Highly multiplexed platforms for diagnosis of infection and immunity

用于诊断感染和免疫的高度多重平台

• 批准号: 9241960
• 负责人: W. Ian Lipkin
• 金额: $ 177.94万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9241960
• 关键词: Acute; Antibodies; Area; Automobile Driving; Base Sequence; Bioinformatics; Biological Assay; Clinical; Clinical Management; Communicable Diseases; Complement; Complex; Computer software; Dengue; Detection; Diagnosis; Diagnostic; Differential Diagnosis; Disease; Disease Outbreaks; Evaluation; Exposure to; Health Personnel; High-Throughput Nucleotide Sequencing; Immunity; Immunologics; Individual; Infection; Infectious Agent; Investments; Knowledge; Length; Mediating; Medicine; Methods; Microbiology; Molecular; Morbidity - disease rate; Nucleic Acids; Peptide Library; Peptides; Preparation; Probability; Protocols documentation; Recording of previous events; Research; Resource Allocation; Risk; Sampling; Serologic tests; Severities; Signs and Symptoms; Specimen; Vaccination; Vaccines; base; clinical material; cost; economic cost; emergency service responder; improved; microbial; mortality; pathogen; pathogen exposure; tool

Rapid, efficient differential diagnosis is critical to controlling the morbidity and mortality of acute infectious diseases and to enabling efficient resource allocation. Many infectious diseases present with non-specific signs and symptoms; hence, history and physical exam alone are typically insufficient to inform clinical management or characterize outbreaks. A wide range of molecular methods have been developed for direct detection of microbial nucleic acids in clinical materials. These advances have transformed microbiology and medicine; nonetheless, high throughput sequencing, the most highly multiplexed of these methods, remains too complex and expensive for application in many clinical settings. Furthermore, none of these methods will serve in instances where microbial nucleic acids are not present in an accessible sample or where disease may have been triggered by an agent that is no longer present. The risk of developing disease and its severity after exposure to an infectious agent is modulated by an individual's previous exposures to similar agents or vaccines. Such exposures may confer complete or partial protection or result in increased risk for more severe disease due to antibody-mediated enhancement, as is the case in dengue fever. Thus, knowledge of an individual's immunological history may influence decisions concerning his/her treatment, vaccination or deployment as a first responder or health care worker in areas with increased probability of encountering specific pathogens. Our objective is to enhance differential diagnosis and management of infectious diseases through pursuit of two aims that will (1) establish a new highly multiplexed serology platform for profiling a subject's pathogen exposure history and (2) improve the efficiency of sequencing for direct detection of microbial nucleic acids in clinical specimens. Investments in sequencing have largely focused on driving down costs per base and on increasing read length and number. We will complement these efforts by establishing new methods for sample preparation that will enrich for relevant template, thereby enhancing efficiency and reducing the complexity of bioinformatic analyses.

快速、高效的鉴别诊断对于控制急性传染病的发病率和死亡率以及实现有效的资源分配至关重要。许多传染性疾病存在非特异性体征和症状;因此，仅病史和体格检查通常不足以告知临床管理或表征爆发。已经开发了广泛的分子方法用于直接检测临床材料中的微生物核酸。这些进步改变了微生物学和医学;尽管如此，高通量测序（这些方法中最高度多重化的）对于在许多临床环境中的应用来说仍然过于复杂和昂贵。此外，这些方法中没有一种将用于微生物核酸不存在于可获得的样品中或疾病可能已由不再存在的试剂触发的情况。暴露于传染性病原体后发生疾病的风险及其严重程度受个人先前暴露于类似病原体或疫苗的影响。这种暴露可能会提供完全或部分保护，或由于抗体介导的增强而导致更严重疾病的风险增加，如登革热。因此，对个体免疫史的了解可能会影响他/她在遇到特定病原体的可能性增加的地区作为第一反应者或卫生保健工作者的治疗，疫苗接种或部署的决定。我们的目标是通过追求两个目标来加强传染病的鉴别诊断和管理，这两个目标将（1）建立一个新的高度多重血清学平台，用于分析受试者的病原体暴露史，以及（2）提高直接检测临床标本中微生物核酸的测序效率。测序方面的投资主要集中在降低每个碱基的成本以及增加读取长度和数量上。我们将通过建立新的样品制备方法来补充这些努力，这些方法将富集相关模板，从而提高效率并降低生物信息学分析的复杂性。