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 and lung cancer

免疫系统和微生物组在决定造血细胞移植受者以及白血病和肺癌患者呼吸道病毒感染结果中的相互作用

• 批准号: 9885882
• 负责人: Marjorie Batista
• 金额: $ 13.86万
• 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/9885882
• 关键词: Address; Affect; Antiviral Agents; Bacteremia; Biological Response Modifiers; Blood; Brazil; Cancer Center; Cancer Patient; Cessation of life; Cohort Studies; Complex; Detection; Diagnostic; 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; Malignant neoplasm of lung; Metagenomics; Methods; Mission; Molecular; National Cancer Institute; Nose; Outcome; Pathogenesis; Patients; Population; Populations at Risk; Pre-Clinical Model; Predisposition; Preventive therapy; Prognostic Marker; Public Health; Recommendation; Research; Research Design; Research Personnel; Respiratory Signs and Symptoms; Response Elements; Risk; Risk Factors; Role; Scientific Advances and Accomplishments; Sister; Socioeconomic Status; Testing; Texas; Therapeutic; Transplant Recipients; Transplantation; Tweens; 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; dysbiosis; epidemiology study; exhaust; geographic difference; 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; response; study population; targeted treatment; tool; 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

摘要 鼻咽微生物组（包括病毒组）和全身或局部免疫应答在预测呼吸道病毒感染（RVIs）并发症及其在免疫功能低下患者中的结局中的复杂相互作用的作用仍然未知，需要确定。长期目标是确定RVI期间与造血细胞移植（HCT）受者和白血病患者的不良结局（主要是下呼吸道感染（LRTI）、死亡或肺损伤（PI））相关的宿主免疫因素和呼吸道微生物组变化。该提案的总体目标是确定宿主和病原体因素作为RVIs癌症患者高危人群不良结局的预测因素。基于初步研究结果，我们的中心假设是呼吸道病毒和微生物组之间的生态失调，以及特定的免疫反应元素，可能是RVI不良结局的触发因素或辅助因素。根据研究者的专业知识，将通过以下两个具体目标对研究假设进行检验。目标1：确定RVI导致的呼吸道微生物组和病毒组的系列变化是否影响HCT接受者和白血病患者1个月、3个月的总生存期（OS）、12个月的无进展生存期（PFS）以及进展为LRTI和PI的风险。次级目标1.1：在有呼吸道症状但常规分子病毒诊断试验阴性的HCT受者中鉴定新型或未诊断的病毒。次级目标1.2：描述HCT接受者和白血病患者中RVI后基于地理位置（美国和巴西）的微生物组/病毒组的变化。目的2明确HCT受者和白血病患者RVIs后的全身和局部免疫反应，以确定免疫特征与更差结局（如1个月、3个月OS、12个月PFS、LRTI进展和PI）之间是否存在相关性。该研究设计将是一项前瞻性多中心队列研究，在两个姐妹机构，得克萨斯大学医学博士安德森癌症中心（美国得克萨斯州）和A.C.巴西圣保罗的卡马戈癌症中心。方法：将通过下一代测序（NGS）获得RVI患者的鼻咽微生物群谱。同时，将使用细胞免疫特征（外周血）的高参数流式细胞术以及使用微珠检测平台（血液和鼻洗液）的免疫介质的多重分析物检测来研究RVI诱导的宿主免疫应答。拟议研究的贡献将提供对风险因素的全面了解，包括微生物组变化和宿主免疫反应的相互作用，在高危人群中RVI后进展为不良结局。这种应用是创新的，因为它代表了一种新的和实质性的偏离现状，将重点从流行病学研究转移到宏基因组学NGS，并产生高维的局部和全身免疫谱，在这个脆弱的人群中的RVIs的结果。这种独创的方法将导致对发病机制的更广泛的理解，以及更好的诊断工具和治疗策略，以改善免疫功能低下患者的预后