Genome-wide screen identifies host loci that modulate Mycobacterium tuberculosis fitness in immunodivergent mice.
Genome-wide screen identifies host loci that modulate Mycobacterium tuberculosis fitness in immunodivergent mice.
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DOI：
10.1093/g3journal/jkad147
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发表时间：
2023-08-30
影响因子：
2.6
通讯作者：
Smith, Clare M.
中科院分区：
文献类型：
--
作者：
Meade, Rachel K.;Long, Jarukit E.;Jinich, Adrian;Rhee, Kyu Y.;Ashbrook, David G.;Williams, Robert W.;Sassetti, Christopher M.;Smith, Clare M.
关键词：
哺乳动物宿主和结核分枝杆菌(Mtb)菌株之间的遗传差异是结核病(TB)患者预后的公认决定因素。重组近亲交配小鼠面板和下一代转座子突变和测序方法的出现使解剖复杂的宿主-病原体相互作用成为可能。为了确定结核分枝杆菌致病的宿主和病原体遗传决定因素，我们用Mtb转座子突变(TnSeq)的全面文库感染高度多样化的BXD家族的成员。BXD家族成员分离出耐Mtb的C57BL/6J(B6或B)和易感Mtb的DBA/2J(D2或D)单倍型。我们量化了每个细菌突变体在每个BXD宿主中的存活率，并确定了不同BXD基因型之间Mtb适合性所需的细菌基因。在宿主菌株家族中存活率不同的突变体被用作“内表型”的报告者，每个细菌的适合度曲线直接探测感染微环境的特定成分。我们对这些细菌的适应内表型进行了数量性状基因座(QTL)定位，确定了140个寄主-病原菌QTL(HpQTL)。我们在第6染色体(75.97-88.58Mb)上定位了一个与多个Mtb基因的遗传需求相关的QTL热点：Rv0127(Mak)、Rv0359(RIP2)、Rv0955(Perm)和Rv3849(Espr)。总之，这一筛选加强了细菌突变文库作为感染期间宿主免疫微环境的精确报告的效用，并突出了特定的宿主-病原体遗传相互作用以供进一步研究。为了能够对细菌和哺乳动物遗传研究社区进行下游跟进，所有细菌适应情况都已存储到GeneNetwork.org中，并添加到MtbTnDB的TnSeq文库的全面集合中。
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.
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影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
DOI：
10.1093/bioinformatics/btx346
发表时间：
2017-10-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Gel B;Serra E
通讯作者：
Serra E
影响因子：
17.1
作者：
Ahmed, Mushtaq;Thirunavukkarasu, Shyamala;Khader, Shabaana A.
通讯作者：
Khader, Shabaana A.
影响因子：
30.8
作者：
Chesler, EJ;Lu, L;Williams, RW
通讯作者：
Williams, RW
影响因子：
9.3
作者：
Ashbrook DG;Arends D;Prins P;Mulligan MK;Roy S;Williams EG;Lutz CM;Valenzuela A;Bohl CJ;Ingels JF;McCarty MS;Centeno AG;Hager R;Auwerx J;Lu L;Williams RW
通讯作者：
Williams RW