The Rv2623-Rv1747 interaction: regulation of the in vivo fate of M. tuberculosis
Rv2623-Rv1747 相互作用:结核分枝杆菌体内命运的调节
基本信息
- 批准号:10553212
- 负责人:
- 金额:$ 85.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-01-16 至 2025-12-31
- 项目状态:未结题
- 来源:
- 关键词:ATP-Binding Cassette TransportersAccelerationAcuteAffectAlanineAmino AcidsAnimal ModelAttenuatedBacillusBacteriaBindingBiochemicalBiogenesisBioinformaticsBiological ProcessC3H/HeJ MouseCaviaCell WallCellsChronicChronic PhaseComplexCuesDataData AnalysesDevelopmentDiseaseExhibitsFHA DomainGenerationsGenesGeneticGenus MycobacteriumGlycolipidsGoalsGrowthHeat shock proteinsHomologous ProteinHypoxiaImmunologicsIn VitroIndividualInfectionKineticsKnock-outKnowledgeLife Cycle StagesMannosidesMediatingModelingMusMutationMycobacterium smegmatisMycobacterium tuberculosisNitric OxideOrangesPathogenesisPathway interactionsPersonsPhasePhenotypePhosphorylationPhosphothreoninePhysiological ProcessesPopulationPositioning AttributePredispositionPropertyProtein DephosphorylationProteinsRegulationRegulonResearchRoleSignal TransductionSignaling ProteinStarvationStressSystemTestingThreonineTissuesTransmembrane DomainTuberculosiscell envelopechronic infectiondesigndifferential expressiondisease transmissionimmunopathologyimmunoregulationin vivoinsightlatent infectionlipooligosaccharidemonomermutantmycobacterialmyoinositolnitrosative stressnoveloverexpressionpathogenpathogenic bacteriareactivation from latency
项目摘要
Abstract
The life cycle of Mycobacterium tuberculosis (Mtb) is complex, encompassing an acute phase, during which
the pathogen replicates exponentially; a chronic phase, when bacterial burden is stably maintained, and a
latent paucibacillary state that can reactivate. Chronic tuberculosis (TB) is associated with the development of
tissue-damaging immunopathology and can promote disease transmission. It has been estimated that
approximately 1/4 of the world's population are infected with Mtb, and a significant proportion of these
individuals harbor latent bacilli that can reactivate to cause diseases. Unraveling the mechanisms that regulate
Mtb growth in an infected host in the different phases of infection is paramount to understanding TB
pathogenesis. It is generally thought that certain host environmental conditions (e.g., hypoxia, nitrosative
stress, starvation) can promote the establishment of a latent infection. However, the precise mechanisms that
regulate TB latency are incompletely defined. Mtb Rv2623, which is among the most upregulated genes in the
dormancy regulon, encodes a universal stress protein (USP) that can regulate bacillary growth both in vivo and
in vitro. A deletion mutant ΔRv2623 is hypervirulent in susceptible mice and Guinea pigs, and in the latter, it is
defective in establishing a chronic persistent infection. In vitro, overexpression of Rv2623 in mycobacteria
retards growth in recipient cells; and Mtb ΔRv2623 exits from the non-replicative phase of the hypoxia-induced
Wayne latency model more expeditiously than wild-type (WT) Mtb upon transfer into O2-sufficient media.
These results provide evidence that Rv2623 regulates Mtb growth, including possibly during the
latent/reactivation phase of infection.
