Human Immunomics & Trained Immunity in Persistent Candidemia

人类免疫组学

• 批准号: 10551710
• 负责人: ELAINE F REED
• 金额: $ 43.61万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-10 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551710
• 关键词: ATAC-seq; Address; Affect; Anti-Infective Agents; Antibiotic Therapy; Antibiotics; Antifungal Therapy; Antigen Presentation; Attenuated; Automobile Driving; Big Data; Biological Assay; Biometry; Blood specimen; Candida albicans; Candidiasis; ChIP-seq; Chromatin; Clinical; Clinical Research; Coculture Techniques; Communicable Diseases; Computer Analysis; Computer Models; DNA Methylation; Data; Disease Outcome; Disseminated candidiasis; Enhancers; Enzymes; Epigenetic Process; Experimental Models; Genetic; Genetic Transcription; Goals; Hematogenous; Hematology; Histone Acetylation; Hospitals; Human; Immune; Immune Response Genes; Immune response; Immune system; Immunity; Immunology; In Vitro; Infection; Innate Immune Response; Integration Host Factors; Interferon Type II; Interferon alpha; Intervention; Life; Link; Macrophage; Maps; Mediating; Methicillin Resistance; Modification; Molecular; Multi-Drug Resistance; Mus; Myeloid Cells; Natural Immunity; Nitrous Oxide; Outcome; Oxygen; Pathologic; Pathway interactions; Patients; Peripheral; Phagocytosis; Plasma; Prophylactic treatment; Proteomics; Research; Role; Sepsis; Shapes; Signal Pathway; Signal Transduction; Specificity; Staphylococcus aureus; Staphylococcus aureus infection; Stimulus; Sulfides; Surface; System; Systems Biology; T cell response; T-Cell Activation; T-Lymphocyte; TNF gene; Training; Vaccines; Validation; adaptive immune response; adaptive immunity; beta-Glucans; candidemia; cathelicidin antimicrobial peptide; chemokine; chronic infection; cytokine; diagnostic tool; epigenome; epigenomic profiling; epigenomics; histone methylation; immune function; in vivo; infection rate; inhibitor; innate immune function; innovation; insight; machine learning model; methylation pattern; mortality; multiple omics; mutant; network models; novel; pathogen; peripheral blood; pharmacologic; predictive modeling; predictive signature; programs; promoter; prophylactic; resistant strain; response; statistical learning; survival outcome; targeted treatment; therapeutic development; therapeutic target; transcription factor; transcriptome; transcriptome sequencing; transcriptomics; whole genome

PROJECT SUMMARY Hematologic disseminated candidiasis (HDC) is the most common invasive fungal species in hospital settings worldwide. The mortality rate is high (40%) for these infections despite treatment with antifungal therapies. Similarly, methicillin-resistant strains of Staphylococcus aureus (MRSA) can cause invasive and life-threatening infections despite treatment with standard anti-infective therapies. Thus, persistence reflects host-pathogen interactions occurring uniquely in context of antibiotic therapy in vivo. However, host factors and mechanisms involved in persistent MRSA and HDC remain unclear. This study will use systems-based, high-throughput multi-omics platforms and novel statistical and computational approaches to provide a comprehensive longitudinal assessment of host in vitro and in vivo innate and adaptive responses to HDC and MRSA infection using patient peripheral blood, stimulus specific PAMPs and patient-derived HDC plasma PAMPs and isolates. Innovative deliverables include: i) Constructing an in-depth immune profile of HDC and MRSA immune profiles; ii) understand the stimulus-specificity of de novo enhancer formation in macrophages and how they affect transcriptional landscapes and functions iii) generate a detailed molecular map of the cross-talk between the innate and adaptive immune response during HDC and MRSA infection; iv) using the combination of biostatistics and computational modeling to explain and predict cellular and molecular networks driving trained immunity and persistent, resolving, and survival outcomes; and v) identification and validation of druggable epigenomic regulators of reprogramming. Detailed insights into the interaction of HDC and MRSA with the host immune system stand to generate fundamentally new mechanistic hypotheses and diagnostic tools to guide development of therapeutic strategies.

项目摘要 血液播散性念珠菌病（HDC）是医院环境中最常见的侵袭性真菌 国际吧尽管使用抗真菌治疗，这些感染的死亡率仍很高（40%）。 同样，耐甲氧西林金黄色葡萄球菌（MRSA）菌株可引起侵袭性和危及生命的 尽管使用标准抗感染疗法治疗，因此，持久性反映了宿主-病原体 在体内抗生素治疗的背景下唯一发生的相互作用。然而，宿主因素和机制 与持续性MRSA和HDC的关系尚不清楚。本研究将使用基于系统的、高通量的 多组学平台和新的统计和计算方法，以提供全面的 对HDC和MRSA感染的宿主体外和体内先天性和适应性应答的纵向评估 使用患者外周血、刺激特异性PAMP和患者来源的HDC血浆PAMP和分离物。 创新的可交付成果包括：i）构建HDC和MRSA免疫谱的深入免疫谱; ii）了解巨噬细胞中从头增强子形成的刺激特异性以及它们如何影响 转录景观和功能iii）生成一个详细的分子图之间的串扰 在HDC和MRSA感染期间的先天性和适应性免疫应答; iv）使用以下的组合： 生物统计学和计算建模，以解释和预测细胞和分子网络驾驶训练 免疫力和持续、消退和存活结果;以及v）鉴定和验证可药用的 重编程的表观基因调控因子详细了解HDC和MRSA与宿主的相互作用 免疫系统将产生全新机制假说和诊断工具， 制定治疗策略。