Dysregulated neutrophil subpopulations as a driving mechanism of liver and gastrointestinal disease in HIV-1-infected individuals

中性粒细胞亚群失调是 HIV-1 感染者肝脏和胃肠道疾病的驱动机制

• 批准号: 10698980
• 负责人: Zdenek Hel
• 金额: $ 70.71万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10698980
• 关键词: Adult; Animal Model; Anti-Inflammatory Agents; Automobile Driving; Bacteria; Bacterial Infections; Biopsy; Blood Circulation; Cause of Death; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Chronic; Circulation; Data; Disease; Disease Progression; Enrollment; Epithelium; Equilibrium; Exhibits; Frequencies; Gastrointestinal Diseases; Gastrointestinal tract structure; Gene Expression Profile; Genes; Gut associated lymphoid tissue; HIV-1; Hepatitis C virus; IL17 gene; Immune; Impairment; Individual; Infection; Inflammation; Inflammatory; Interferons; Intervention; Intestinal permeability; Kupffer Cells; Liver; Liver Fibrosis; Liver diseases; Macrophage; Mediating; Methods; Morbidity - disease rate; Mucous Membrane; NADPH Oxidase; Neutrophil Activation; Neutrophil Infiltration; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Patients; Permeability; Persons; Phenotype; Play; Population; Prevalence; Property; Publishing; Reactive Oxygen Species; Reporting; Research; Role; Secondary to; Severity of illness; Structural defect; Testing; Tight Junctions; Tissues; comorbidity; extracellular; firewall; gastrointestinal; gastrointestinal epithelium; immune activation; liver injury; microbial; monocyte; mortality; neutrophil; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; pharmacologic; predictive marker; response

7. PROJECT SUMMARY / ABSTRACT. Gastrointestinal (GI) mucosal damage and destruction of the gut epithelial barrier are the defining features of the pathogenesis of HIV-1 infection. Accumulated evidence indicates that neutrophils play a critical role in the gastrointestinal and liver damage in HIV-1 infection. Neutrophils infiltrate the GI tract in HIV-1- infected individuals at high levels and their presence is associated with damage to the epithelial barrier, elevated epithelial permeability, and increased disease severity in animal models and HIV-1-infected patients. In this application, we propose that microbial translocation and the resulting systemic innate immune dysregulation mediated by changes in neutrophil subpopulations in circulation, gut-associated lymphoid tissue (GALT), and liver plays a fundamental role in HIV-1 disease progression. The overall objectives of this proposal are to define the role of neutrophil subpopulations and NETosis as driving mechanisms of gastrointestinal and liver damage in HIV-1 infection and to identify the mechanisms responsible for chronic neutrophilic activation in HIV-1 infection in order to reveal the specific checkpoints for intervention. Our central hypothesis is that HIV-1 infection is associated with the induction and expansion of specific neutrophilic subpopulations with increased capacity to produce reactive oxygen species (ROS) and undergo NETosis. ROS and NETs released from activated neutrophils promote damage in the GI mucosa and liver and drive the progression of HIV-1 infection. This hypothesis has been formulated on the basis of our preliminary data and recently published reports demonstrating the critical role of neutrophils in HIV-1 infection. In preliminary studies, we optimized methods for detailed neutrophil characterization and demonstrated that neutrophils from HIV-1-infected individuals display an activated phenotype, immunosuppressive properties, specific transcriptional profile, increased rate of degranulation, and a high capacity to undergo NETosis. Specific properties of the newly identified neutrophil subpopulations strongly indicate that they play a critical role in damaging GI mucosa and the pathogenesis of liver disease in HIV-1-infected individuals. We propose to determine the effect of induction of specific neutrophil subpopulations on the progression of liver disease in ART-treated HIV-1-infected individuals, to identify specific properties of neutrophil subpopulations in the GALT and liver of HIV-1-infected individuals, and determine whether the innate immune dysregulation in these tissues is associated with a shift in the ratio of tissue macrophages exhibiting M1 versus M2 phenotype resulting in lowered efferocytosis and accumulation of neutrophils undergoing NETosis. The significance of the proposed studies is that once the role of neutrophils in the progression of HIV-1 infection is defined, neutrophil activation and induction of pathogenic populations can be pharmacologically targeted.

7. 项目摘要/摘要。 胃肠道 (GI) 粘膜损伤和肠上皮屏障破坏是决定性因素 HIV-1感染的发病机制的特点。累积的证据表明中性粒细胞在 HIV-1 感染引起的胃肠道和肝脏损伤中的作用。 HIV-1-中性粒细胞浸润胃肠道 感染个体的水平很高，它们的存在与上皮屏障的损伤有关， 动物模型和 HIV-1 感染患者的上皮通透性升高，疾病严重程度增加。 在本申请中，我们提出微生物易位和由此产生的系统先天免疫 循环系统、肠道相关淋巴组织中中性粒细胞亚群的变化介导的失调 (GALT)，肝脏在 HIV-1 疾病进展中发挥着重要作用。本次活动的总体目标 建议定义中性粒细胞亚群和 NETosis 作为驱动机制的作用 HIV-1 感染引起的胃肠道和肝脏损伤，并确定导致慢性感染的机制 HIV-1 感染中的中性粒细胞激活，以揭示干预的具体检查点。我们的中央 假设 HIV-1 感染与特定中性粒细胞的诱导和扩增有关 产生活性氧 (ROS) 和经历 NETosis 的能力增强的亚群。活性氧 活化的中性粒细胞释放的 NET 会促进胃肠道粘膜和肝脏的损伤，并驱动 HIV-1 感染的进展。这个假设是根据我们的初步数据和 最近发表的报告证明了中性粒细胞在 HIV-1 感染中的关键作用。在初步 研究中，我们优化了详细中性粒细胞表征的方法，并证明中性粒细胞来自 HIV-1 感染者表现出激活的表型、免疫抑制特性、特异性 转录谱、脱颗粒率增加以及进行 NETosis 的高能力。具体的 新发现的中性粒细胞亚群的特性强烈表明它们在 HIV-1 感染者的胃肠道粘膜损伤和肝脏疾病的发病机制。我们建议 确定特定中性粒细胞亚群的诱导对肝病进展的影响 接受 ART 治疗的 HIV-1 感染者，以确定 GALT 中中性粒细胞亚群的特定特性 和 HIV-1 感染者的肝脏，并确定这些人中是否存在先天免疫失调 组织与表现出 M1 与 M2 表型的组织巨噬细胞比例的变化相关 导致胞吞作用降低和进行 NETosis 的中性粒细胞积累。的意义 拟议的研究是，一旦中性粒细胞在 HIV-1 感染进展中的作用被明确，中性粒细胞 病原菌群的激活和诱导可以通过药理学来靶向。