Profiling the Lung Transcriptome for Precision Diagnosis of Respiratory Infections using Host/Pathogen Metagenomic Sequencing

使用宿主/病原体宏基因组测序分析肺转录组以精确诊断呼吸道感染

• 批准号: 10201724
• 负责人: Charles Langelier
• 金额: $ 16.04万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201724
• 关键词: Acute; Acute Lung Injury; Acute respiratory failure; Address; Adult; Algorithm Design; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Antimicrobial susceptibility; Area; Aspirate substance; Benchmarking; Bioinformatics; Biological Assay; Biometry; Blood; Caring; Censuses; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clinical; Clinical Medicine; Clinical Research; Clinical Trials; Clostridium difficile; Communicable Diseases; Coupled; Coupling; Critical Care; Critical Illness; DNA; Data; Databases; Development; Diagnosis; Diagnostic; Disease; Drug resistance; Enrollment; Epidemiology; Etiology; Evaluation; Faculty; Foundations; Future; Gene Expression; Gene Expression Profiling; Genetic Determinism; Genetic Transcription; Genomic medicine; Genomics; Goals; Grant; Hospital Costs; Hour; Human; Immune response; Immunology; Infection; Informatics; Infrastructure; Laboratories; Lead; Liquid substance; Logistic Regressions; Lower Respiratory Tract Infection; Lung; Lung diseases; Lung infections; Manuscripts; Mechanical ventilation; Medicine; Mentors; Metagenomics; Methods; Microbe; Microbiology; Modality; Molecular Medicine; NCI Scholars Program; Outcome Study; Pathogen detection; Patient Care; Patient-Focused Outcomes; Patients; Peer Review; Performance; Personal Satisfaction; Pharmaceutical Preparations; Phenotype; Physicians; Positioning Attribute; Precision therapeutics; Predisposition; Prospective cohort; Pulmonology; RNA; Research; Research Design; Research Personnel; Resistance; Respiratory Failure; Respiratory Tract Infections; Sampling; Scientist; Seminal; Sensitivity and Specificity; Speed; Technology; Testing; Training; Transcript; Work; Writing; adjudicate; adjudication; adverse outcome; bacterial resistance; base; career; career development; clinical Diagnosis; clinical care; cohort; design; endotracheal; experience; genome sequencing; improved; inflammatory lung disease; innovation; metagenomic sequencing; microbial; microbial genomics; microbiota; mortality; next generation sequencing; novel; pathogen; pathogenic microbe; patient oriented; prediction algorithm; prospective; resistance gene; respiratory; respiratory microbiota; respiratory pathogen; skills; standard of care; systemic inflammatory response; targeted treatment; tool; transcriptome; treatment strategy; trial design

PROJECT SUMMARY/ABSTRACT As a young clinician-investigator, I am focused and committed to improving human wellbeing through patient-oriented respiratory infection research, applied genomics and clinical medicine. This K23 will provide the support and training needed to build a successful research career focused on improving the diagnosis and treatment of respiratory diseases using advanced genomic technologies. Working with my mentor and co-mentors, I have assembled a K23 Research Committee of outstanding and dedicated faculty who are leaders in genomics, pulmonary and critical care medicine, infectious diseases, immunology and bioinformatics. They have helped me devise a robust training plan to acquire expertise in three key areas: 1) clinical research design and analysis, 2) biostatistics and epidemiology and 3) bioinformatics. This plan includes coursework, direct mentoring, hands-on experiences, and weekly manuscript peer review sessions, grant writing seminars and career advisement via the UCSF K Scholars program. The goals of my proposal are inspired by the many critically ill patients that I have cared for with acute respiratory illnesses who receive empiric, sometimes ineffective, and in many cases protracted treatments for acute respiratory illnesses because available diagnostics are unable to provide an informative microbiologic diagnosis. These experiences have made me realize the outstanding need for better assays that can provide a data driven – and not empiric – approach to treating severe lower respiratory tract infections (LRTIs). My K23 proposal directly addresses this need by engaging metagenomic next generation sequencing (mNGS) to assay both the host transcriptome and microbial pathogens from the airways of critically ill patients. An actively enrolling, prospective cohort of adults with acute respiratory failure requiring mechanical ventilation will be studied via three specific aims. Aim 1 will develop a host gene expression classifier that distinguishes LRTI from non-infectious acute respiratory conditions. Aim 2 will evaluate the performance of mNGS for pathogen detection in patients with clinically adjudicated LRTI. Aim 3 will determine the performance of mNGS genome-based antimicrobial resistance prediction in patients with drug-resistant bacterial LRTI. This proposal incorporates metagenomics and bioinformatics with a focus on patient-centered pulmonary infection research. The results generated from this work will provide the foundation for a subsequent prospective clinical trial evaluating the impact of mNGS diagnostics on patient outcomes. This proposal directly aligns with my career goals of becoming an independent physician-scientist working to advance the field of pulmonary medicine by developing new tools that enhance clinical diagnosis and inform precision treatment strategies. Through patient-focused molecular medicine research inspired by unique and challenging cases, I aim to reduce the burden of respiratory infections.

