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）粘膜损伤和肠道上皮屏障的破坏是定义 HIV-1感染的发病机理的特征。积累的证据表明中性粒细胞起着关键 HIV-1感染中胃肠道和肝损伤的作用。中性粒细胞在HIV-1-中浸润胃肠道 受感染的个体高水平，他们的存在与上皮屏障的损害有关， 在动物模型和HIV-1感染的患者中，上皮渗透性升高，并增加了疾病的严重程度。 在此应用程序中，我们建议微生物易位和由此产生的全身先天免疫 由循环中嗜中性粒细胞亚群的变化介导的失调，肠道相关淋巴组织 （GALT），肝脏在HIV-1疾病进展中起着基本作用。总体目标 提案是将中性粒细胞亚群和netosis的作用定义为驱动机制 HIV-1感染中的胃肠道和肝损害，并确定负责慢性的机制 HIV-1感染中的嗜中性粒细胞激活，以揭示干预的特定检查点。我们的中心 假设是HIV-1感染与特异性嗜中性粒细胞的诱导和扩展有关 产生活性氧（ROS）并经历Netosis的能力增加的亚群。罗斯 从活化的中性粒细胞释放的网和肝脏造成损害，并驱动 HIV-1感染的进展。该假设是根据我们的初步数据提出的 最近发表的报告表明，中性粒细胞在HIV-1感染中的关键作用。在初步 研究，我们优化了用于详细嗜中性粒细胞表征的方法，并证明了来自 HIV-1感染的个体显示活化的表型，免疫抑制特性，特定的 转录曲线，脱粒率提高，并具有高能力发生Netosis。具体的 新确定的中性粒细胞亚群的特性强烈表明它们在 在HIV-1感染的个体中损害GI粘膜和肝病的发病机理。我们建议 确定诱导特异性嗜中性粒细胞亚群对肝病进展的影响 经过艺术处理的HIV-1感染个体，以识别GALT中嗜中性粒细胞亚群的特定特性 和HIV-1感染的个体的肝脏，并确定这些先天免疫失调是否存在 组织与表现出M1与M2表型的组织巨噬细胞之比的变化有关 导致患有Netosis的嗜中性粒细胞的肿瘤细胞增多症降低。意义的意义 拟议的研究是，一旦确定了中性粒细胞在HIV-1感染进展中的作用，中性粒细胞就可以 致病种群的激活和诱导可以针对药理。