Defensins in Innate Immunity to Viruses

对病毒的先天免疫中的防御素

基本信息

批准号：
8524035
负责人：
Jason G Smith
金额：
$ 29.89万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-16 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8524035
关键词：
Adenoviruses Anti-Bacterial Agents Antibiotics Antiviral Agents Bacteria Capsid Proteins Cell Culture Techniques Cell Degranulation Cell Nucleus Cell membrane Cell surface Cessation of life Controlled Study Cytolysis Defensins Development Disease Enteral Epithelial Cells Exposure to Family Gastrointestinal Diseases Goals Host Defense Human Human Adenoviruses Immune Immune System Part Immune response Immune system Immunity In Vitro Infection Intestinal Bypasses Knockout Mice Lipid Bilayers Measures Mediating Membrane Methods Modeling Mucosal Immunity Mus Natural Immunity Natural Killer Cells Oral Paneth Cells Pathogenesis Pathway interactions Peptide Hydrolases Peptides Phenocopy Phenotype Process Protozoa Reporting Resistance Role Rotavirus Serotyping Testing Therapeutic Transgenic Mice Vaccine Design Vaccines Validation Viral Viral Pathogenesis Viral Proteins Virus Virus Diseases alpha-Defensins antimicrobial peptide design enteritis functional loss fungus in vivo insight macrophage mortality mutant neutrophil novel pathogen prevent protein protein interaction research study response vector vaccine virus pathogenesis

项目摘要

DESCRIPTION (provided by applicant): The innate immune response is a critical component of host defense against infection. 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 anti-viral immunity is less well understood. The potent neutralization of diverse viruses by alpha-defensins has been described in vitro and in cell culture. Recent studies have also described enhancement of virus infection by alpha-defensins; however, controlled studies to determine whether these peptides impact virus infection and pathogenesis in vivo have not been reported. This proposal will explore the hypothesis that alpha-defensins modulate enteric non-enveloped virus infection and pathogenesis in vivo, using replicating viruses in a natural host. We will determine the spectrum of activity of mouse enteric alpha-defensins against mouse enteric viruses in vitro. Using this information, we will determine whether alpha-defensin expression directly or indirectly impacts enteric virus infection and pathogenesis in vivo. We will also determine whether host Paneth cells respond to virus infection by degranulating and releasing alpha-defensins into the gut. These studies will provide insight into a critical component of the immune system that may be a common first line of defense against many viral pathogens. In addition, a deeper understanding of enteric virus infection will aid in the design of vaccine vectors to elicit mucosal immunity. Finally, these studies will provide validation for continued studies of the antiviral mechanisms of defensins as well as the development of these molecules as therapeutics for adenovirus and other viral pathogens.

描述（由申请人提供）：先天免疫反应是宿主防御感染的关键组成部分。防御素是一种抗菌肽家族，是一种具有良好描述的抗细菌活性的先天免疫效应子的一类。但是，它们在抗病毒免疫中的作用知之甚少。在体外和细胞培养中已经描述了α-防御素对各种病毒的有效中和。最近的研究还描述了α-防御素对病毒感染的增强。然而，尚未报道对这些肽影响病毒感染和体内发病机理的对照研究。该提案将探讨α-防御素在体内调节体内的肠道非发育性病毒感染和发病机理的假设，并使用天然宿主中的复制病毒。我们将在体外确定小鼠肠α-防御素对小鼠肠道病毒的活性谱。使用这些信息，我们将确定α-防御素表达是直接还是间接影响肠道病毒感染和体内发病机理。我们还将确定宿主Paneth细胞是否通过脱粒和释放α-防御素脱粒来反应病毒感染。这些研究将为免疫系统的关键组成部分提供洞察力，这可能是针对许多病毒病原体的普遍防御。此外，对肠道病毒感染的更深入了解将有助于设计疫苗向量以引起粘膜免疫。最后，这些研究将为防御素的抗病毒机制以及这些分子作为腺病毒和其他病毒病原体的治疗剂的发展提供验证。