Towards a molecular understanding of persistent tuberculosis infection
Towards a molecular understanding of persistent tuberculosis infection
批准号:
9554177
负责人:
Jeremy Michael Rock
金额:
$254.25万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-09-30 至 2023-06-30
关键词:
AntibioticsAntitoxinsArchitectureBacillus (bacterium)Bacterial GenesBacterial InfectionsBiologicalCRISPR interferenceCause of DeathCellular ImmunityChronicCommunicable DiseasesDevelopmentDrug ToleranceExposure toFoundationsGene FamilyGenesGeneticGenetic ScreeningImmune systemInfectionKineticsKnowledgeMediatingMolecularMycobacterium tuberculosisPathogenesisPharmaceutical PreparationsProgressive DiseaseStressTestingToxinTreatment ProtocolsTuberculosisWorkantibiotic tolerancechronic infectionimprovedmouse modelnovelnovel therapeuticspandemic diseasepathogenresponsesuccesstooltuberculosis treatment
中文摘要
摘要
英文摘要
ABSTRACT
Mycobacterium tuberculosis (Mtb) remains the leading cause of death due to infectious disease and is
estimated to infect one-third of the world. Tuberculosis (TB) is a chronic, progressive disease, often with a long
period of latency following initial infection. In most cases, the host immune system is capable of restraining but
not eliminating Mtb, leading to lifelong infection. Mtb infection can be treated with antibiotics. However, unlike
most other bacterial infections, effective TB treatment requires a combination of four drugs taken for a
minimum of six months. This lengthy treatment regimen is a critical barrier to effective TB control, and is
thought to be necessitated by the presence of antibiotic-tolerant bacilli that arise during infection. These
combined abilities: 1) to persist in the face of strong, cell-mediated immunity and sustain chronic infection; and
2) tolerate prolonged exposure to lethal concentrations of antibiotic, are central to the continued global success
of this pathogen. Due to the difficulties associated with traditional Mtb genetics, the biological mechanisms
underpinning these phenomena remain largely unexplored. To close this knowledge gap, I recently developed
a CRISPR interference (CRISPRi) platform to accelerate the genetic interrogation of Mtb pathogenesis. Here, I
propose to leverage this transformative new tool to define the genetic basis for persistent Mtb infection.
Specifically, I will perform a kinetic-genetic screen in a murine model of TB to identify the bacterial
determinants that enable chronic Mtb infection. Subsequent functional characterization of these genes will
define their mechanisms of action, thereby revealing the molecular architecture that supports chronic TB. In
addition, it is well documented that the stress of host infection can induce antibiotic tolerance in Mtb. Here, I
will test the hypothesis that the massively expanded and enigmatic gene family, the toxin-antitoxins, function
through a divergent stringent response to mediate antibiotic tolerance in Mtb. I anticipate that these collective
findings will remove important roadblocks to progress in the field by vertically advancing our scientific
knowledge and technical capability. Furthermore, this work will serve as an intellectual foundation for the
development of novel TB therapies capable of shortening the course of treatment and improving control of this
pandemic.
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会议论文
Molecular mechanisms of inherent drug resistance in non-tuberculous mycobacteria
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批准号:10771645
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项目类别:
-
资助金额:$75.97万
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财政年份:2023
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负责人:Jeremy Michael Rock
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依托单位:
Bacterial Genetics Core D
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批准号:10438915
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项目类别:
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资助金额:$54.97万
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财政年份:2021
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负责人:Jeremy Michael Rock
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依托单位:
Bacterial Genetics Core D
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批准号:10271482
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项目类别:
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资助金额:$40.26万
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财政年份:2021
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负责人:Jeremy Michael Rock
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依托单位:
Bacterial Genetics Core D
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批准号:10612029
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项目类别:
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资助金额:$41.07万
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财政年份:2021
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负责人:Jeremy Michael Rock
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依托单位:
海外基金