Virulence Mechanisms of Multifunctional Borrelial Proteins
多功能疏螺旋体蛋白的毒力机制
基本信息
- 批准号:10620725
- 负责人:
- 金额:$ 71.34万
- 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:2020-06-15 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAddressAffinityAmino AcidsAnimal ModelAntibodiesAsiaBacteriaBindingBiochemicalBiologicalBiological AssayBiophysicsBorreliaBorrelia InfectionsBorrelia afzeliiBorrelia burgdorferiBorrelia burgdorferi GroupBorrelia gariniiBorrelia miyamotoiBorrelia turicataeClassical Complement PathwayClinicalCommunicable DiseasesComplementComplement 1qComplement ActivationComplement component C1rComplexCytolysisDataDiseaseDisease modelEtiologyEuropeEventExperimental DesignsExperimental ModelsFamilyGenesGeneticGoalsHematogenousHomologous GeneHumanImmuneImmunityImmunocompetentImmunomodulatorsImpairmentIn VitroInfectionLife Cycle StagesLipoproteinsLyme DiseaseLyticMeasuresMediatingMedicalMicrobeMinorModelingMolecularMusNatural ImmunityNatureOrder SpirochaetalesOrthologous GenePathogenesisPathway interactionsPattern RecognitionPeptide HydrolasesPhenotypePhylogenetic AnalysisPlayPredispositionProteinsReactionRelapsing FeverReportingResolutionRoleSerumSpirochaetales InfectionsStructureSurfaceTestingTicksUnited StatesVector-transmitted infectious diseaseVirulenceX-Ray Crystallographyarmbiophysical techniquescomplement deficiencycomplement pathwaycomplement systemdesignhuman diseaseimaging approachimmunoregulationin vitro activityin vivoin vivo Modelin vivo imaginginhibitorinterdisciplinary approachlyme pathogenesismouse modelmultidisciplinarymutantpathogenrelapsing fever borreliatick borne spirochetevector-bornevector-borne pathogen
项目摘要
PROJECT SUMMARY
Spirochetes of the Borrelia genus are the cause of several prevalent vector-borne diseases. The most
well-known pathogen from this group is Borrelia burgdorferi sensu stricto, which causes over 300,000 cases of
Lyme disease in the United States each year. B. garinii and B. afzelii, which belong to the B. burgdorferi sensu
lato complex, are the primary agent of Lyme disease in Europe and Asia. Borrelia spirochetes are also the
etiological agent of the ancient human disease relapsing fever, as well as a newly recognized infectious
condition called Borrelia miyamotoi disease. Lyme-associated, relapsing fever-associated, and B. miyamotoi
spirochetes have differing lifecycles and their infections are accompanied by distinct clinical presentations.
However, each of these pathogens are known to encode multifunctional surface-expressed lipoproteins that
interact with vertebrate host molecules. Among these proteins are a small arsenal of immunomodulators that
specifically target and inactivate a primary arm of innate immunity known as the complement system. We have
recently reported two independent lines of evidence that support the hypothesis that one of these pathways,
known as the classical pathway, is important in controlling B. burgdorferi infections. First, we have shown that
mice deficient in the pattern recognition molecule of the classical pathway, C1q, are significantly more
susceptible to B. burgdorferi infection. Secondly, we have shown that the lipoprotein B. burgdorferi BBK32 is a
high-affinity inhibitor of the initiating protease of the classical pathway, C1r.
In Aim 1 of this project we seek to understand the C1r inhibitory activity of BBK32 sensu lato proteins at
the molecular level. In Aim 2 we will determine the immunomodulatory roles and virulence contribution of three
BBK32 orthologues known as FbpA, FbpB, and FbpC which are found uniquely in relapsing fever and B.
miyamotoi spirochetes. In Aim 3 we will delineate the role of C1r inhibition in borrelial pathogenesis using in
vivo models of disease. To achieve this, we propose a multi-disciplinary strategy that employs x-ray
crystallography, biophysical approaches, and complement functional assays to pinpoint key ‘hot-spot’ residues
on BBK32 that give rise to its potent anti-C1r activity. These data will inform the design of bbk32 mutants which
will be used in mouse infectivity studies to connect structural features of BBK32, at the amino-acid level, to an
in vivo phenotype. Parallel studies will use genetic deletion mutants of fbp genes from the relapsing fever-
associated spirochetes B. turicatae and B. hermsii. These studies will be paired with experimental models of
Lyme and relapsing fever borrelioses using C1r-/- mice to better understand the role of the classical pathway
initiating protease in the control of borrelial infections. By addressing fundamental questions of how medically
important Borrelia spirochetes recognize and evade host immunity, the studies proposed here stand to have a
broad and significant impact on the field of bacterial pathogenesis.
项目总结
项目成果
期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Outer surface lipoproteins from the Lyme disease spirochete exploit the molecular switch mechanism of the complement protease C1s.
- DOI:10.1016/j.jbc.2022.102557
- 发表时间:2022-11
- 期刊:
- 影响因子:4.8
- 作者:Garrigues, Ryan J.;Thomas, Sheila;Leong, John M.;Garcia, Brandon L.
- 通讯作者:Garcia, Brandon L.
Lipoproteome screening of the Lyme disease agent identifies inhibitors of antibody-mediated complement killing.
- DOI:10.1073/pnas.2117770119
- 发表时间:2022-03-29
- 期刊:
- 影响因子:11.1
- 作者:
- 通讯作者:
"Conformational dynamics of C1r inhibitor proteins from Lyme disease and relapsing fever spirochetes".
“莱姆病和回归热螺旋体 C1r 抑制剂蛋白的构象动力学”。
- DOI:10.1101/2023.03.01.530473
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Roy,Sourav;BoothJr,CharlesE;Powell-Pierce,AlexandraD;Schulz,AnnaM;Skare,JonT;Garcia,BrandonL
- 通讯作者:Garcia,BrandonL
Complement Evasion by Lyme Disease Spirochetes.
- DOI:10.1016/j.tim.2020.05.004
- 发表时间:2020-11
- 期刊:
- 影响因子:15.9
- 作者:Skare JT;Garcia BL
- 通讯作者:Garcia BL
A Structural Basis for Inhibition of the Complement Initiator Protease C1r by Lyme Disease Spirochetes.
- DOI:10.4049/jimmunol.2100815
- 发表时间:2021-12-01
- 期刊:
- 影响因子:0
- 作者:Garrigues RJ;Powell-Pierce AD;Hammel M;Skare JT;Garcia BL
- 通讯作者:Garcia BL
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Brandon Lee Garcia其他文献
Brandon Lee Garcia的其他文献
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{{ truncateString('Brandon Lee Garcia', 18)}}的其他基金
Virulence Mechanisms of Multifunctional Borrelial Proteins
多功能疏螺旋体蛋白的毒力机制
- 批准号:
10407450 - 财政年份:2020
- 资助金额:
$ 71.34万 - 项目类别:
Virulence Mechanisms of Multifunctional Borrelial Proteins
多功能疏螺旋体蛋白的毒力机制
- 批准号:
10192642 - 财政年份:2020
- 资助金额:
$ 71.34万 - 项目类别:
Virulence Mechanisms of Multifunctional Borrelial Proteins
多功能疏螺旋体蛋白的毒力机制
- 批准号:
9985574 - 财政年份:2019
- 资助金额:
$ 71.34万 - 项目类别:
Development of Small Molecule Inhibitors of the Classical Complement Pathway
经典补体途径小分子抑制剂的开发
- 批准号:
9375741 - 财政年份:2017
- 资助金额:
$ 71.34万 - 项目类别:
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