Network Dissection of Host-Pathogen Interactions in Mycobacterium tuberculosis Infection

结核分枝杆菌感染中宿主-病原体相互作用的网络剖析

基本信息

批准号：
10672236
负责人：
Shuyi Ma
金额：
$ 56.55万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-03 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10672236
关键词：
Attenuated Binding Biological Biological Assay Bone Marrow Cells Cessation of life Data Detection Disease Dissection Drug Antagonism Drug Synergism Equilibrium Exposure to FDA approved Feedback Future Gene Expression Profile Genes Genetic Genetic Transcription Goals Growth Homeostasis Human Immunology Individual Infection Infection Control Inflammation Inflammatory Intervention Investigation Joints Macrophage Measures Microbiology Molecular Mus Mycobacterium tuberculosis Organism Outcome Pathogenesis Pathogenicity Pathologic Pathway interactions Pharmaceutical Preparations Phenotype Phosphotransferases Physiological Postdoctoral Fellow Regimen Research Rifampin Signal Transduction Stress Symptoms Testing Therapeutic Effect Transcriptional Regulation Treatment Protocols Tuberculosis Work analytical tool clinically relevant design empowerment gene regulatory network in vivo inhibitor innovation insight interest isoniazid kinase inhibitor molecular dynamics monocyte novel novel therapeutic intervention novel therapeutics pathogen predictive tools programs response synergism tool tool development transcription factor transcriptome transcriptomic profiling tuberculosis drugs tuberculosis treatment

项目摘要

ABSTRACT Infection is a dynamic interplay between host and pathogen, coordinated through each organism's signaling and gene regulatory networks. The world's deadliest pathogen, Mycobacterium tuberculosis (Mtb), can exploit its network of molecular interactions with the host to elicit an infection steady state that enables it to persist asymptomatically for up to decades. Perturbations in Mtb's or the host's network activities that tip the balance of this molecular homeostasis will alter infection outcomes: either pathogenically toward a symptomatic tuberculosis (TB) disease with rampant Mtb growth and pathological inflammation that could lead to death, or protectively toward infection clearance. I will dissect host signaling and Mtb regulatory network activities for infection fate- deciding tipping-point genes that impact Mtb viability and host inflammation during infection in primary human monocyte-derived macrophages (MDMs), a major infected host cell in vivo. I will profile the host and pathogen transcriptional responses to these infection-altering perturbations to define molecular mechanisms underlying the host-pathogen interplay, and I will use this information to identify synergistic joint interventions that concurrently target host and pathogen. Identifying these tipping-point genes at the host-pathogen interface should inform new therapeutic intervention strategies that jointly target host and pathogen to elicit host protection, while also revealing fundamental insights into pathogenesis.

抽象的感染是宿主和病原体之间的动态相互作用，通过每个生物体的信号传导和基因调控网络。世界上最致命的病原体结核分枝杆菌 (Mtb) 可以利用其与宿主的分子相互作用网络，引发感染稳定状态，使其持续存在无症状长达数十年。 Mtb 或主机网络活动的扰动会破坏平衡这种分子稳态将改变感染结果：要么在致病性上导致有症状的结核病 (TB) 结核杆菌猖獗生长和病理性炎症可能导致死亡或保护性的疾病走向感染清除。我将剖析宿主信号传导和结核分枝杆菌调节网络活动对感染命运的影响- 决定在原代人类感染期间影响结核分枝杆菌活力和宿主炎症的临界点基因单核细胞衍生的巨噬细胞（MDM）是体内主要的感染宿主细胞。我将分析宿主和病原体对这些感染改变扰动的转录反应来定义潜在的分子机制宿主与病原体之间的相互作用，我将利用这些信息来确定协同联合干预措施，同时靶向宿主和病原体。在宿主-病原体界面识别这些临界点基因应为联合针对宿主和病原体以引起宿主保护的新治疗干预策略提供信息，同时还揭示了发病机制的基本见解。