CRASP-mediated Serum Resistance by Borrelia burgdorferi
CRASP 介导的伯氏疏螺旋体的血清耐药性
基本信息
- 批准号:9087098
- 负责人:
- 金额:$ 20.09万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-06-15 至 2019-05-31
- 项目状态:已结题
- 来源:
- 关键词:AntibodiesBacteremiaBacteriaBacterial AntigensBindingBinding ProteinsBiologicalBiteBloodBlood CirculationBorrelia burgdorferiCarbohydratesComplementComplement 3 ConvertaseComplement 3bComplement ActivationComplement Factor HComplexCytolysisDefectDepositionDermatan SulfateDetectionDevelopmentDisease modelDown-RegulationEnvironmentEventFosteringGenesHealthHost DefenseImmune responseIn VitroIndividualInfectionInflammationInvestigationJointsKnowledgeLaboratoriesLyme DiseaseMannose Binding LectinMannose-Binding LectinsMediatingMembrane ProteinsModelingMusMutateOrder SpirochaetalesPathway interactionsPhenotypePlasmidsProteinsRegulationResistanceRoleSerumSiteSkinStagingSurfaceSystemSystemic diseaseTest ResultTestingTicksTissue SurvivalTissuesVector-transmitted infectious diseaseWorkcomplement systemdecoringenetic regulatory proteininsightmicrobialmouse modelmutantparalogous genepathogenpreventpromoterprotein complex
项目摘要
DESCRIPTION (provided by applicant): Lyme disease, caused by the spirochete Borrelia burgdorferi, is the most common vector-borne disease in U.S. B. burgdorferi can infect the skin at the site of the tick bite and spread via blood to diverse tissues, indicating that the bacterium
can withstand bloodstream defenses. The complement system is a bloodstream defense that is activated via three different pathways. A critical step of the activation of this system is the formation of C3 convertases, C4b2a or C3bBb, which catalyze events resulting in inflammation, opsonization and pathogen lysis. Potential host damage following complement activation necessitates tight regulation by serum complement regulators that bind to complement components and promote their degradation. For example, the complement regulator factor H (FH) and C4BP modulates formation of C3bBb and C4b2a, respectively. We recently showed that B. burgdorferi produces DbpA, a surface protein that promotes tissue colonization by binding to dermatan sulfate and decorin, also fosters bacteremia by binding to C4BP. A B. burgdorferi strain producing DbpA-I156A, a point mutant deficient in C4BP binding, showed a delay in bacteremia and joint colonization. In addition, B. burgdorferi also produces CRASPs (Complement Regulator Acquiring Surface Proteins) that bind to complement regulators. The paralogs CspA, CspZ bind to FH and FH-like protein (FHL), and the paralogs ErpP, ErpC, and ErpA bind to FH and complement factor H-related protein (CFHR). Although several CRASPs have been demonstrated to contribute to serum resistance in vitro, none have been definitely shown to contribute to mammalian infection. Recently, we found that a B. burgdorferi strain harboring an erpA::Tn insertion displayed a defect in tissue colonization at early stages of infection. These results suggest that DbpA and ErpA modulate C4b2a and C3bBb, respectively, to promote bacteremia and tissue colonization. The ability of DbpA and ErpA to inhibit the formation of both classes of C3 convertases may signify a coordinated attack on host bloodstream defenses by B. burgdorferi. To test this hypothesis, the following aims will be pursued. (1) Test the role of FH-binding in bacteremia and colonization. We will test if a targeted, non-polar erpA deletion mutant display defects in FH/CFHR binding, complement activation in vitro, and bacteremia and tissue colonization in the murine model. If the mutant displays defects, we will test if FH binding by ErpA is essential for these functions, and whether other CRASPs can functionally complement the defects. (2). Test if C4BP- and FH-binding by B. burgdorferi provide non-redundant roles to promote bacteremia and colonization. To determine if a dramatic dissemination defect requires loss of both C4BP- and FH-binding activities, we will mutate erpA in the strain background of the B. burgdorferi DbpA-I156A mutant. These double mutant strains will be tested for the severe bacteremia and colonization defect in the murine model.
描述(由申请人提供):莱姆病由螺旋体伯氏疏螺旋体引起,是美国最常见的媒介传播疾病。伯氏疏螺旋体可以感染蜱虫叮咬部位的皮肤,并通过血液传播到不同的组织,这表明细菌
补体系统是一种通过三种不同途径激活的血流防御,激活该系统的关键步骤是 C3 转化酶、C4b2a 或 C3bBb 的形成,它们催化导致炎症、调理作用和病原体的事件。补体激活后的潜在宿主损伤需要血清补体调节剂的严格调节,这些调节剂与补体成分结合并促进其降解,例如补体调节因子 H (FH) 和C4BP 分别调节 C3bBb 和 C4b2a 的形成,我们最近表明,伯氏疏螺旋体产生 DbpA,这是一种通过与硫酸皮肤素和核心蛋白聚糖结合促进组织定植的表面蛋白,还通过与产生 DbpA 的伯氏疏螺旋体菌株结合来促进菌血症。 -I156A 是一种 C4BP 结合缺陷的点突变体,显示菌血症和关节定植延迟。此外,伯氏疏螺旋体还产生与补体调节因子结合的 CRASP(补体调节剂获取表面蛋白),旁系同源物 CspA、CspZ 与 FH 和 FH 样蛋白 (FHL) 结合,旁系同源物 ErpP、ErpC 和 ErpA 与 FH 结合。和补体因子 H 相关蛋白 (CFHR) 虽然一些 CRASP 已被证明有助于体外血清抵抗,但没有一个明确显示有助于哺乳动物。最近,我们发现带有 erpA::Tn 插入的伯氏疏螺旋体菌株在感染早期表现出组织定植缺陷。这些结果表明,DbpA 和 ErpA 分别调节 C4b2a 和 C3bBb,以促进菌血症和组织。 DbpA 和 ErpA 抑制两类 C3 转化酶形成的能力可能意味着 B.为了检验这一假设,我们将追求以下目标:(1)测试 FH 结合在菌血症和定植中的作用,我们将测试靶向的非极性 erpA 缺失突变体在 FH/CFHR 结合中是否表现出缺陷。体外补体激活以及小鼠模型中的菌血症和组织定植如果突变体表现出缺陷,我们将测试 ErpA 的 FH 结合是否对这些功能至关重要,以及其他 CRASP 是否可以在功能上补充该突变体。 (2). 测试伯氏疏螺旋体的 C4BP 和 FH 结合是否提供促进菌血症和定植的非冗余作用 为了确定显着的传播缺陷是否需要 C4BP 和 FH 结合活性的丧失。在伯氏疏螺旋体 DbpA-I156A 突变体的菌株背景中突变 erpA 将在小鼠中测试这些双突变菌株的严重菌血症和定植缺陷。模型。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JOHN M LEONG其他文献
JOHN M LEONG的其他文献
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