Exploring the role of type I interferon in Rickettsia pathogenesis
探讨I型干扰素在立克次体发病机制中的作用
基本信息
- 批准号:9764949
- 负责人:
- 金额:$ 19.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-03-06 至 2021-02-28
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelAnti-Bacterial AgentsAntiviral AgentsBacteriaBinding ProteinsBiologicalBone MarrowC57BL/6 MouseCandidate Disease GeneCellsChromosomes, Human, Pair 3DataDermalDevelopmentDiagnosisDiseaseEndothelial CellsExhibitsFeverGenesGrowthHumanImmune responseImmune signalingIn VitroIndividualInfectionInnate Immune ResponseInnate Immune SystemInterferon Gamma Receptor ComplexInterferon Type IInterferon Type IIInterferonsIntravenousKineticsKnock-outKnowledgeLeadLesionMicrobeMolecularMusMutant Strains MiceMutateNecrotic LesionOrganPathogenesisPathogenicityPathologyPathway interactionsPlayResistanceRickettsiaRickettsia InfectionsRoleSignal PathwaySignal TransductionSiteStudy modelsSymptomsTestingTimeTissuesTransgenic OrganismsTyphusUp-RegulationWild Type MouseWorkantimicrobialcell typecytokineexperimental studygene productguanylatehuman diseasehuman modelin vivomacrophagemouse modelmutantnovel strategiespathogenpathogenic bacteriareceptorresponsetooltranscription factortranscriptome sequencing
项目摘要
PROJECT SUMMARY / ABSTRACT
The Rickettsiae are a diverse group of Gram-negative, obligate intracellular bacterial pathogens that cause
human diseases, including typhus and spotted fever. Among the causative agents of spotted fever group
(SFG) rickettsiosis in the U.S., Rickettsia parkeri has proven to be a uniquely powerful model for studying
pathogenicity at the cellular level, because it causes a non-lethal eschar-associated disease and therefore can
be grown under biosafety level 2 conditions, facilitating cell biological studies. However, progress toward
developing R. parkeri as a model for studying the innate immune response to SFG Rickettsia infection has
been hindered by a dearth of studies employing mutant mice. As such, key questions regarding the innate
immune response to SFG Rickettsia remain unanswered, including how the bacteria respond to type I
interferon (IFN-I), an important cytokine of the innate immune system. Our new preliminary data indicate that
intradermal infection of mice lacking both receptors for IFN-I and type II interferon (IFN-g) with R. parkeri
results in a necrotic lesion at the site of infection and occasional lethality, whereas mice lacking each individual
receptor exhibit no symptoms. This demonstrates a role for IFN-I (and IFN-g) in restricting R. parkeri growth in
vivo. Moreover, the pathology of the double mutant is similar to (but more severe than) that occurring during
human infection, suggesting it may represent a new animal model of human disease. We have also observed
that IFN-I severely restricts R. parkeri growth in primary mouse macrophages, and that this is partially due to
killing by the IFN-I regulated gene products, including antimicrobial guanylate binding proteins (GBPs). Despite
these advances, there remain two key gaps in knowledge: (1) it is unclear how IFN-I restricts R. parkeri growth
at the organ/tissue/cellular level in vivo; and (2) it is not known how gene products upregulated by IFN-I kill R.
parkeri at the cellular/molecular level. We hypothesize that that IFN-I plays an important role in restricting
Rickettsia growth in vivo and in vitro via the upregulation of cytosolic antibacterial molecules. We will test this
hypothesis in two aims. In Aim 1, we will characterize the kinetics of intravenous and intradermal infection, the
resulting organ and tissue pathologies, and the cell types infected by R. parkeri in mice lacking both receptors
for IFN-I/IFN-g. These studies will reveal how IFN-I restricts growth of R. parkeri in vivo and will establish a
robust murine model for investigating SFG Rickettsia pathogenesis. In Aim 2, we will test the effect of
activating or mutating candidate antimicrobial factors (identified by RNAseq) on bacterial killing downstream of
IFN-I signaling, and will test whether the GBPs restrict R. parkeri growth in endothelial cells in vitro and mice in
vivo. Our findings will reveal how IFN-I restricts the growth of R. parkeri, and perhaps other microbes, in vitro
and in vivo. Furthermore, we will develop a new animal model to investigate R. parkeri pathogenesis.
项目摘要/摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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专利数量(0)
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Matthew D Welch其他文献
Matthew D Welch的其他文献
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{{ truncateString('Matthew D Welch', 18)}}的其他基金
Exploring the role of type I interferon in Rickettsia pathogenesis
探讨I型干扰素在立克次体发病机制中的作用
- 批准号:
9888303 - 财政年份:2019
- 资助金额:
$ 19.63万 - 项目类别:
Microbial mobilization of the actin cytoskeleton
肌动蛋白细胞骨架的微生物动员
- 批准号:
9912779 - 财政年份:2018
- 资助金额:
$ 19.63万 - 项目类别:
Microbial mobilization of the actin cytoskeleton
肌动蛋白细胞骨架的微生物动员
- 批准号:
10623626 - 财政年份:2018
- 资助金额:
$ 19.63万 - 项目类别:
Microbial mobilization of the actin cytoskeleton
肌动蛋白细胞骨架的微生物动员
- 批准号:
10395934 - 财政年份:2018
- 资助金额:
$ 19.63万 - 项目类别:
Mechanisms of Rickettsia invasion, intracellular survival, and actin-based motility
立克次体侵袭、细胞内存活和基于肌动蛋白的运动的机制
- 批准号:
10461986 - 财政年份:2014
- 资助金额:
$ 19.63万 - 项目类别:
Roles for host cytoskeletal, cell adhesion and membrane trafficking proteins in b
宿主细胞骨架、细胞粘附和膜运输蛋白在 b 中的作用
- 批准号:
8623547 - 财政年份:2014
- 资助金额:
$ 19.63万 - 项目类别:
Roles for host cytoskeletal, cell adhesion and membrane trafficking proteins in b
宿主细胞骨架、细胞粘附和膜运输蛋白在 b 中的作用
- 批准号:
8830430 - 财政年份:2014
- 资助金额:
$ 19.63万 - 项目类别:
Mechanisms of Rickettsia invasion, intracellular survival, and actin-based motility
立克次体侵袭、细胞内存活和基于肌动蛋白的运动的机制
- 批准号:
9615323 - 财政年份:2014
- 资助金额:
$ 19.63万 - 项目类别:
Mechanisms of Rickettsia invasion, intracellular survival, and actin-based motility
立克次体侵袭、细胞内存活和基于肌动蛋白的运动的机制
- 批准号:
10238082 - 财政年份:2014
- 资助金额:
$ 19.63万 - 项目类别:
Rickettsia mobilization of the cytoskeleton during invasion, motility, and spread
立克次体在入侵、运动和扩散过程中动员细胞骨架
- 批准号:
8761830 - 财政年份:2014
- 资助金额:
$ 19.63万 - 项目类别:
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