助 解决临床相关病毒载体的结构研究。从这两个方面的比较研究 不同的非包膜病毒家族，结合我们先前对人腺病毒和 对于乳头瘤病毒，我们将对免疫的一个关键组成部分的功能有了更深入的了解 该系统可能是许多病毒致病的共同因素。这些研究也可能有助于 α-防御素作为治疗药物和疫苗设计的开发。

Project Summary The innate immune response is a critical component of host defense against infection. Alpha-defensins, one family of antimicrobial peptides, are an evolutionarily conserved class of innate immune effectors with well- described anti-bacterial activity; however, their role in viral immunity is less well understood. The potent neutralization of diverse viruses by alpha-defensins has been described in vitro and in cell culture. By focusing on human adenovirus and papillomavirus, we have identified a common mechanism whereby alpha-defensins bind to the viral capsid and alter uncoating during cell entry to block infection. Recently, we have found that viruses transmitted by the oral/fecal route (e.g., rotavirus and enteric adenovirus) are selectively resistant to the antiviral activity of alpha-defensins from their host species while remaining sensitive to non-host alpha- defensins. In some cases, the host alpha-defensins even increase or enhance the infection of these viruses, leading us to hypothesize that enteric viruses have evolved to either evade or hijack these host defense peptides to increase infection and transmission. To test this hypothesis, we will study the enhancement and neutralization of rotavirus by host and non-host alpha-defensins. Rotaviruses are important human pathogens and a deeper understanding of host factors that dictate their tropism is important for understanding transmission. These studies will combine biochemical and genetic approaches to identify alpha-defensin binding determinants on the viral capsids and to identify alpha-defensin properties that differentiate neutralizing and enhancing activities. We will also identify the mechanisms of rotavirus neutralization and enhancement. Finally, we will determine whether or not these mechanisms alter viral infection in vivo. To determine whether the antiviral mechanism that we have uncovered in our studies of adenovirus and HPV is general, we will also dissect the mechanism of parvovirus inhibition. Parvoviruses, particularly adeno- associated virus, are important viral vectors. In addition, there are well known (e.g., B19) and emerging (e.g., bocavirus) parvoviruses that are important human pathogens. These studies will be facilitated by high resolution structural studies of clinically relevant viral vectors. From these comparative studies of two disparate families of non-enveloped viruses in combination with our prior insights from human adenovirus and papillomavirus, we will gain a deeper understanding of the function of a critical component of the immune system that may be a common factor in the pathogenesis of many viruses. These studies may also aid in the development of alpha-defensins as therapeutics and inform vaccine design.