Academic Journal
Genome-wide screen identifies host loci that modulate Mycobacterium tuberculosis fitness in immunodivergent mice
| العنوان: | Genome-wide screen identifies host loci that modulate Mycobacterium tuberculosis fitness in immunodivergent mice |
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| المؤلفون: | Meade, Rachel K, Long, Jarukit E, Jinich, Adrian, Rhee, Kyu Y, Ashbrook, David G, Williams, Robert W, Sassetti, Christopher M, Smith, Clare M |
| المساهمون: | Microbiology and Physiological Systems |
| المصدر: | G3 (Bethesda, Md.) ; 13 ; 9 ; United States ; England |
| سنة النشر: | 2024 |
| المجموعة: | University of Massachusetts, Medical School: eScholarship@UMMS |
| مصطلحات موضوعية: | BXD, QTL mapping, TnSeq, bacterial genetics, complex traits, genetic diversity, genomics, host–pathogen interactions, mouse models, mycobacteria, natural variation, systems genetics, tuberculosis |
| الوصف: | Genetic differences among mammalian hosts and among strains of Mycobacterium tuberculosis (Mtb) are well-established determinants of tuberculosis (TB) patient outcomes. The advent of recombinant inbred mouse panels and next-generation transposon mutagenesis and sequencing approaches has enabled dissection of complex host-pathogen interactions. To identify host and pathogen genetic determinants of Mtb pathogenesis, we infected members of the highly diverse BXD family of strains with a comprehensive library of Mtb transposon mutants (TnSeq). Members of the BXD family segregate for Mtb-resistant C57BL/6J (B6 or B) and Mtb-susceptible DBA/2J (D2 or D) haplotypes. The survival of each bacterial mutant was quantified within each BXD host, and we identified those bacterial genes that were differentially required for Mtb fitness across BXD genotypes. Mutants that varied in survival among the host family of strains were leveraged as reporters of "endophenotypes," each bacterial fitness profile directly probing specific components of the infection microenvironment. We conducted quantitative trait loci (QTL) mapping of these bacterial fitness endophenotypes and identified 140 host-pathogen QTL (hpQTL). We located a QTL hotspot on chromosome 6 (75.97-88.58 Mb) associated with the genetic requirement of multiple Mtb genes: Rv0127 (mak), Rv0359 (rip2), Rv0955 (perM), and Rv3849 (espR). Together, this screen reinforces the utility of bacterial mutant libraries as precise reporters of the host immunological microenvironment during infection and highlights specific host-pathogen genetic interactions for further investigation. To enable downstream follow-up for both bacterial and mammalian genetic research communities, all bacterial fitness profiles have been deposited into GeneNetwork.org and added into the comprehensive collection of TnSeq libraries in MtbTnDB. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 2160-1836 |
| Relation: | G3 (Bethesda, Md.); https://doi.org/10.1093/g3journal/jkad147; Meade RK, Long JE, Jinich A, Rhee KY, Ashbrook DG, Williams RW, Sassetti CM, Smith CM. Genome-wide screen identifies host loci that modulate Mycobacterium tuberculosis fitness in immunodivergent mice. G3 (Bethesda). 2023 Aug 30;13(9):jkad147. doi:10.1093/g3journal/jkad147. PMID: 37405387; PMCID: PMC10468300.; http://hdl.handle.net/20.500.14038/53752 |
| DOI: | 10.1093/g3journal/jkad147 |
| الاتاحة: | https://doi.org/10.1093/g3journal/jkad147 https://hdl.handle.net/20.500.14038/53752 |
| Rights: | © The Author(s) 2023. Published by Oxford University Press on behalf of The Genetics Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. ; https://creativecommons.org/licenses/by/4.0/ |
| رقم الانضمام: | edsbas.DAA6650D |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 21601836 |
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| DOI: | 10.1093/g3journal/jkad147 |