We showed that Rv2623 interacts with the FHA domain-containing Mtb Rv1747, a putative exporter of
lipooligosaccharides. The FHA domain is a signaling protein module that mediates a wide variety of biological
processes via phosphorylation-dependent mechanisms. We further showed that the Rv2623-Rv1747
interaction is mediated through binding of the FHAI domain of Rv1747 with a phosphothreonine (at position
237)-containing motif of Rv2623, and that the T237 residue is essential for mediating the growth-regulatory
attribute of Rv2623. In contrast to the hypervirulent ΔRv2623, ΔRv1747 is attenuated for growth in vivo. And
while the hypervirulent ΔRv2623 expresses enhanced levels of the immunoregulatory phosphatidyl-myo-
inositol mannosides (PIMs) relative to WT Mtb, the hypovirulent ΔRv1747 is a hypo-producer of PIMs. In
addition, we showed that Rv1747-overexpressing strains hyperproduce PIMs. The correlation of Rv1747's
expression levels and Mtb cell wall PIMs amounts suggests that Rv1747 may function as an exporter of Mtb
cell wall biogenesis intermediates. This, together with the opposing PIMs phenotype and in vivo growth
phenotype of ΔRv2623 and ΔRv1747, has led us to hypothesize that Rv2623 negatively regulates the
functional activity of Rv1747 to modulate the levels of Mtb cell wall PIMs, which immunoregulatory properties
can alter Mtb-host interactions, thereby influencing the in vivo fate of the tubercle bacillus. We will use
biochemical, genetics, and immunological approaches, in conjunction with animal modeling and integrative
bioinformatics and computational data analysis, to rigorously test this hypothesis. Finally, accumulating
knowledge derived from functional and structural analysis of Rv1747, and the discovery of the relationship
between Rv1747 expression and PIM levels, will enable the generation of a set of isogenic Mtb mutants
expressing graded levels of PIMs, which can be used to stringently probe the significance of these
immunoregulatory glycoplids in influencing the in vivo fate of Mtb. The proposed studies should illuminate how
the Rv2623-Rv1747-PIM pathway regulates in vivo Mtb growth. The data generated may help gain insight into
the function of Rv1747 in modulating the cell wall PIM levels, the roles of PIMs in impacting the fate of the
tubercle bacillus in an infected host, Mtb cell wall biogenesis, and potentially the mechanisms that regulate TB
latency and reactivation.
抽象的
结核分枝杆菌 (Mtb) 的生命周期很复杂,包括一个急性期,在此期间
病原体呈指数复制;慢性阶段,细菌负荷稳定维持,并且
可以重新激活的潜伏的寡杆菌状态。慢性结核病 (TB) 与以下疾病的发生有关:
破坏组织的免疫病理学并可促进疾病传播。据估计
世界上大约 1/4 的人口感染了 Mtb,其中很大一部分
个体体内潜伏着细菌,这些细菌可以重新激活而引起疾病。揭示调节机制
受感染宿主在不同感染阶段的结核分枝杆菌生长对于了解结核病至关重要
发病。人们普遍认为某些宿主环境条件(例如缺氧、亚硝化)
压力、饥饿)可以促进潜伏感染的建立。然而,精确的机制
调节结核潜伏期的定义不完全。 Mtb Rv2623 是 Mtb Rv2623 中表达最上调的基因之一
休眠调节子,编码通用应激蛋白(USP),可以调节体内和体内的细菌生长
体外。缺失突变体 ΔRv2623 在易感小鼠和豚鼠中具有高毒力,而在后者中,它是
无法建立慢性持续感染。体外,分枝杆菌中 Rv2623 的过度表达
