Investigating the effect of oral microbiome on cognition in HIV-infected chronic cannabis users

研究口腔微生物组对感染艾滋病毒的长期大麻使用者认知的影响

• 批准号: 10708001
• 负责人: Sylvia Fitting
• 金额: $ 71.57万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708001
• 关键词: Acceleration; Actinomyces; Actinomyces odontolyticus; Age; Alzheimer' s Disease; Amyloid beta-42; Amyloid beta-Protein; Anti-Bacterial Agents; Anti-Retroviral Agents; Bacteria; Bacterial Antigens; Behavioral; Biological Process; Blood; Brain; Cannabis; Cardiovascular Diseases; Central Nervous System; Chronic; Clinical; Cocaine Users; Cognition; Cognitive deficits; Data; Dental Hygiene; Deposition; Disease; Dose; Drug usage; Endocannabinoids; Feces; Frequencies; Genetic Transcription; Goals; HIV; HIV Infections; HIV-associated neurocognitive disorder; Human; Immune; Impaired cognition; In Vitro; Individual; Infiltration; Inflammatory; Inflammatory Response; Link; Long-Term Effects; Macrophage; Mediating; Memory; Memory Loss; Memory impairment; Modeling; Molecular; Morbidity - disease rate; Mus; Myeloid Cells; Neurocognition; Neurocognitive; Neuropathogenesis; Oral; Oral cavity; Pathogenesis; Pathway interactions; Patients; Peptides; Peptidoglycan; Performance; Persons; Pharmaceutical Preparations; Plasma; Play; Premature Birth; Probiotics; Production; Prospective cohort; Proteins; Regulation; Reporting; Role; Saliva; Signal Pathway; Smoker; THC exposure; TLR2 gene; Therapeutic; Time; Transgenic Mice; Transgenic Organisms; Virus Diseases; Work; antiretroviral therapy; bacteriome; cell free DNA; cell motility; cognitive enhancement; cognitive function; cognitive performance; comparison control; cytokine; immune function; in vivo; in vivo Model; inhibitor; marijuana smoker; marijuana use; marijuana user; memory recognition; microbiome; mortality; mouse model; mycobiome; neuroAIDS; neuropathology; neurotoxicity; novel; oral bacteria; oral microbiome; pre-clinical; tobacco smokers; transcription factor

Project Summary In the context of human immunodeficiency virus (HIV) infection, cannabis use is an important topic and is the most commonly used drug among HIV-infected individuals. Positive and negative effects of cannabis use in the context of HIV have been reported for various biological processes, including cognitive performance and immune function. Reports vary from cannabis enhancing cognitive function to causing synergistic decline in cognition. Thus, the exact role and limits of chronic cannabis use on HIV cognition under immune perturbations remain unclear. The aim of the present study is to investigate the effects of cannabis-associated oral microbiome on neurocognitive performance in HIV disease by focusing on clinical (Aim 1) and preclinical (Aim 2) neuroHIV models. We and other colleagues have found that Actinomyces species bacteria (e.g. A. meyeri and A. odontolyticus) in the oral cavity of humans, are enriched in the saliva from chronic cannabis users compared to non-users and A. meyeri is enriched in HIV-infected individuals compared to uninfected individuals. But oral A. species enrichment was not demonstrable in tabacco smokers or chronic cocaine users. Further, oral enrichment of A. meyeri was associated with younger age of first cannabis use. Here, we aim to investigate if A. species bacteria has a significant role in HIV neuropathogenesis. To achieve this goal, in Specific Aim 1, HIV cannabis users will be assessed to determine the link between cannabis use-associated oral microbiome (i.e., enrichment of A. meyeri) and cognitive performance by focusing on 1) saliva bacteriome and mycobiome and plasma translocation of A. species bacterial antigens; 2) molecular mechanisms of A. species bacteria mediated TLR2 signaling pathway activation in myeloid cells; 3) neurocognitive performance and its association with microbiome. Specific Aim 2 will make use of two well-established transgenic (tg) mouse models of neuroHIV, including the HIV Tg26 tg and the HIV Tat tg mice, to allow us to determine: 1) the chronic effects of THC and CBD exposure on neurocognition and neuropathology; 2) the chronic effects of THC and CBD exposure on enrichment of A. species bacteria and myeloid cell infiltration to the brain under antiretroviral (ART) drugs; and 3) the mechanisms of cannabis-associated A. meyeri bacteria on neurocognition, neuropathology, and endocannabinoid levels. Understanding the role of chronic cannabis use on oral microbiome and it’s effects on neurocognitive performance in HIV disease is critical to determine its therapeutic benefits and limits in the treatment of patients with accelerated central nervous system pathogenesis under traditional combination antiretroviral therapy (cART).

项目摘要 在人类免疫缺陷病毒（HIV）感染的背景下，大麻使用是一个重要的话题，是 艾滋病毒感染者中最常用的药物。大麻使用的积极和负面影响 已经报道了各种生物学过程的艾滋病毒背景，包括认知表现和免疫 功能。报告因增强认知功能而导致认知协同下降的报告各不相同。 这，在免疫扰动下，慢性大麻使用在HIV认知中的确切作用和限制仍然存在 不清楚。本研究的目的是研究与大麻相关的口服微生物组对 通过关注临床（AIM 1）和临床前（AIM 2）NeuroHiv，在HIV疾病中的神经认知表现 型号。我们和其他同事发现放线菌种类细菌（例如A. Meyeri和A. 与慢性大麻使用者相比 与未感染的个体相比，非用户和梅耶里在艾滋病毒感染的个体中富含艾滋病毒。但是口服A. 在塔巴科吸烟者或慢性可卡因使用者中，物种富集无法证明。此外，口服富集 A. Meyeri与首次使用大麻的年龄相关。在这里，我们旨在调查A.种类是否 细菌在HIV神经病发生中具有重要作用。为了实现这一目标，在特定的目标1中，艾滋病毒大麻 将评估用户以确定与大麻使用相关的口服微生物组之间的联系（即富集 通过关注1）唾液组和霉菌组和血浆，属于A. Meyeri）和认知表现。 A.种细菌抗原的易位； 2）A。物种的分子机制细菌介导的TLR2 髓样细胞中的信号通路激活； 3）神经认知性能及其与微生物组的关联。 特定的目标2将利用两种公认的转基因（TG）小鼠模型，包括 HIV TG26 TG和HIV TAT TG小鼠，使我们确定：1）THC和CBD暴露的慢性影响 关于神经认知和神经病理学； 2）THC和CBD暴露对A的富集的慢性作用。 在抗逆转录病毒（ART）药物下，物种细菌和髓样细胞浸润到大脑； 3）机制 与大麻相关的梅耶里菌细菌在神经认知，神经病理学和内源性大麻素水平上的掌握。 了解慢性大麻在口服微生物组中的作用及其对神经认知的影响 艾滋病毒疾病的表现对于确定其治疗益处和治疗的限制至关重要 在传统组合抗逆转录病毒疗法下加速中枢神经系统发病机理 （大车）。