دورية أكاديمية
أعرض في EDS

Multiplexed Strain Phenotyping Defines Consequences of Genetic Diversity in Mycobacterium tuberculosis for Infection and Vaccination Outcomes.

التفاصيل البيبلوغرافية
العنوان: Multiplexed Strain Phenotyping Defines Consequences of Genetic Diversity in Mycobacterium tuberculosis for Infection and Vaccination Outcomes.
المؤلفون: Carey AF; Department of Immunology & Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.; Division of Microbiology & Immunology, Department of Pathology, University of Utah, Salt Lake City, Utah, USA., Wang X; Department of Immunology & Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA., Cicchetti N; Division of Microbiology & Immunology, Department of Pathology, University of Utah, Salt Lake City, Utah, USA., Spaulding CN; Department of Immunology & Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA., Liu Q; Department of Immunology & Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA., Hopkins F; Department of Immunology & Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA., Brown J; Department of Immunology & Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA., Sixsmith J; Department of Immunology & Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA., Sutiwisesak R; Immunology and Microbiology Program, Graduate School of Biomedical Science, University of Massachusetts Medical Schoolgrid.168645.8, Worcester, Massachusetts, USA.; Department of Microbiology and Physiological Systems, University of Massachusetts Medical Schoolgrid.168645.8, Worcester, Massachusetts, USA., Behar SM; Immunology and Microbiology Program, Graduate School of Biomedical Science, University of Massachusetts Medical Schoolgrid.168645.8, Worcester, Massachusetts, USA.; Department of Microbiology and Physiological Systems, University of Massachusetts Medical Schoolgrid.168645.8, Worcester, Massachusetts, USA., Ioerger TR; Department of Computer Science, Texas A&M University, College Station, Texas, USA., Fortune SM; Department of Immunology & Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.; Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA.
المصدر: MSystems [mSystems] 2022 Jun 28; Vol. 7 (3), pp. e0011022. Date of Electronic Publication: 2022 Apr 18.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: American Society for Microbiology Country of Publication: United States NLM ID: 101680636 Publication Model: Print-Electronic Cited Medium: Print ISSN: 2379-5077 (Print) Linking ISSN: 23795077 NLM ISO Abbreviation: mSystems
أسماء مطبوعة: Original Publication: Washington, DC : American Society for Microbiology, [2016]-
مواضيع طبية MeSH: Mycobacterium tuberculosis*/genetics , Tuberculosis*/epidemiology, Animals ; Mice ; Humans ; BCG Vaccine ; Vaccination ; Genetic Variation/genetics
مستخلص: There is growing evidence that genetic diversity in Mycobacterium tuberculosis, the causative agent of tuberculosis, contributes to the outcomes of infection and public health interventions, such as vaccination. Epidemiological studies suggest that among the phylogeographic lineages of M. tuberculosis, strains belonging to a sublineage of Lineage 2 (mL2) are associated with concerning clinical features, including hypervirulence, treatment failure, and vaccine escape. The global expansion and increasing prevalence of this sublineage has been attributed to the selective advantage conferred by these characteristics, yet confounding host and environmental factors make it difficult to identify the bacterial determinants driving these associations in human studies. Here, we developed a molecular barcoding strategy to facilitate high-throughput, experimental phenotyping of M. tuberculosis clinical isolates. This approach allowed us to characterize growth dynamics for a panel of genetically diverse M. tuberculosis strains during infection and after vaccination in the mouse model. We found that mL2 strains exhibit distinct growth dynamics in vivo and are resistant to the immune protection conferred by Bacillus Calmette-Guerin (BCG) vaccination. The latter finding corroborates epidemiological observations and demonstrates that mycobacterial features contribute to vaccine efficacy. To investigate the genetic and biological basis of mL2 strains' distinctive phenotypes, we performed variant analysis, transcriptional studies, and genome-wide transposon sequencing. We identified functional genetic changes across multiple stress and host response pathways in a representative mL2 strain that are associated with variants in regulatory genes. These adaptive changes may underlie the distinct clinical characteristics and epidemiological success of this lineage. IMPORTANCE Tuberculosis, caused by the bacterium Mycobacterium tuberculosis, is a remarkably heterogeneous disease, a feature that complicates clinical care and public health interventions. The contributions of pathogen genetic diversity to this heterogeneity are uncertain, in part due to the challenges of experimentally manipulating M. tuberculosis, a slow-growing, biosafety level 3 organism. To overcome these challenges, we applied a molecular barcoding strategy to a panel of M. tuberculosis clinical isolates. This novel application of barcoding permitted the high-throughput characterization of M. tuberculosis strain growth dynamics and vaccine resistance in the mouse model of infection. Integrating these results with genomic analyses, we uncover bacterial pathways that contribute to infection outcomes, suggesting targets for improved therapeutics and vaccines.
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معلومات مُعتمدة: T32 AI007061 United States AI NIAID NIH HHS; T32 CA009216 United States CA NCI NIH HHS; R01 AI106725 United States AI NIAID NIH HHS; P01 AI132130 United States AI NIAID NIH HHS; K08 AI139339 United States AI NIAID NIH HHS
فهرسة مساهمة: Keywords: BCG; TnSeq; clinical strains; genomics; mycobacterium; tuberculosis; vaccination
المشرفين على المادة: 0 (BCG Vaccine)
تواريخ الأحداث: Date Created: 20220418 Date Completed: 20221222 Latest Revision: 20221222
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC9239107
DOI: 10.1128/msystems.00110-22
PMID: 35430871
قاعدة البيانات: MEDLINE
الوصف
تدمد:2379-5077
DOI:10.1128/msystems.00110-22