The interplay of the immune system, and microbiome in determining outcome of respiratory viral infections in hematopoietic cell transplant recipients and in patients with leukemia

免疫系统和微生物组在决定造血细胞移植受者和白血病患者呼吸道病毒感染结果中的相互作用

• 批准号: 10410521
• 负责人: Marjorie Batista
• 金额: $ 12.56万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-22 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10410521
• 关键词: Address; Affect; Bacteremia; Biological Response Modifiers; Blood; Brazil; Cancer Center; Cancer Patient; Cells; Cessation of life; Cohort Studies; Complex; Detection; Development; Diagnostic tests; Diarrhea; Disease Outcome; Disease Progression; Epidemiologic Factors; Etiology; Feces; Flow Cytometry; Generations; Geography; Goals; Human; Immune; Immune response; Immune system; Immunoassay; Immunocompromised Host; Immunologic Factors; Immunologic Markers; Impairment; Infection; Inflammatory; Institution; Intervention; Knowledge; Longitudinal Studies; Lower Respiratory Tract Infection; Lung; Lung infections; Metagenomics; Methods; Mission; Molecular; National Cancer Institute; Nose; Outcome; Pathogenesis; Patients; Persons; Population; Populations at Risk; Pre-Clinical Model; Predisposition; Preventive therapy; Prognostic Marker; Progression-Free Survivals; Public Health; Recommendation; Reporting; Research; Research Design; Research Personnel; Respiratory Signs and Symptoms; Response Elements; Risk; Risk Factors; Role; Scientific Advances and Accomplishments; Sister; Site; Socioeconomic Status; Testing; Texas; Therapeutic; Transplant Recipients; Transplantation; United States; Vaccines; Variant; Viral; Viral Cancer; Viral Respiratory Tract Infection; Virus; Virus Diseases; Vulnerable Populations; acute infection; anticancer research; antimicrobial; base; clinically relevant; cofactor; detection platform; diagnostic tool; dysbiosis; epidemiology study; exhaust; geographic difference; gut dysbiosis; hematopoietic cell transplantation; high dimensionality; high risk population; host microbiome; improved outcome; innovation; insight; leukemia; lung microbiota; microbiome; microbiota profiles; mortality; next generation sequencing; novel; pathogen; peripheral blood; personalized approach; personalized medicine; post-transplant; prevent; profiles in patients; prophylactic; prospective; respiratory; respiratory microbiome; respiratory virus; targeted treatment; treatment response; treatment strategy; tumor progression; virome

ABSTRACT The role of the complex interplay of the nasopharyngeal microbiome, including the virome, and the systemic or local immune response in predicting complications from respiratory viral infections (RVIs) and their outcomes in immunocompromised patients, remains unknown and needs to be determined. The long-term goal is to identify host immunologic factors and respiratory microbiome changes during RVIs that are associated with poor outcome, mainly lower respiratory tract infection (LRTI), death, or pulmonary impairment (PI) in hematopoietic cell transplant (HCT) recipients, and in patients with leukemia. The overall objective of this proposal is to identify host and pathogen factors as predictors of poor outcome in a high-risk population of cancer patients with RVIs. Based on preliminary findings, our central hypothesis is that dysbiosis between respiratory viruses and the microbiome, in conjunction with specific immune response elements, could act as a trigger or cofactor for poor outcome in RVIs. Building on the investigators’ expertise, the study hypothesis will be tested through the following two specific aims. Aim 1: To determine whether serial changes in the respiratory microbiome and virome resulting from RVIs affect the overall survival (OS) at 1 month, 3 months, progression free survival (PFS) at 12 months, and the risk of progression to LRTI, and PI in HCT recipients and in patients with leukemia. Sub-aim 1.1: To identify novel or undiagnosed viruses in HCT recipients with respiratory symptoms but negative routine molecular viral diagnostic tests. Sub-aim 1.2: To characterize variations in the microbiome/virome based on geography (US and Brazil) after RVIs in HCT recipients and in patients with leukemia. Aim 2 To de-fine systemic and local immune responses after RVIs in HCT recipients and in patients with leukemia to deter-mine whether an association exists between immune profiles and worse outcomes such as OS at 1 month, 3 months, PFS at 12 months, and progression to LRTI, and PI. The research design will be a prospective multi-site cohort study between two sister institutions, The Univ. of Texas MD Anderson Cancer Center in Texas, US, and the A.C. Camargo Cancer Center in Sao Paulo, Brazil. Methods: Nasopharyngeal microbiota profiles of patients with RVIs will be achieved by next-generation sequencing (NGS). In parallel, RVI-induced host immune responses will be investigated using high parameter flow cytometry of cellular immune profiles (peripheral blood), as well as multiplex analyte detection of immune mediators using a bead detection platform (blood and nasal wash). The contribution of the proposed research will provide a comprehensive understanding of risk factors, including the interplay of microbiome changes and host immune responses, for progression to poor outcome after RVIs in a high-risk population. This application is innovative as it represents a new and substantive departure from the status quo by shifting focus from epidemiological studies to metagenomics NGS and to generation of high dimensional local and systemic immune profiles, on outcome in RVIs in this vulnerable population. This original approach will lead to broader understanding of pathogenesis and to better diagnostic tools and treatment strategies to improve outcome in immunocompromised patients