项目总结/摘要 作为一名年轻的临床研究员，我专注于并致力于通过以下方式改善人类福祉： 以病人为中心的呼吸道感染研究、应用基因组学和临床医学。K23将提供 支持和培训需要建立一个成功的研究生涯，重点是改善诊断和 使用先进的基因组技术治疗呼吸系统疾病。 与我的导师和共同导师合作，我组建了一个K23研究委员会， 以及在基因组学、肺部和重症监护医学、传染病、 免疫学和生物信息学。他们帮助我设计了一个强大的培训计划，以获得三个方面的专业知识 关键领域：1）临床研究设计和分析，2）生物统计学和流行病学，3）生物信息学。这 计划包括课程作业、直接指导、实践经验和每周手稿同行评审 会议，赠款写作研讨会和职业生涯通过UCSF K学者计划。 我的提案的目标是受到我照顾过的许多重症患者的启发， 呼吸道疾病接受经验性，有时无效，在许多情况下， 急性呼吸道疾病，因为现有的诊断无法提供有用的微生物 诊断.这些经历使我意识到，我们迫切需要更好的检测方法， 数据驱动-而不是经验-治疗严重下呼吸道感染（LRTI）的方法。K23 一项提案通过使用宏基因组下一代测序（mNGS）来测定 宿主转录组和来自重症患者气道的微生物病原体。 一项积极招募的需要机械通气的急性呼吸衰竭成人前瞻性队列研究 通风将通过三个具体目标进行研究。目标1将开发一种宿主基因表达分类器， 将LRTI与非传染性急性呼吸道疾病区分开来。目标2将评估 mNGS用于临床判定的LRTI患者的病原体检测。目标3将决定性能 基于mNGS基因组的耐药性预测在耐药细菌LRTI患者中的应用。 该提案结合了宏基因组学和生物信息学，重点关注以患者为中心的肺肿瘤。 感染研究。从这项工作中产生的结果将为随后的前景奠定基础 评估mNGS诊断对患者结局影响的临床试验。该提案直接与 我的职业目标是成为一名独立的医生科学家，致力于推动肺疾病领域的发展。 通过开发新的工具，加强临床诊断和精确的治疗策略。 通过以患者为中心的分子医学研究，受到独特和具有挑战性的病例的启发，我的目标是减少 呼吸道感染的负担。

项目成果

Integrated host/microbe metagenomics enables accurate lower respiratory tract infection diagnosis in critically ill children.

• DOI: 10.1172/jci165904
• 发表时间: 2023-04-03
• 期刊: JOURNAL OF CLINICAL INVESTIGATION
• 影响因子: 15.9
• 作者: Mick, Eran;Tsitsiklis, Alexandra;Kamm, Jack;Kalantar, Katrina L.;Caldera, Saharai;Lyden, Amy;Tan, Michelle;Detweiler, Angela M.;Neff, Norma;Osborne, Christina M.;Williamson, Kayla M.;Soesanto, Victoria;Leroue, Matthew;Maddux, Aline B.;Simoes, Eric A. F.;Carpenter, Todd C.;Wagner, Brandie D.;DeRisi, Joseph L.;Ambroggio, Lilliam;Mourani, Peter M.;Langelier, Charles R.
• 通讯作者: Langelier, Charles R.

Host-Microbe Metagenomics: a Lens To Refocus Our Perspective on Infectious and Inflammatory Diseases.

• DOI: 10.1128/msystems.00404-21
• 发表时间: 2021-08-31
• 期刊: mSystems
• 影响因子: 6.4
• 作者: Kalantar KL;Langelier CR
• 通讯作者: Langelier CR

Aerosolized nicotine from e-cigarettes alters gene expression, increases lung protein permeability, and impairs viral clearance in murine influenza infection.

• DOI: 10.3389/fimmu.2023.1076772
• 发表时间: 2023
• 期刊: FRONTIERS IN IMMUNOLOGY
• 影响因子: 7.3
• 作者: Maishan, Mazharul;Sarma, Aartik;Chun, Lauren F.;Caldera, Saharai;Fang, Xiaohui;Abbott, Jason;Christenson, Stephanie A.;Langelier, Charles R.;Calfee, Carolyn S.;Gotts, Jeffrey E.;Matthay, Michael A.
• 通讯作者: Matthay, Michael A.

A 2-Gene Host Signature for Improved Accuracy of COVID-19 Diagnosis Agnostic to Viral Variants.

• DOI: 10.1128/msystems.00671-22
• 发表时间: 2023-02-23
• 期刊: mSystems
• 影响因子: 6.4

Prolonged silent carriage, genomic virulence potential and transmission between staff and patients characterize a neonatal intensive care unit (NICU) outbreak of methicillin-resistant Staphylococcus aureus (MRSA).

新生儿重症监护病房 (NICU) 耐甲氧西林金黄色葡萄球菌 (MRSA) 爆发的特点是长期沉默携带、基因组毒力潜力以及工作人员和患者之间的传播。

• DOI: 10.1017/ice.2022.48
• 发表时间: 2023
• 期刊: Infection control and hospital epidemiology
• 影响因子: 4.5
• 作者: Madera,Sharline;McNeil,Nicole;Serpa,PaulaHayakawa;Kamm,Jack;Pak,Christy;Caughell,Carolyn;Nichols,Amy;Dynerman,David;Li,LucyM;Sanchez-Guerrero,Estella;Phelps,MairaS;Detweiler,AngelaM;Neff,Norma;Reyes,Helen;Miller,SteveA;Y
• 通讯作者: Y