Cardiac microlesion formation during invasive pneumococcal disease
Cardiac microlesion formation during invasive pneumococcal disease
批准号:
10517516
负责人:
Carlos J Orihuela
金额:
$44.48万
依托单位国家:
美国
项目类别:
财政年份:
2014
资助国家:
美国
项目状态:
已结题
起止时间:
2014-11-01 至 2024-11-30
关键词:
AcetatesAdultAdverse eventAntibodiesAntioxidantsAreaArrhythmiaAttenuatedAutopsyBacteremiaBloodBlood CirculationCarbonCardiacCardiac Electrophysiologic TechniquesCardiac MyocytesCardiotoxicityCell DeathCell membraneCellsCessation of lifeDiseaseDropsEnzymesEventFormatesGene ExpressionGenesGlucoseGlucose-6-PhosphateGoalsGram-Positive BacteriaGram-Positive CocciHeartHeart InjuriesHeart failureHospitalizationHumanHydrogen PeroxideIn VitroIndividualInflammatoryInvadedIonsLearningLesionLinkMetabolicMetabolismMicrobial BiofilmsMusMutationMyocardialMyocardial InfarctionMyocardiumPassive ImmunizationPathogenesisPneumococcal InfectionsPneumoniaProcessProductionPyruvatePyruvate Metabolism PathwayPyruvate OxidaseResearchRisk FactorsRoleSamplingSeminalStreptococcusStreptococcus pneumoniaeStreptococcus pneumoniae plY proteinTestingTherapeutic InterventionToxinVirulenceWorkacetyl phosphatecell killingclinical epidemiologycommunity acquired pneumoniacytotoxicepidemiology studyexperienceexperimental studyheart damagein vivomortalitymutantnonhuman primateoxidative damageprogramsprototypetargeted treatmenttempoltranscriptome sequencinguptake
中文摘要
摘要:
四分之一因社区获得性肺炎(CAP)住院的成年人出现心脏不良反应
事件。临床流行病学研究,以及在小鼠、非人类灵长类动物和
人类尸检样本表明,引起CAP的主要原因肺炎链球菌(Spn)可以入侵
从血液中分离出心脏并造成直接的心脏毒性。心肌内Spn引起的局灶区
我们称之为微损伤,这些损伤破坏了收缩能力。我们的一项最新突破
对Spn发病机制的理解是观察到肺炎球菌被心肌细胞摄取
Spn从内部杀死这些细胞。更重要的是,致孔毒素肺炎毒素和链球菌
丙酮酸氧化酶(SpxB)产生的过氧化氢都是心脏毒性所必需的。在这里,我们的目标是获得一个
了解摄取Spn后立即在心肌细胞内发生的事件。
沿着这样的思路,来自体外和体内实验的结果,包括Spn-2的双物种RNA测序。
受感染的心脏,揭示了碳可获得性、过氧化氢变化之间的高度引人注目的联系
产生,生物膜/心脏微损伤的形成,和肺溶素的产生。因此,我们假设
Spn在心肌细胞内遇到的葡萄糖限制,以及再次在心脏微小病变中遇到的血糖限制,导致
代谢和基因表达的变化,增强细菌的心脏毒性。来检验这一假设并学习
肺炎溶血素和过氧化氢如何协同作用杀死心肌细胞,我们将:
目的1:确定环境中的葡萄糖、新陈代谢和毒力是如何相互关联的。为了澄清
这些联系的基础、范围和后果我们将:1)决定如何有目的地进行分流
丙酮酸代谢(通过突变)对醋酸盐、乳酸盐和/或甲酸盐的产生的影响
基因在高糖和低糖条件下的表达;2)确定Spn基因的表达如何变化
心肌细胞摄取细菌后的纵向变化及其与Spn变化的关系
新陈代谢;3)确定新陈代谢相关基因对心肌细胞内Spn存活的重要性,
杀死心肌细胞,以及整个疾病过程。
目的2:确定细菌衍生的过氧化氢和肺溶血素是如何杀死心肌细胞的。SPXB
衍生的过氧化氢和肺溶酶都是Spn杀死心肌细胞所必需的;单独使用这两种物质是不够的。
为了确定原因,我们将:1)确定不同的过氧化氢和肺炎溶血素的产生如何共同调节
心肌细胞死亡的形式;2)确定过氧化氢是否促进肺炎溶血素的产生,其从
SPN,或宿主细胞膜靶向;以及,3)确定SpxB衍生的过氧化氢是否对离子有贡献
以前被认为与肺炎溶血素引起的坏死性下垂有关的调节失调。这个目标,在它的
完成,将促进我们对Spn如何杀死宿主细胞的理解。
英文摘要
ABSTRACT:
One-in-four adults hospitalized for community-acquired pneumonia (CAP) experience an adverse cardiac
event. Clinical epidemiological studies, as well as those performed in mice, non-human primates, and with
human autopsy samples indicate that Streptococcus pneumoniae (Spn), the leading cause of CAP, can invade
the heart from the bloodstream and cause direct cardiotoxicity. Within the myocardium Spn cause focal areas
of damage we have called microlesions and these disrupt contractility. One recent break-through in our
understanding of Spn pathogenesis was the observation that pneumococci are taken up by cardiomyocytes
and Spn kill these cells from within. What is more, the pore-forming toxin pneumolysin and Streptococcal
pyruvate oxidase (SpxB) derived H2O2 were both requisite for cardiotoxicity. Herein, our goal is to gain an
understanding of the events that take place within a cardiomyocyte immediately after Spn uptake.
