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.

摘要 单纯疱疹病毒1型(HSV1)可以通过以下方式建立裂解性和潜伏性感染： 已知的和正在出现的神经病理后果。挑衅性数据现在将重新激活 阿尔茨海默病(AD)的病因学基础尚不完全清楚。 在这里，我们建议使用强大的新基因组技术来鉴定和表征实际的细胞类型 该病毒潜伏并重新激活了HSV1，扩展了最近的发现，揭示了 人类阿尔茨海默病大脑中受影响区域的疱疹病毒转录本。使用改良的单核测序 方法，允许在同一个核中评估DNA可获得性和全局转录，我们 将询问人类对照和AD大脑样本以及HSV1感染的脑器官和小鼠模型 由HSV1引起的急性和进行性神经毒性。这些研究有望揭示特定细胞类型 大脑中HSV1裂解、潜伏或重新激活后的增强子景观和转录图谱 同时还提供了对其存在的细胞自主与非细胞自主影响的洞察。在……里面 此外，我们建议阐明一种新的先天性免疫途径，即HSV1裂解转录本通过该途径触发 前哨蛋白激酶受体启动一系列核事件，其中包括二次激活 转录调节因子PARP1并最终形成依赖于核因子-kB的炎症基因表达程序， 潜在地提供了一种分子机制，大脑中偶尔重新激活HSV1可能有助于 促进阿尔茨海默病发病的炎症环境。此外，这一分子途径可能 大脑中各种微生物和可能的非微生物炎症触发因素已经被牵连 在公元后。我们还假设HSV1潜伏期相关转录本(LAT)具有截然不同和相反的 宿主神经元以及可能的非神经性脑细胞的基因组功能和非基因组作用， 它的平衡保护神经细胞的完整性，但可能促进低级别的慢性炎症。 潜伏感染的背景下，无论病毒重新激活。基于诱人的初步证据，我们建议 探讨正义(S)和反义(AS)LAT对部分二分性肿瘤细胞转录的影响 通过与HSV1和宿主基因组中的特定调控元件相关联，与 Krab锌指蛋白(KZFP)共调控蛋白KAP1。我们假设这些基因组事件会影响 KZFP介导的人AD过程调节对神经元功能的影响 内源性逆转录病毒(HERV)重复。我们进一步假设LAT有一个互补的非- 减轻先天免疫反应和抑制细胞死亡程序的基因组作用，至少部分地， 通过抑制PKR。最后，我们建议利用HSV1 LAT的这些保护属性作为一种独特的 AD的预防策略。