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).

项目概要 在人类免疫缺陷病毒（HIV）感染的背景下，大麻的使用是一个重要的话题，也是 HIV 感染者中最常用的药物。吸食大麻的积极和消极影响。 据报道，艾滋病毒的背景涉及各种生物过程，包括认知表现和免疫 功能的报告多种多样，从增强大麻认知功能到导致认知协同下降。 因此，长期使用大麻对免疫扰动下的艾滋病毒认知的确切作用和限制仍然存在 目前尚不清楚，本研究的目的是调查与大麻相关的口腔微生物组的影响。 HIV 疾病中的神经认知表现，重点关注临床（目标 1）和临床前（目标 2）neuroHIV 我们和其他同事发现放线菌属细菌（例如 A. meyeri 和 A. 与其他人相比，人类口腔中的溶齿杆菌）在长期吸食大麻的人的唾液中含量丰富 与未感染者相比，非使用者和 A. meyeri 在 HIV 感染者中含量较高。 在吸烟者或长期可卡因使用者中未发现物种丰富化。此外，口服丰富化。 A. meyeri 的数量与首次使用大麻的年龄较小有关。在这里，我们的目的是调查 A. 物种是否与首次使用大麻的年龄有关。 细菌在 HIV 神经发病机制中发挥着重要作用，为实现这一目标，在具体目标 1 中，HIV 大麻。 将评估用户以确定与大麻使用相关的口腔微生物组之间的联系（即浓缩 A. meyeri）和认知表现，重点关注 1）唾液细菌组、真菌组和血浆 A.种细菌抗原的易位；2) A.种细菌介导的TLR2的分子机制 骨髓细胞信号通路激活；3）神经认知功能及其与微生物组的关联。 具体目标 2 将利用两种成熟的神经艾滋病毒转基因 (tg) 小鼠模型，包括 HIV Tg26 tg 和 HIV Tat tg 小鼠，使我们能够确定：1) THC 和 CBD 暴露的慢性影响 对神经认知和神经病理学的影响；2) THC 和 CBD 暴露对 A. 抗逆转录病毒 (ART) 药物作用下细菌和骨髓细胞浸润至大脑；3) 机制； 大麻相关的 A. meyeri 细菌对神经认知、神经病理学和内源性大麻素水平的影响。 了解长期使用大麻对口腔微生物组的作用及其对神经认知的影响 HIV 疾病的表现对于确定其治疗益处和治疗患者的局限性至关重要 传统联合抗逆转录病毒治疗下加速中枢神经系统发病机制 （大车）。