دورية أكاديمية
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Identification of bacterial determinants of tuberculosis infection and treatment outcomes: a phenogenomic analysis of clinical strains.

التفاصيل البيبلوغرافية
العنوان: Identification of bacterial determinants of tuberculosis infection and treatment outcomes: a phenogenomic analysis of clinical strains.
المؤلفون: Stanley S; Department of Immunology and Infectious Diseases, Harvard T H Chan School of Public Health, Boston, MA, USA., Spaulding CN; Department of Immunology and Infectious Diseases, Harvard T H Chan School of Public Health, Boston, MA, USA., Liu Q; Department of Immunology and Infectious Diseases, Harvard T H Chan School of Public Health, Boston, MA, USA., Chase MR; Department of Immunology and Infectious Diseases, Harvard T H Chan School of Public Health, Boston, MA, USA., Ha DTM; Pham Ngoc Thach Hospital, Ho Chi Minh City, Viet Nam., Thai PVK; Pham Ngoc Thach Hospital, Ho Chi Minh City, Viet Nam., Lan NH; Pham Ngoc Thach Hospital, Ho Chi Minh City, Viet Nam., Thu DDA; Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Viet Nam., Quang NL; Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Viet Nam., Brown J; Department of Immunology and Infectious Diseases, Harvard T H Chan School of Public Health, Boston, MA, USA., Hicks ND; Department of Immunology and Infectious Diseases, Harvard T H Chan School of Public Health, Boston, MA, USA., Wang X; Department of Immunology and Infectious Diseases, Harvard T H Chan School of Public Health, Boston, MA, USA., Marin M; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA; Department of Systems Biology, Harvard Medical School, Boston, MA, USA., Howard NC; Department of Immunology and Infectious Diseases, Harvard T H Chan School of Public Health, Boston, MA, USA., Vickers AJ; Department of Immunology and Infectious Diseases, Harvard T H Chan School of Public Health, Boston, MA, USA., Karpinski WM; Department of Immunology and Infectious Diseases, Harvard T H Chan School of Public Health, Boston, MA, USA., Chao MC; Department of Immunology and Infectious Diseases, Harvard T H Chan School of Public Health, Boston, MA, USA., Farhat MR; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA; Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA, USA., Caws M; Liverpool School of Tropical Medicine, Liverpool, UK; Birat Nepal Medical Trust, Kathmandu, Nepal., Dunstan SJ; Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC, Australia., Thuong NTT; Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Viet Nam; Nuffield Department of Medicine, Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK., Fortune SM; Department of Immunology and Infectious Diseases, Harvard T H Chan School of Public Health, Boston, MA, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: sfortune@hsph.harvard.edu.
المصدر: The Lancet. Microbe [Lancet Microbe] 2024 Jun; Vol. 5 (6), pp. e570-e580. Date of Electronic Publication: 2024 May 08.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier Ltd Country of Publication: England NLM ID: 101769019 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2666-5247 (Electronic) Linking ISSN: 26665247 NLM ISO Abbreviation: Lancet Microbe Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [Oxford] : Elsevier Ltd., [2020]-
مواضيع طبية MeSH: Mycobacterium tuberculosis*/genetics , Mycobacterium tuberculosis*/drug effects , Tuberculosis*/drug therapy , Tuberculosis*/microbiology , Antitubercular Agents*/therapeutic use , Antitubercular Agents*/pharmacology, Humans ; Vietnam/epidemiology ; Genome-Wide Association Study ; Treatment Outcome ; Phenotype ; Phylogeny ; Mutation ; Phenomics ; Genotype ; Female ; Adult ; Male
مستخلص: Background: Bacterial diversity could contribute to the diversity of tuberculosis infection and treatment outcomes observed clinically, but the biological basis of this association is poorly understood. The aim of this study was to identify associations between phenogenomic variation in Mycobacterium tuberculosis and tuberculosis clinical features.
Methods: We developed a high-throughput platform to define phenotype-genotype relationships in M tuberculosis clinical isolates, which we tested on a set of 158 drug-sensitive M tuberculosis strains sampled from a large tuberculosis clinical study in Ho Chi Minh City, Viet Nam. We tagged the strains with unique genetic barcodes in multiplicate, allowing us to pool the strains for in-vitro competitive fitness assays across 16 host-relevant antibiotic and metabolic conditions. Relative fitness was quantified by deep sequencing, enumerating output barcode read counts relative to input normalised values. We performed a genome-wide association study to identify phylogenetically linked and monogenic mutations associated with the in-vitro fitness phenotypes. These genetic determinants were further associated with relevant clinical outcomes (cavitary disease and treatment failure) by calculating odds ratios (ORs) with binomial logistic regressions. We also assessed the population-level transmission of strains associated with cavitary disease and treatment failure using terminal branch length analysis of the phylogenetic data.
Findings: M tuberculosis clinical strains had diverse growth characteristics in host-like metabolic and drug conditions. These fitness phenotypes were highly heritable, and we identified monogenic and phylogenetically linked variants associated with the fitness phenotypes. These data enabled us to define two genetic features that were associated with clinical outcomes. First, mutations in Rv1339, a phosphodiesterase, which were associated with slow growth in glycerol, were further associated with treatment failure (OR 5·34, 95% CI 1·21-23·58, p=0·027). Second, we identified a phenotypically distinct slow-growing subclade of lineage 1 strains (L1.1.1.1) that was associated with cavitary disease (OR 2·49, 1·11-5·59, p=0·027) and treatment failure (OR 4·76, 1·53-14·78, p=0·0069), and which had shorter terminal branch lengths on the phylogenetic tree, suggesting increased transmission.
Interpretation: Slow growth under various antibiotic and metabolic conditions served as in-vitro intermediate phenotypes underlying the association between M tuberculosis monogenic and phylogenetically linked mutations and outcomes such as cavitary disease, treatment failure, and transmission potential. These data suggest that M tuberculosis growth regulation is an adaptive advantage for bacterial success in human populations, at least in some circumstances. These data further suggest markers for the underlying bacterial processes that contribute to these clinical outcomes.
Funding: National Health and Medical Research Council/A∗STAR, National Institutes of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, and the Wellcome Trust Fellowship in Public Health and Tropical Medicine.
Competing Interests: Declaration of interests We declare no competing interests.
(Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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معلومات مُعتمدة: 75N93019C00071 United States AI NIAID NIH HHS; T32 AI049928 United States AI NIAID NIH HHS; T32 GM135014 United States GM NIGMS NIH HHS; U19 AI142793 United States AI NIAID NIH HHS; P01 AI132130 United States AI NIAID NIH HHS; P01 AI143575 United States AI NIAID NIH HHS; T32 HD040128 United States HD NICHD NIH HHS; U19 AI107774 United States AI NIAID NIH HHS; T32 AI132120 United States AI NIAID NIH HHS; United Kingdom WT_ Wellcome Trust
المشرفين على المادة: 0 (Antitubercular Agents)
تواريخ الأحداث: Date Created: 20240511 Date Completed: 20240607 Latest Revision: 20240709
رمز التحديث: 20240709
مُعرف محوري في PubMed: PMC11229950
DOI: 10.1016/S2666-5247(24)00022-3
PMID: 38734030
قاعدة البيانات: MEDLINE
الوصف
تدمد:2666-5247
DOI:10.1016/S2666-5247(24)00022-3