Autophagy and ER stress during varicella infection

水痘感染期间的自噬和内质网应激

基本信息

批准号：
8803757
负责人：
Charles F. Grose
金额：
$ 38.24万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8803757
关键词：
Adult American Animal Experiments Apoptosis Arvin Attenuated Attenuated Live Virus Vaccine Autophagocytosis Autophagosome Binding Proteins Biological Process Boxing Cell Culture Techniques Cells Chickenpox Chickenpox Vaccine Childhood Collaborations Cultured Cells Data Detection Elderly Elements Epithelial Cells Evaluation Event GRP78 gene Genes Glycoproteins Hepatitis C virus Herpes zoster disease Herpesviridae Herpesvirus 1 Herpesvirus Type 3 Homologous Gene Human Indium Infection Investigation Laboratories Lead Life Lytic Virus Measures Methods Modeling Mutate Mutation Natural Immunity Neurons Parents Pathway interactions Phenotype Postherpetic neuralgia Proteins RNA Interference RNA Splicing Recombinants Relative (related person)Research Risk Role SCID Mice SCID-hu Mice Satellite Viruses Simplexvirus Site Skin Small Interfering RNA Stress Stroke System Techniques Testing Tissues Tunicamycin Vaccination Vaccines Vesicle Viral Viral Genome Virion Virus Virus Diseases base biological adaptation to stress cell type cis-trans-Isomerases disease natural history in vivo mouse model mutant novel prevent recombinant virus relating to nervous system research study response satellite cell secretory protein sensor skin xenograft

项目摘要

Autophagy has recently been demonstrated in both cultured cells infected with varicella- zoster virus (VZV) as well as in a human zoster vesicle. The presence of punctate autophagosomes in a zoster skin vesicle firmly established that autophagy (macroautophagy) is a relevant biological process during the natural history of disease caused by this herpesvirus. Of importance, we have carried out sufficient preliminary studies to document that autophagy induced by VZV infection does not resemble HSV-induced autophagy. First of all, the VZV genome lacks a homolog of the HSV ICP 34.5 gene. Secondly, we have now shown by two different methods that VZV infection quickly induces marked ER stress, an event not known to occur in the HSV system. Therefore, the re-stated central hypothesis for this proposal is that ER stress is a critical component of VZV infection, that ER stress is related to an over abundance of misfolded VZV glycoproteins in the ER, and that ER-associated degradation and autophagy are consequences that relieve ER stress. These events allow the infected cell to survive longer, to avoid apoptosis, and in that sense can be considered pro-viral. The Research Plan to test this hypothesis involves three Specific Aims. Aim 1 is called Induction of autophagy as a consequence of VZV induced ER stress. Aim 2 is called Activation of the unfolded protein response (UPR) by VZV induced ER stress. Aim 3, which involves the A. Arvin laboratory, includes Studies of autophagy and ER stress in the SCID-hu mouse model, following infection with various recombinant mutated VZV genomes. In our Research Plan, we will continue prior investigations with an expanded experimental approach directed toward the three sensor pathways that lead from ER stress to the UPR (IRE1, ATF6 and PERK). We have already detected four proteins associated with the UPR in VZV infected cells, including BiP (HSPA5), HSPA8, HSPD1 and PPIA: peptidyl-propyl-cis-trans-isomerase). More recently we have detected the spliced form of XBP1 (X-Box binding protein) in VZV infected cells, another marker of the UPR. The final approach will include animal experiments with already prepared recombinant viruses containing numerous gE mutations. The phenotypes of these mutant viruses have already been determined in both cell culture and the SCID mouse model. Thus the above experimental plan will determine the relative importance of ER stress and autophagy in the cellular response to VZV infection. The results are relevant not only to our understanding of varicella vaccination but also the debilitating zoster-related illness called post-herpetic neuralgia.

最近在感染水痘的培养细胞中证实了自噬带状疱疹病毒（VZV）以及人类带状疱疹囊泡。点状自噬体的存在在带状疱疹皮肤囊泡中，自噬（巨自噬）是一种相关的生物学机制。由这种疱疹病毒引起的疾病的自然史过程。重要的是，我们有进行了充分的初步研究以证明 VZV 感染诱导的自噬与 HSV 诱导的自噬不同。首先，VZV 基因组缺乏与 HSV ICP 34.5 基因。其次，我们现在通过两种不同的方法证明了水痘带状疱疹病毒感染迅速诱发显着的内质网应激，这是 HSV 系统中未知发生的事件。因此，该提案重申的中心假设是 ER 应激是 VZV 的关键组成部分感染，内质网应激与内质网中错误折叠的 VZV 糖蛋白过多有关，内质网相关的降解和自噬是缓解内质网应激的结果。这些事件允许受感染的细胞存活更长时间，避免细胞凋亡，从这个意义上说可以被认为是亲病毒的。检验这一假设的研究计划涉及三个具体目标。目的 1 称为自噬诱导，是 VZV 诱导 ER 应激的结果。目标 2 称为 VZV 激活未折叠蛋白反应 (UPR) 诱导 ER 应激。目标 3，其中涉及 A. Arvin 实验室，包括 SCID-hu 中自噬和 ER 应激的研究感染各种重组突变 VZV 基因组后的小鼠模型。在我们的研究计划，我们将通过扩展的实验方法继续先前的研究指向从 ER 应激到 UPR 的三个传感器通路（IRE1、ATF6 和津贴）。我们已经在 VZV 感染细胞中检测到四种与 UPR 相关的蛋白质，包括 BiP (HSPA5)、HSPA8、HSPD1 和 PPIA：肽基丙基顺反异构酶）。更多的最近我们在VZV感染的细胞中检测到XBP1（X-Box结合蛋白）的剪接形式，普遍定期审议的另一个标志。最终的方法将包括已经进行的动物实验制备了含有大量gE突变的重组病毒。这些突变体的表型病毒已在细胞培养物和 SCID 小鼠模型中得到确定。因此上述实验计划将决定 ER 应激和自噬在细胞中的相对重要性细胞对 VZV 感染的反应。结果不仅与我们的理解相关水痘疫苗接种还包括与带状疱疹相关的使人衰弱的疾病，即带状疱疹后神经痛。

项目成果

期刊论文数量（23）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Bioinformatics of varicella-zoster virus: single nucleotide polymorphisms define clades and attenuated vaccine genotypes.

水痘带状疱疹病毒的生物信息学：单核苷酸多态性定义进化枝和减毒疫苗基因型。

DOI：
10.1016/j.meegid.2012.11.008
发表时间：
2013-08
期刊：
Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases
影响因子：
0
作者：
Chow, Vincent T.;Tipples, Graham A.;Grose, Charles
通讯作者：
Grose, Charles

Pangaea and the Out-of-Africa Model of Varicella-Zoster Virus Evolution and Phylogeography.

盘古大陆和非洲以外的水痘带状疱疹病毒进化模型和系统发育地理学。