Infectious Influence: Using fate mapping to determine the impact of viral infection sites on Alzheimer's disease initiation

感染影响：利用命运图谱确定病毒感染位点对阿尔茨海默病发病的影响

基本信息

批准号：
10468164
负责人：
E. Ashley Moseman
金额：
$ 20.13万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10468164
关键词：
2019-nCoV APP-PS1 Acute Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Amyloid deposition Anatomy Animal Model Animals Astrocytes Bacteria Benign Brain Cell Death Cell physiology Cells Central Nervous System Infections Central Nervous System Viral Diseases Data Development Diphtheria Toxin Disease Enterobacteria phage P1 Cre recombinase Environment Evaluation Excision Fire - disasters Fostering Future Gene Expression Genetic Transcription Herpesviridae Human Immune Immune response Immunologics Individual Infection Inflammation Inflammatory Influenza Interferons Invaded Knowledge Label Lead Link Location Microbe Microglia Modeling Mus Nerve Degeneration Neuraxis Neurologic Neurons Normalcy Olfactory Epithelium Olfactory Pathways Olfactory dysfunction Outcome Pathogenesis Pathogenicity Pathology Pathway interactions Patients Play Positioning Attribute Predisposition RNA Recombinants Reporter Role Seeds Signal Transduction Site Survivors Testing Tissues Upper respiratory tract Vesicular stomatitis Indiana virus Viral Viral Genome Virus Virus Diseases Virus Replication Work acute infection base behavioral impairment chromatin remodeling cognitive testing empowered fitness fungus genetic variant imprint in vivo neglect neuron loss neurotoxic olfactory sensory neurons pathogen pathogenic virus preservation pressure spatial relationship transcriptomics

项目摘要

Abstract: Direct evidence that human olfactory and central nervous system CNS infections play a causal role in AD remains elusive. The difficulty connecting viruses to AD arises from attempts to detect viral genomes remaining in AD patient brains, even if immune pressure has long since removed any trace of active viral replication. Indeed, recent studies have not found evidence for the continued presence of any CNS virus, including herpes and influenza in the brains of AD patients (3). There is significant evidence that SARS-Cov-2 infects the olfactory system and can result in neuroinvasion (4), potentially accelerating AD in a rapidly increasing number of individuals. The common assumption that pathogens render a host acutely ill followed by a return to the preinfection normalcy, neglects the existence of inflammatory imprinting that drives local and regional changes in tissue functions even after acute infection is controlled. Infection can permanently remodel chromatin and alter transcriptional networks of surviving cells. Long lasting infection-dependent transcriptional changes may contribute to long-term impacts on cellular function and regional/network changes within surrounding cells that are relevant to host neurological fitness. Rather than focusing on a specific single microbe, our study utilizes olfactory CNS viral infection models to determine the capacity of seemingly benign infections to specifically drive long term pathologies. Identifying the long-term functional consequences of infection at the cellular level requires in vivo lineage tracing. We and others have generated replication competent and pathogenic Cre- recombinase expressing viruses that specifically label surviving cells following viral clearance. These Cre- expressing viruses pinpoint the precise anatomical localization of previously infected cells empowering evaluation of neurodegeneration as a function of proximity to previous infection, as well as allowing identification of surviving cells fluorescently or through RNA based transcriptomic identification. While disease associated genetic variants have been identified, and functional alterations shown, the mechanistic underpinnings of AD initiation are poorly understood, especially given that most AD cases are sporadic. This proposal seeks to fill gaps in knowledge regarding how viral infection may lead to AD disease: 1) What mechanistic changes caused by viral infection can lead to AD, and 2) are these mechanistic changes conserved across different types of infections, or are unique pressures applied to achieve a similar outcome. This lack of detailed understanding regarding the initiation and ongoing pathogenesis behind AD remains a critical barrier to the development of new treatments. Our proposal will suggest how infection increases susceptibility among individuals without known familial gene variants.

抽象的：直接证据表明人类嗅觉和中枢神经系统CNS感染在AD中起因果作用仍然难以捉摸。将病毒连接到AD的困难是由于试图检测仍然存在的病毒基因组而引起的在AD患者的大脑中，即使免疫压力已经消除了任何活性病毒复制的痕迹。实际上，最近的研究没有发现任何CNS病毒的持续存在的证据，包括疱疹和AD患者大脑中的流感（3）。有大量证据表明SARS-COV-2感染嗅觉系统并可能导致神经侵袭（4），可能会在数量迅速增加的AD加速AD 个人。病原体使宿主急性病随后返回到宿主的普遍假设预发现正常，忽略了炎症印记的存在，驱动局部和区域变化在组织功能中，即使控制了急性感染。感染可以永久重塑染色质和改变幸存细胞的转录网络。长期持续的感染依赖性转录变化可能对周围细胞内细胞功能和区域/网络变化的长期影响与宿主神经健康有关。我们的研究不是专注于特定的单一微生物，而是利用嗅觉中枢神经系统病毒感染模型，以确定看似良性感染的能力驱动长期病理。确定感染在细胞水平上的长期功能后果需要体内谱系跟踪。我们和其他人产生了复制能力和致病性的Cre- 重组酶表达病毒，这些病毒在病毒清除率后专门标记存活的细胞。这些表达病毒指出了先前感染的细胞的精确解剖学定位评估神经退行性因素与先前感染的接近性以及允许通过基于RNA的转录组识别鉴定存活的细胞。虽然已经鉴定出与疾病相关的遗传变异，并显示了功能改变，但广告启动的机械基础知之甚少，特别是考虑到大多数AD案例是零星。该建议旨在填补有关病毒感染如何导致AD疾病的知识的空白： 1）病毒感染引起的机械变化可能导致AD，2）这些机械变化是在不同类型的感染中保守，或者是实现类似结果的独特压力。关于AD背后的启动和持续发病机理的缺乏详细的理解仍然是开发新疗法的关键障碍。我们的建议将暗示感染如何增加没有已知家族基因变异的个体之间的敏感性。