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.

项目概要 Covid-19 感染已达到大流行状态，确诊病例数超过 1.25 亿，确诊病例数超过 2.75 数百万人死亡，使其成为历史上最致命的流行病之一。它与严重的急性 呼吸系统综合症症状死亡率很高。当其 S 蛋白 与血管紧张素转换酶 2 (ACE2) 受体结合，通过该受体进入宿主细胞 （Kuba 等人，2005 年；Walls 等人，2020 年）。 ACE2 在肺部高度表达，在肺部表达程度较低 其他器官，如心脏、肾脏和肠道 (Bavishi et al., 2020)，这解释了 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 研究表明，患有 SUD 的人感染新冠病毒的风险更高，并且会遭受更严重的后果。 19 尤其是非裔美国人。患有阿片类药物使用障碍 (OUD) 的人的可能性高出 2.4 倍 患有 COVID-19 的人比可卡因使用障碍（1.6 倍）、酒精使用障碍（1.4 倍）和 烟草使用障碍（吸烟或电子烟；1.3 倍）。我们最近的初步数据显示，慢性阿片类药物 对阿片类药物滥用小鼠模型进行治疗导致 ACE2 表达显着增加 这些动物的肺部和大脑中的表达。该数据表明，长期接触阿片类药物 肺部 ACE2 表达增加会增加对 COVID 19 感染及其表达的易感性 在大脑中表明很可能存在神经侵袭性。在本补充材料中，我们将检验以下假设： 阿片类物质使用障碍会增加肺部感染 COVID 19 的风险，并将 与脑细胞中 ACE2 表达增加导致的神经病理学后果相关。 目标 1：我们将研究 ACE2 在男性和女性的小肠、肺和脑细胞中的表达。 长期接受吗啡治疗的雌性小鼠。我们将进一步调查是否存在药物滥用情况 HIV 进一步加剧感染和疾病进展。在目标 2 中；我们将使用人性化的方法进行调查 小鼠 ACE2 受体被敲入的小鼠模型，SARS-CoV2 刺突蛋白的感染性 使用体外和体内靶细胞的假型 GFP。在目标 3 中，我们将研究肠道的作用 微生物组调节小肠、肺和大脑中 ACE2 表达水平。