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CNS感染在AD中起因果作用的直接证据 仍然难以捉摸将病毒与AD联系起来的困难来自于试图检测剩余的病毒基因组 在AD患者大脑中，即使免疫压力早已消除了任何活跃病毒复制的痕迹。 事实上，最近的研究没有发现任何CNS病毒（包括疱疹病毒）持续存在的证据 和AD患者脑中的流感（3）。有重要证据表明，SARS-Cov-2感染了 嗅觉系统，并可能导致神经侵入（4），可能加速AD的迅速增加 个人。通常的假设是病原体使宿主急性患病，然后返回宿主体内。 感染前的正常状态，忽略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，感染可以永久重塑染色质， 改变存活细胞的转录网络。长期的感染依赖性转录变化可能 有助于对周围细胞内的细胞功能和区域/网络变化产生长期影响， 与宿主的神经健康有关我们的研究并没有集中在一种特定的微生物上，而是利用了 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， 导致长期的病理学改变在细胞水平确定感染的长期功能后果 需要体内谱系追踪。我们和其他人已经产生了复制能力和致病性Cre- 重组酶表达病毒，其在病毒清除后特异性标记存活细胞。这些Cre- 表达病毒精确定位先前感染细胞的解剖学位置， 评估神经变性作为与先前感染的接近度的函数，以及允许 通过荧光或通过基于RNA的转录组学鉴定来鉴定存活细胞。 虽然已经鉴定了疾病相关的遗传变异，并且显示了功能改变， AD启动的机制基础知之甚少，特别是考虑到大多数AD病例 零星的。该提案旨在填补有关病毒感染如何导致AD疾病的知识空白： 1)病毒感染引起的哪些机制变化可导致AD，以及2）这些机制变化是 在不同类型的感染中是保守的，或者是为实现类似结果而施加的独特压力。 这种缺乏详细了解的启动和正在进行的发病机制背后的AD仍然是一个 这是开发新疗法的关键障碍。我们的建议将表明感染如何增加 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.