Targeted next-generation sequencing to enhance detection and genomic characterization of Mycobacterium tuberculosis and high-impact bacterial pathogens among HIV-infected adults with sepsis in Uganda

靶向下一代测序可增强乌干达感染艾滋病毒的脓毒症成人中结核分枝杆菌和高影响细菌病原体的检测和基因组特征

• 批准号: 10116263
• 负责人: Max O'Donnell
• 金额: $ 28.25万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116263
• 关键词: Address; Adopted; Adult; Affect; Africa; Africa South of the Sahara; Antimicrobial Resistance; Applications Grants; Autopsy; Bacteremia; Bacteria; Bacterial Antibiotic Resistance; Biological Assay; Blood; Blood specimen; Caring; Cessation of life; Characteristics; Clinical; Clinical Data; Clinical Research; Collaborations; Country; Critical Illness; DNA; Data; Detection; Diagnosis; Diagnostic; Disease; Drug resistance; Drug resistance in tuberculosis; Etiology; Genomics; Goals; HIV; HIV Infections; HIV-infected adolescents; HIV/TB; High Prevalence; High-Throughput Nucleotide Sequencing; Human; Immunity; In Vitro; Incidence; Infection; Laboratories; Medicine; Methods; Molecular; Morbidity - disease rate; Mycobacterium tuberculosis; Nested Case-Control Study; Nucleic Acids; Organism; Pathogenicity; Pathway interactions; Patients; Performance; Population; Prevalence; Prospective Studies; Prospective cohort; Reaction; Reference Standards; Research Institute; Resistance; Resolution; Resources; Reverse Transcriptase Polymerase Chain Reaction; Rifampicin resistance; Role; Sampling; Scientist; Sensitivity and Specificity; Sepsis; Sputum; Testing; Time; Translational Research; Tuberculosis; Uganda; Universities; Virus; Work; accurate diagnosis; biobank; case control; college; design; detection limit; detection sensitivity; diagnostic accuracy; diagnostic platform; drug resistant pathogen; emerging pathogen; experimental study; genomic biomarker; improved; innovation; molecular diagnostics; mortality; next generation; next generation sequencing; non-tuberculosis mycobacteria; novel; novel diagnostics; pathogen; pathogenic bacteria; peripheral blood; point-of-care diagnostics; priority pathogen; resistance gene; septic patients; sequencing platform; tuberculosis diagnostics; tuberculosis drugs

Project Summary Over the past two decades, disseminated Mycobacterium tuberculosis (MTB) has been increasingly recognized as the leading cause of fatal bloodstream infection in HIV-infected patients with sepsis in high- burden tuberculosis (TB)/HIV settings worldwide. In these settings, estimated prevalence of MTB bacteremia in HIV-infected adults presenting with sepsis is as high as 40% with mortality approaching 50%. Despite high prevalence and mortality, timely and accurate diagnosis of MTB bacteremia and concomitant TB drug resistance remains challenging and is often diagnosed post-mortem. Novel diagnostic strategies are needed to expedite identification and treatment of critically ill patients with MTB bacteremia and other severe bloodstream infections in high-burden TB/HIV settings. The overall goal of this study is to enhance rapid molecular detection of MTB and other high-impact bacterial pathogens among HIV-infected adults with sepsis through use of an innovative, highly sensitive next-generation sequencing approach. We propose to utilize a novel positive- selection nucleic acid enrichment and high-throughput sequencing platform (BacCapSeq) to detect MTB bacteremia and drug-resistant organisms, optimized at the bench and trialed in a nested case control study of HIV-associated sepsis in Uganda. Specifically, we will evaluate the performance of BacCapSeq and emerging, near-point-of-care diagnostics (Xpert MTB/RIF Ultra) for the detection and characterization of MTB bacteremia and MTB drug resistance using biobanked samples from a prospective cohort of HIV-infected adults with sepsis in Uganda (Aim 1); and identify and characterize high-priority, antibiotic-resistant bacterial pathogens associated with sepsis in HIV-infected patients without MTB infection in Uganda (Aim 2). At the conclusion of this work we will have addressed critical diagnostic gaps for severe HIV/TB disease while providing high- resolution genomic characterization of pathogens and antimicrobial resistance associated with sepsis, a frequent pathway to death for HIV-infected adolescents and adults worldwide.

项目总结