Revealing the roles of HSV1 lytic and latent transcripts in AD pathogenesis and therapy

揭示 HSV1 裂解转录物和潜伏转录物在 AD 发病机制和治疗中的作用

• 批准号: 10621810
• 负责人: MICHAEL G ROSENFELD
• 金额: $ 79.85万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621810
• 关键词: Acute; Affect; Afferent Neurons; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid; Appearance; Astrocytes; Attenuated; Binding; Biological Models; Brain; Cell Death; Cell Death Inhibition; Cell Nucleus; Cells; Chronic; Clinical; Collaborations; DNA; Data; Dementia; Deposition; Disease Progression; Ectopic Expression; Endogenous Retroviruses; Enhancers; Environmental Risk Factor; Equilibrium; Etiology; Event; Gene Expression; Gene Expression Profile; Gene Family; Genes; Genetic; Genetic Risk; Genetic Transcription; Genetic Variation; Genome; Genomics; Herpes Simplex Infections; Herpesviridae; Herpesviridae Infections; Herpesvirus 1; Human; Impaired cognition; Incidence; Inflammation; Inflammatory; Innate Immune Response; Intervention; Investigation; Laboratories; Licensing; Link; Lytic; Lytic Phase; Mediating; Methods; Microglia; Modality; Molecular; NF-kappa B; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroglia; Neurons; Nuclear Accidents; Nucleic Acid Regulatory Sequences; Organoids; POU Domain; POU domain factors; Pathogenesis; Pathologic Processes; Pathway interactions; Phosphotransferases; Pituitary Gland; Population; Predisposition; Process; Property; Proteins; RNA; Recurrence; Regulation; Regulatory Element; Reporting; Role; Sampling; Sentinel; Specimen; Symptoms; Technology; Testing; Therapeutic; Transcript; Transcriptional Activation; Untranslated RNA; Viral; Viral Genome; Virus; Virus Latency; Zinc Fingers; abeta accumulation; abeta toxicity; brain cell; cell type; effective therapy; epidemiology study; extracellular; genome wide association study; genome-wide analysis; inflammatory milieu; innate immune pathways; insight; latency associated transcript; latent infection; member; microbial; mouse model; mutant; neuron loss; neuropathology; neurotoxicity; non-genomic; novel; pandemic disease; preservation; programs; prophylactic; reactivation from latency; risk variant; single nucleus RNA-sequencing; transcriptome

ABSTRACT Herpes Simplex Virus 1 (HSV1) can establish both lytic and latent infections in a cell type-specific fashion with known and emerging neuropathological ramifications, respectively. Provocative data now link reactivation of latent HSV1 infection to Alzheimer’s disease (AD), the etiological basis of which remains incompletely defined. Here we propose to employ powerful new genomic technologies to identify and characterize the actual cell types that harbor latent and reactivated HSV1, extending recent findings that have revealed an increased abundance of herpes virus transcripts in affected regions of human AD brains. Using a modified single-nucleus sequencing approach, which allows for DNA accessibility and global transcription to be assessed in the same nucleus, we will interrogate human control and AD brain samples as well a HSV1-infected brain organoids and mouse models of acute and progressive HSV1-induced neurotoxicity. These studies promise to reveal cell type-specific enhancer landscapes and transcriptional profiles consequent to lytic, latent, or reactivated HSV1 in the brain while also providing insights into the cell autonomous versus non-cell autonomous effects of its presence. In addition, we propose to elucidate a novel innate immune pathway by which HSV1 lytic transcripts trigger the sentinel kinase PKR to initiate a cascade of nuclear events that include the secondary activation of the transcriptional regulator PARP1 and culminate in a NF-kB-dependent inflammatory gene expression program, potentially providing a molecular mechanism by which occasional HSV1 reactivation in the brain could contribute to an inflammatory milieu that promotes the pathogenesis of AD. Furthermore, this molecular pathway may underlie diverse microbial and possibly non-microbial inflammatory triggers in the brain that have been implicated in AD. We also hypothesize that HSV1 latency-associated transcripts (LATs) have distinct and opposing genomic functions as well as non-genomic actions in host neurons and possibly non-neuronal brain cells, the balance of which preserves neuronal cell integrity but may facilitate low-grade, chronic inflammation in the context of latent infection irrespective of viral reactivation. Based on enticing preliminary evidence, we propose to investigate the idea that the sense (S) and antisense (AS) LATs impact transcription in a partially dichotomous fashion by associating with specific regulatory elements in the HSV1 and host genomes in collaboration with the KRAB zinc-finger protein (KZFP) co-regulator KAP1. We hypothesize that these genomic events influence the AD process by affecting neuronal function through modulation of KZFP-mediated regulation of human endogenous retrovirus (HERV) repeats. We further hypothesize that the LATs have a complementary non- genomic role that mitigates the innate immune response and suppresses cell death programs, at least in part, by inhibition of PKR. Finally, we propose to exploit these protective properties of the HSV1 LATs as a unique prophylactic strategy for AD.

抽象的 单纯疱疹病毒1（HSV1）可以用特定于细胞类型的方式来建立裂解和潜在感染 已知和新兴的神经病理学分别。挑衅性数据现在将重新激活的重新激活 对阿尔茨海默氏病（AD）的潜在HSV1感染，其病因基础仍未完全定义。 在这里，我们建议采用强大的新基因组技术来识别和表征实际细胞类型 该掩盖了潜在的和重新激活的HSV1，扩大了最近发现的发现，这些发现表明抽象增加了 人类广告大脑受影响地区的疱疹病毒转录本。使用修改的单核测序 方法，可以在同一核中评估DNA的可及性和全局转录，我们 将询问人类控制和AD脑样本，以及HSV1感染的脑器官和小鼠模型 急性和进行性HSV1诱导的神经毒性。这些研究有望揭示细胞类型特异性 增强剂的景观和转录曲线造成裂解，潜在或重新激活的HSV1 同时还可以洞悉其存在的细胞自治与非细胞自主效应。 此外，我们建议阐明一种新型的先天免疫途径，HSV1裂解转录本触发了 前哨激酶PKR发起一系列核事件，包括次要激活 转录调节剂PARP1并在NF-KB依赖性炎症基因表达程序中达到高潮， 可能提供一种分子机制 促进AD发病机理的炎症环境。此外，这种分子途径可能 潜水员微生物和可能的非微生物炎症触发因素是大脑中与 在广告中。我们还假设HSV1延迟相关的成绩单（LATS）具有独特的相反 宿主神经元和可能的非神经元细胞中的基因组功能以及非基因组作用， 其平衡可以保留神经元细胞完整性，但可能促进低级，慢性炎症 潜在感染的背景不论病毒重新激活。基于诱人的初步证据，我们建议 调查感官和反义（AS）的想法影响部分二分法中的转录 通过与HSV1中的特定监管元素和宿主基因组合作通过与该时尚 KRAB锌指蛋白（KZFP）共同调节器KAP1。我们假设这些基因组事件影响 通过调节KZFP介导的人类调节来影响神经元功能通过AD过程 内源性逆转录病毒（HERV）重复。我们进一步假设，LATS具有完整的非 - 减轻先天免疫反应并抑制细胞死亡程序的基因组作用，至少部分部分是 通过抑制PKR。最后，我们建议探索HSV1 LATS的这些受保护特性 AD的预防策略。