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

摘要： 人类嗅觉和中枢神经系统感染在阿尔茨海默病中起致病作用的直接证据 仍然难以捉摸。将病毒与阿尔茨海默病联系起来的困难来自于试图检测剩余的病毒基因组 在AD患者的大脑中，即使免疫压力早已消除了任何活跃的病毒复制的痕迹。 事实上，最近的研究没有发现任何中枢神经系统病毒持续存在的证据，包括疱疹 以及AD患者大脑中的流感(3)。有重要证据表明，SARS-CoV-2感染了 嗅觉系统，并可导致神经侵入(4)，潜在地加速AD的数量迅速增加 关于个人的。一种常见的假设是，病原体使宿主严重患病，随后又会回到 感染前的正常，忽视了驱动局部和区域变化的炎性印记的存在 即使在急性感染得到控制后，组织功能也是如此。感染可以永久性地重塑染色质和 改变存活细胞的转录网络。长期感染依赖的转录变化可能 有助于对蜂窝功能和周围蜂窝内的区域/网络变化产生长期影响 与宿主的神经健康状况有关。我们的研究不是关注特定的单一微生物，而是利用 嗅觉中枢神经系统病毒感染模型确定对看似良性感染的特异性 驱使长期的病态。在细胞水平上确定感染的长期功能后果 需要活体血统追踪。我们和其他人已经产生了复制能力强和致病的Cre- 重组酶表达病毒，在病毒清除后对存活细胞进行特异性标记。这些CRE- 表达的病毒精确地定位了以前感染的细胞的精确解剖定位 评估神经退行性变作为与先前感染的接近程度的函数，以及允许 对存活细胞的荧光鉴定或通过基于RNA的转录鉴定。 虽然与疾病相关的基因变异已经被识别，并显示出功能变化，但 人们对AD启动的机制基础了解甚少，特别是考虑到大多数AD病例是 零星的。这项建议旨在填补有关病毒感染如何导致AD疾病的知识空白： 1)病毒感染引起的机制改变会导致AD，以及2)这些机制改变是什么 在不同类型的感染中保守，或施加独特的压力以实现类似的结果。 对阿尔茨海默病的启动和正在进行的发病机制缺乏详细的了解仍然是 开发新疗法的关键障碍。我们的提案将表明感染是如何增加的 没有已知家族性基因变异的个体的易感性。

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.