Anti-viral Mechanisms of Defensins

防御素的抗病毒机制

• 批准号: 9815285
• 负责人: Mavis Agbandje-Mckenna
• 金额: $ 68.14万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-10 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9815285
• 关键词: Adenoviruses; Alphavirus; Animals; Anti-Bacterial Agents; Antiviral Agents; Attention; Binding; Binding Sites; Biochemical; Biochemical Genetics; Biology; Capsid; Cell Culture Techniques; Cells; Clinical; Comparative Study; Complement; Confocal Microscopy; Defensins; Dependovirus; Development; Directed Molecular Evolution; Disease; Enteral; Epitopes; Evolution; Family; Genetic study; Goals; Host Defense; Human; Human Papillomavirus; Immune; Immune system; Immunity; In Vitro; Infection; Innate Immune Response; Innate Immune System; Integration Host Factors; Knowledge; Lipid Bilayers; Maps; Mediating; Modeling; Molecular; Mus; Mutagenesis; Myelogenous; Oral; Papillomavirus; Parvovirus; Pathogenesis; Pathogenicity; Peptides; Property; Publishing; Race; Resistance; Resolution; Role; Rotavirus; Rotavirus Infections; Route; Shapes; Site; Small Intestines; Structure; Testing; Therapeutic; Time; Tropism; Vaccine Design; Vaccines; Viral; Viral Drug Resistance; Viral Pathogenesis; Viral Vector; Virus; Virus Diseases; Work; alpha-Defensins; antimicrobial peptide; arm; base; clinically relevant; design; enteric adenovirus infection; experimental study; gastrointestinal epithelium; genetic approach; human pathogen; in vivo; insight; mouse model; pathogen; pathogenic bacteria; pressure; prevent; reverse genetics; trafficking; transmission process; viral resistance; viral transmission; virus envelope

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.

项目概要 先天免疫反应是宿主防御感染的关键组成部分。 α-防御素，一 抗菌肽家族是一类进化上保守的先天免疫效应物，具有良好的 描述了抗菌活性；然而，它们在病毒免疫中的作用尚不清楚。强效的 α-防御素对多种病毒的中和作用已在体外和细胞培养中得到描述。通过聚焦 对于人类腺病毒和乳头瘤病毒，我们已经确定了一种共同机制，即α-防御素 与病毒衣壳结合并在细胞进入过程中改变脱壳以阻止感染。最近，我们发现 通过口腔/粪便途径传播的病毒（例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增强这些病毒的感染， 使我们假设肠道病毒已经进化到逃避或劫持这些宿主防御 肽以增加感染和传播。为了检验这个假设，我们将研究增强和 宿主和非宿主α-防御素中和轮状病毒。轮状病毒是重要的人类病原体 更深入地了解决定其趋向性的宿主因素对于理解 传播。这些研究将结合生化和遗传学方法来鉴定α-防御素 结合病毒衣壳上的决定簇并鉴定区分中和的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病毒感染。 确定我们在腺病毒和 HPV 研究中发现的抗病毒机制是否有效 总而言之，我们还将剖析细小病毒的抑制机制。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）细小病毒是重要的人类病原体。这些研究将得到高水平的促进 临床相关病毒载体的分辨率结构研究。从这两个方面的比较研究来看 不同的无包膜病毒家族结合我们之前对人类腺病毒和 乳头瘤病毒，我们将对免疫关键组成部分的功能有更深入的了解 系统可能是许多病毒发病机制的共同因素。这些研究也可能有助于 开发α-防御素作为治疗剂并为疫苗设计提供信息。