Role of eosinophils in SIV infection

嗜酸性粒细胞在 SIV 感染中的作用

• 批准号: 10533909
• 负责人: Cordelia Manickam
• 金额: $ 24.15万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-20 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10533909
• 关键词: Adaptive Immune System; Affect; Allergic; Anatomy; Antigen Presentation; Antiviral Response; Biopsy; Cardiovascular Diseases; Cell physiology; Cells; Chronic; Colon; Cytomegalovirus; Data; Data Analyses; Diabetes Mellitus; Disease; Disease Outcome; Eosinophilia; Eosinophilic Gastrointestinal Disease; Epigenetic Process; Epithelial Cells; Exclusion; Exhibits; Exposure to; Extravasation; Fibroblasts; Food Hypersensitivity; Functional disorder; Gastrointestinal tract structure; Generations; Goals; HIV; HIV Infections; Human; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Immunoglobulin A; Immunology; Infection; Infectious Agent; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Intestinal Mucosa; Intestines; Knowledge; Large Intestine; Lead; Lentivirus Infections; Leukocytes; Lymphoid Tissue; Macaca; Macaca mulatta; Maintenance; Malignant Neoplasms; Mediating; Memory; Metabolic Pathway; Modeling; Modernization; Molecular Profiling; Mucous Membrane; Normal tissue morphology; Outcome; Parasitic infection; Pathogenicity; Pathologic; Pathology; Patients; Permeability; Phenotype; Population; Prevention strategy; Primates; Production; Publications; Reactive Oxygen Species; Regulation; Research; Risk; Role; SIV; Sampling; Signal Pathway; Site; Small Intestines; Surface; T-Lymphocyte; Testing; Time; Tissues; Training; Vaccines; Viral; Virus; Virus Diseases; Virus Replication; arm; cell motility; clinically relevant; comorbidity; cytokine; cytotoxic; cytotoxicity; eosinophil; granulocyte; gut homeostasis; gut inflammation; intestinal barrier; jejunum; methylation pattern; mouse model; mucosal site; nonhuman primate; organ growth; pathogen; programmed cell death ligand 1; response; tissue regeneration; tissue repair

PROJECT SUMMARY Chronic HIV infection is associated with increased risk of co-morbidities including diabetes mellitus, cardiovascular diseases, neuro-dysfunctions and cancer, due to the state of persistent inflammation and immune dysfunction induced by the virus. Further, HIV causes gut leakage and intestinal inflammation in the gastrointestinal tract of infected patients. Eosinophils are an important innate cell subset that are highly enriched in small and large intestines with gut homeostatic functions, but their role in mucosal viral infections have been mostly overlooked. In our recent publication (Jones et al, 2021; Immunology), we phenotypically characterized different subsets of granulocytes in rhesus macaques and found non-human primate (NHP) eosinophils analogous to human eosinophils and were found enriched in jejunum, suggesting that these tissue-resident eosinophils are well situated and capable of eliciting early antiviral mucosal responses. However, the pro-inflammatory responses of eosinophils- cytotoxicity, cytokine secretion, reactive oxygen species generation can also cause tissue damage. Further, there is a lack of knowledge of potential reprogramming of eosinophils in HIV infection that could contribute to clearance of pathogens and/or pathologic manifestations. In this new exploratory proposal, we will test the role of eosinophils contributing to antiviral responses that lead to viral clearance or pathogenic mechanisms that lead to persistent inflammation in lentivirus infection. Our two specific aims towards this goal are: (1) Determine the relative contribution of eosinophils to lentiviral pathology and control and (2) Evaluate mechanisms of trained immunity in eosinophils upon de novo infection with SIV in rhesus macaques. The outcomes of this proposal will provide first time detailed analysis of an eosinophil depleted immune system in any viral infection and reprogrammed eosinophils ‘trained’ in the context of SIV infection.

项目概要 慢性艾滋病毒感染与合并症的风险增加有关，包括糖尿病、 由于持续炎症状态导致心血管疾病、神经功能障碍和癌症 此外，艾滋病毒还会导致肠道渗漏和肠道免疫功能障碍。 感染患者胃肠道炎症中，嗜酸性粒细胞是一种重要的先天细胞。 在具有肠道稳态功能的小肠和大肠中高度富集的子集，但它们 在我们最近的出版物中（Jones 等人， 2021；免疫学），我们对恒河猴的不同粒细胞亚群进行了表型特征分析 猕猴并发现非人灵长类（NHP）嗜酸性粒细胞与人类嗜酸性粒细胞类似，并被 发现在空肠中富集，表明这些组织驻留的嗜酸性粒细胞位置良好并且 能够引发早期抗病毒粘膜反应，然而，促炎症反应。 嗜酸性粒细胞-细胞毒性、细胞因子分泌、活性氧的产生也会引起组织 此外，人们对 HIV 感染中嗜酸性粒细胞的潜在重编程缺乏了解。 这可能有助于清除病原体和/或病理表现。 探索性建议，我们将测试嗜酸性粒细胞在抗病毒反应中的作用，从而导致 导致慢病毒感染持续炎症的病毒清除或致病机制。 我们实现这一目标的两个具体目标是：（1）确定嗜酸性粒细胞的相对贡献 慢病毒病理学和控制；(2) 评估训练有素的免疫机制 恒河猴从头感染 SIV 后的嗜酸性粒细胞。 将首次对任何病毒感染中嗜酸性粒细胞耗尽的免疫系统进行详细分析 并在 SIV 感染的背景下重新编程的嗜酸性粒细胞“训练”。