Role of Gut Microbiome- Brain Axis in Modulating CNS Inflammasomes in the Neuropathology Produced by Opioid Exposure and HIV

肠道微生物组-脑轴在阿片类药物暴露和 HIV 产生的神经病理学中调节中枢神经系统炎症小体的作用

• 批准号: 10653501
• 负责人: Sabita Roy
• 金额: $ 15.35万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10653501
• 关键词: Acquired Immunodeficiency Syndrome; Animals; Antibiotics; Attention; Attenuated; Bacterial Translocation; Binding; Biological; Brain; Breeding; Cells; Chronic; Complex; Data; Development; Disease; Disease Progression; Drug abuse; Drug usage; Drug user; Endotoxins; Enterococcus faecalis; Extravasation; Firmicutes; Functional disorder; Genes; Germ-Free; Gram-Negative Bacteria; Gram-Positive Bacteria; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-1; Immune; Immune system; Individual; Infection; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Lead; Leaky Gut; Ligands; LoxP-flanked allele; Microglia; Modeling; Molecular; Morphine; Mus; Neurocognitive; Neuropathogenesis; Opiate Addiction; Opioid; Patients; Pattern; Predisposition; Prevalence; Probiotics; Production; Proteins; Ribosomes; Rodent Model; Role; Signal Pathway; Signal Transduction; TLR2 gene; Testing; Tissues; Toll-like receptors; antagonist; bacterial community; cytokine; drug abuser; dysbiosis; gut microbiome; gut microbiota; marenostrin; microbial; microbial composition; microbiota; neurocognitive disorder; neuroinflammation; neuropathology; opioid abuse; opioid exposure; opioid use; pathogen; receptor; sex; substance use; systemic inflammatory response

Project Summary Infection with Covid-19 has reached pandemic status with more than 125 million confirmed cases and 2.75 million deaths making it one of the most deadliest pandemics in history. It is associated with severe acute respiratory syndrome symptoms with high fatality rates. SARS-CoV-2 infection is initiated when its S-protein binds to the angiotensin-converting enzyme 2 (ACE2) receptor through which it gains entry into the host's cells (Kuba et al., 2005; Walls et al., 2020). ACE2 is highly expressed in the in the lungs and to a lesser degree in other organs, such as the heart, kidneys, and intestines (Bavishi et al., 2020), which explains the increased prevalence of lung infection. An analysis of electronic health record data from more than 73 million patients showed that people with SUDs are at higher risk of contracting and suffering worse consequences from COVID- 19 particularly among African Americans. Those with an opioid use disorder (OUD) were 2.4 times more likely to have COVID-19 than those with cocaine use disorder (1.6 times), alcohol use disorder (1.4 times), and tobacco use disorder (smoking or vaping; 1.3 times). Our recent preliminary data show that chronic opioid treatment in a mouse model of opioid substance abuse resulted in significant increase in the expression ACE2 expression in the lungs and brain of these animals. This data suggests that long term exposure to opioids by increasing ACE2 expression in the lung will increase the susceptibility to COVID 19 infection and its expression in the brain suggests high likely hood of neuro-invasiveness. In this supplement we will test the hypothesis that substance use disorders with opioids will increase the risk for COVID 19 infection in the lung and will be associated with neuropathological consequence as a consequence of increased ACE2 expression in brain cells. In Aim 1: We will investigate the expression of ACE2 in small intestine, lung and brain cells in both male and female mice that are chronically treated with morphine. We will further investigate if substance abuse in context of HIV further exacerbates infection and disease progression. In Aim 2; we will investigate using a humanized mouse model where the murine ACE2 receptor is knocked in, the infectivity of the SARS-CoV2 Spike Protein- Pseudotyped GFP using both in vitro and in vivo target cells. In Aim 3 we will investigate the role of the gut microbiome in modulating ACE2 expression levels in the small intestine, lung and brain.

项目摘要 COVID-19的感染已达到大流行状况，已确认超过1.25亿个病例和2.75 数百万人死亡使其成为历史上最致命的大流行之一。它与严重的急性有关 呼吸综合症症状高死亡率。 SARS-COV-2感染是在其S蛋白 与血管紧张素转换酶2（ACE2）受体结合，它通过该酶进入宿主的细胞进入 （Kuba等，2005; Walls等，2020）。 ACE2在肺中高度表达，并且在较小的程度上 其他器官，例如心脏，肾脏和肠道（Bavishi等，2020），这解释了增加 肺部感染的患病率。对超过7300万患者的电子健康记录数据的分析 表明患有泡沫的人的签约风险较高，而Covid的后果更严重 19特​​别是在非裔美国人中。那些患有阿片类药物障碍（OUD）的人的可能性高2.4倍 比可卡因使用障碍（1.6次），酒精使用障碍（1.4次）和可卡因使用障碍患者的共同-19和 烟草使用障碍（吸烟或烟； 1.3次）。我们最近的初步数据表明慢性阿片类药物 阿片类药物滥用的小鼠模型中的治疗导致表达ACE2的显着增加 这些动物的肺和大脑的表达。该数据表明长期暴露于阿片类药物 肺中ACE2表达的增加将增加Covid 19感染的敏感性及其表达 在大脑中，表明神经侵入性的可能很高。在这种补充中，我们将检验以下假设 阿片类药物的药物使用障碍将增加肺部的covid 19感染的风险，将是 由于脑细胞中ACE2表达增加而与神经病理学后果有关。 在AIM 1中：我们将研究ACE2在小肠，肺和脑细胞中的表达 长期用吗啡治疗的雌性小鼠。我们将进一步调查是否在上下文中滥用药物 HIV进一步加剧了感染和疾病进展。在AIM 2中；我们将使用人性化调查 小鼠模型中鼠ACE2受体被敲入，SARS-COV2峰值蛋白的感染性 使用体外和体内靶细胞使用伪型GFP。在AIM 3中，我们将研究肠道的作用 在小肠，肺和大脑中调节ACE2表达水平的微生物组。