延缓受体细胞的生长; Mtb ΔRv2623 退出缺氧诱导的非复制期
在转移至 O2 充足的培养基中时,Wayne 潜伏期模型比野生型 (WT) Mtb 更迅速。
这些结果提供了 Rv2623 调节 Mtb 生长的证据,包括可能在
感染的潜伏/再激活阶段。
我们发现 Rv2623 与包含 FHA 结构域的 Mtb Rv1747 相互作用,Mtb Rv1747 是假定的
脂寡糖。 FHA 结构域是一种信号蛋白模块,可介导多种生物信号
通过磷酸化依赖性机制进行的过程。我们进一步表明 Rv2623-Rv1747
相互作用是通过 Rv1747 的 FHAI 结构域与磷酸苏氨酸(位于位置
237) 包含 Rv2623 的基序,并且 T237 残基对于介导生长调节至关重要
Rv2623的属性。与高毒力的 ΔRv2623 相比,ΔRv1747 在体内生长减弱。和
而高毒力 ΔRv2623 表达的免疫调节磷脂酰肌醇水平增强。
相对于 WT Mtb,低毒力的 ΔRv1747 是 PIM 的低生产者。在
此外,我们发现 Rv1747 过表达菌株过度产生 PIM。 Rv1747的相关性
表达水平和 Mtb 细胞壁 PIM 量表明 Rv1747 可能充当 Mtb 的输出者
细胞壁生物发生中间体。这与相反的 PIM 表型和体内生长一起
ΔRv2623 和 ΔRv1747 的表型,使我们推测 Rv2623 负调节
Rv1747 调节 Mtb 细胞壁 PIM 水平的功能活性,其免疫调节特性
可以改变结核分枝杆菌与宿主的相互作用,从而影响结核杆菌的体内命运。我们将使用
生物化学、遗传学和免疫学方法,结合动物建模和综合
生物信息学和计算数据分析,严格检验这一假设。最后,积累
来自 Rv1747 功能和结构分析的知识,以及关系的发现
Rv1747 表达和 PIM 水平之间的差异,将能够产生一组同基因 Mtb 突变体
表达 PIM 的分级水平,可用于严格探究这些的重要性
免疫调节糖苷脂影响结核分枝杆菌的体内命运。拟议的研究应阐明如何
Rv2623-Rv1747-PIM 通路调节体内 Mtb 生长。生成的数据可能有助于深入了解
Rv1747 在调节细胞壁 PIM 水平中的功能、PIM 在影响细胞命运中的作用
感染宿主中的结核杆菌、结核分枝杆菌细胞壁生物发生以及调节结核病的潜在机制
潜伏期和重新激活。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Mycobacteriophages as Potential Therapeutic Agents against Drug-Resistant Tuberculosis.
- DOI:10.3390/ijms22020735
- 发表时间:2021-01-13
- 期刊:
- 影响因子:5.6
- 作者:Allué-Guardia A;Saranathan R;Chan J;Torrelles JB
- 通讯作者:Torrelles JB
Evolution of Drug-Resistant Mycobacterium tuberculosis Strains and Their Adaptation to the Human Lung Environment.
- DOI:10.3389/fmicb.2021.612675
- 发表时间:2021
- 期刊:
- 影响因子:5.2
- 作者:Allué-Guardia A;García JI;Torrelles JB
- 通讯作者:Torrelles JB
Drug-resistant strains of Mycobacterium tuberculosis: cell envelope profiles and interactions with the host.
- DOI:10.3389/fcimb.2023.1274175
- 发表时间:2023
- 期刊:
- 影响因子:5.7
- 作者:
- 通讯作者:
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John R. Chan其他文献
John R. Chan的其他文献
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{{ truncateString('John R. Chan', 18)}}的其他基金
The Rv2623-Rv1747 interaction: regulation of the in vivo fate of M. tuberculosis
Rv2623-Rv1747 相互作用:结核分枝杆菌体内命运的调节
- 批准号:
9973940 - 财政年份:2020
- 资助金额:
$ 85.65万 - 项目类别:
The Rv2623-Rv1747 interaction: regulation of the in vivo fate of M. tuberculosis
Rv2623-Rv1747 相互作用:结核分枝杆菌体内命运的调节
- 批准号:
10685658 - 财政年份:2020
- 资助金额:
$ 85.65万 - 项目类别:
The Rv2623-Rv1747 interaction: regulation of the in vivo fate of M. tuberculosis
Rv2623-Rv1747 相互作用:结核分枝杆菌体内命运的调节
- 批准号:
10529446 - 财政年份:2020
- 资助金额:
$ 85.65万 - 项目类别:
Immunoregulation by indoleamine 2,3-dioxygenases in tuberculosis
结核病中吲哚胺 2,3-双加氧酶的免疫调节
- 批准号:
9921293 - 财政年份:2018
- 资助金额:
$ 85.65万 - 项目类别:
Immunoregulation by indoleamine 2,3-dioxygenases in tuberculosis
结核病中吲哚胺 2,3-双加氧酶的免疫调节
- 批准号:
10395488 - 财政年份:2018
- 资助金额:
$ 85.65万 - 项目类别:
Humoral immunity against the M. tuberculosis kasB persistent mutant
针对结核分枝杆菌 kasB 持久突变体的体液免疫
- 批准号:
9624948 - 财政年份:2018
- 资助金额:
$ 85.65万 - 项目类别:
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