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.

项目总结