抽象的 鼻咽微生物组的复杂相互作用（包括病毒蛋白酶）的作用以及全身或局部免疫响应在预测呼吸道病毒感染（RVI）并发症中的并发症中的作用及其在免疫繁殖患者中的结局仍然未知，并且需要确定。长期的目标是在RVIS期间鉴定与不良预后，主要是下呼吸道感染（LRTI），死亡或肺部障碍（PI）相关的宿主免疫学因素和呼吸微生物组的变化（HCT），以及在白血病患者中。该提案的总体目的是将宿主和病原体因素识别为RVI癌症患者中预后不良的预测指标。基于初步发现，我们的中心假设是呼吸道病毒和微生物组之间的营养不良，以及特定的免疫响应元素，可以作为RVIS不良结果的触发或辅助因子。在研究人员的专业知识的基础上，将通过以下两个具体目标进行研究假设。目标1：确定RVIS引起的呼吸微生物组和病毒蛋白的串行变化是否会影响1个月，3个月的总生存期（OS），在12个月时在12个月时不受进展生存率（PFS），而在HCT接受者和患有白血病患者的HCT接受者中会影响LRTI的风险。 Sub-aim 1.1：识别患有呼吸道症状的HCT受体中的新型或未诊断病毒，但常规的分子病毒诊断测试。 Sub-aim 1.2：在HCT接受者和白血病患者中，基于地理（美国和巴西）的微生物组/病毒瘤的变化。目的2在HCT接受者和白血病患者的RVIS后脱离了FINE-FINE系统和局部免疫反应，以确定免疫特征和较差的结果之间是否存在关联，例如1个月，3个月的OS，12个月，PFS，12个月，以及向LRTI的进展和PI。研究设计将是两个姊妹机构大学之间的前瞻性多站点队列研究。德克萨斯州德克萨斯州的安德森癌症中心和巴西圣保罗的A.C. Camargo癌症中心的安德森癌症中心。方法：下一代测序（NGS）将实现RVIS患者的鼻咽微生物群。同时，将使用高参数流式细胞仪（外周血）以及使用珠子检测平台（血液和鼻腔洗涤）对免疫接触者进行多个分析物检测，将研究RVI诱导的宿主免疫复杂。拟议的研究的贡献将提供对危险因素的全面理解，包括微生物组变化和宿主免疫调查的相互作用，以在高危人群中RVI后发展为不良结果。该应用具有创新性，因为它通过将重点从流行病学研究转变为宏基因组学NG以及对这个脆弱人群的RVI的高度局部和系统性免疫特征的产生，代表了与现状的新事物。这种原始方法将导致对发病机理的更广泛理解，并更好地诊断工具和治疗策略，以改善免疫功能低下的患者的预后