Along such lines, results from in vitro and in vivo experiments, including dual-species RNA sequencing of Spn-
infected hearts, have revealed highly compelling connections between changes in carbon availability, H2O2
production, biofilm / cardiac microlesion formation, and pneumolysin production. Thus, we hypothesize that
glucose restriction encountered by Spn within a cardiomyocyte, and again in cardiac microlesions, results in
metabolic and gene expression changes that enhance bacterial cardiotoxicity. To test this hypothesis and learn
how pneumolysin and H2O2 work together to kill cardiomyocytes we will:
AIM 1: Determine how environmental glucose, metabolism, and virulence are interlinked. To elucidate
the basis, extent, and consequences of these connections we will: 1) determine how purposeful shunting of
pyruvate metabolism (by means of mutation) towards the production of acetate, lactate, and/or formate impacts
gene expression under high and low glucose conditions; 2) identify how Spn gene expression changes in
longitudinal fashion after bacterial uptake by a cardiomyocyte and how this is linked to changes in Spn
metabolism; 3) determine the importance of metabolism-linked genes to Spn survival within a cardiomyocyte,
killing of the cardiomyocyte, and the overall disease process.
AIM 2: Determine how bacterial derived H2O2, together with pneumolysin, kills cardiomyocytes. SpxB
derived H2O2 and pneumolysin are both required for Spn killing of cardiomyocytes; each alone is insufficient.
To determine why we will: 1) determine how varying production of H2O2 and pneumolysin together modulate
the form of cardiomyocyte death; 2) determine if H2O2 potentiates pneumolysin production, its release from
Spn, or host cell membrane targeting; and, 3) determine if SpxB-derived H2O2 contributes to the ion
dysregulation that has previously been implicated in pneumolysin-induced necroptosis. This aim, at its
completion, will advance our understanding of how Spn kills host cells.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Cardiomyocyte self-defense against Streptococcus pneumoniae
-
批准号:10639102
-
项目类别:
-
资助金额:$17.97万
-
财政年份:2023
-
负责人:Carlos J Orihuela
-
依托单位:
Molecular mechanisms underlying organ penetration in disseminated pneumococcal infection
-
批准号:10555548
-
项目类别:
-
资助金额:$65.71万
-
财政年份:2022
-
负责人:Carlos J Orihuela
-
依托单位:
PspA binds necroptotic cells to cause disease and transmit
-
批准号:10269932
-
项目类别:
-
资助金额:$41.18万
-
财政年份:2020
-
负责人:Carlos J Orihuela
-
依托单位:
PspA binds necroptotic cells to cause disease and transmit
-
批准号:10470379
-
项目类别:
-
资助金额:$40.77万
-
财政年份:2020
-
负责人:Carlos J Orihuela
-
依托单位:
PspA binds necroptotic cells to cause disease and transmit
-
批准号:10685976
-
项目类别:
-
资助金额:$41.02万
-
财政年份:2020
-
负责人:Carlos J Orihuela
-
依托单位:
Inhibition of necroptosis during inflamm-aging and pneumonia
-
批准号:9248088
-
项目类别:
-
资助金额:$18.38万
-
财政年份:2016
-
负责人:Carlos J Orihuela
-
依托单位:
Cardiac microlesion formation during invasive pneumococcal disease
-
批准号:9179589
-
项目类别:
-
资助金额:$36.43万
-
财政年份:2015
-
负责人:Carlos J Orihuela
-
依托单位:
Cardiac microlesion formation during invasive pneumococcal disease
-
批准号:10307592
-
项目类别:
-
资助金额:$43.72万
-
财政年份:2014
-
负责人:Carlos J Orihuela
-
依托单位:
Cardiac microlesion formation during invasive pneumococcal disease
-
批准号:9891766
-
项目类别:
-
资助金额:$45.55万
-
财政年份:2014
-
负责人:Carlos J Orihuela
-
依托单位:
Statins protect against adverse cardiac events during pneumonia
-
批准号:8245700
-
项目类别:
-
资助金额:$18.6万
-
财政年份:2011
-
负责人:Carlos J Orihuela
-
依托单位:
Statins protect against adverse cardiac events during pneumonia
-
批准号:8094796
-
项目类别:
-
资助金额:$18.56万
-
财政年份:2011
-
负责人:Carlos J Orihuela
-
依托单位:
Mechanism of PsrP mediated adhesion
-
批准号:7995950
-
项目类别:
-
资助金额:$25.47万
-
财政年份:2009
-
负责人:Carlos J Orihuela
-
依托单位:
Mechanism of PsrP mediated adhesion
-
批准号:7759609
-
项目类别:
-
资助金额:$25.73万
-
财政年份:2009
-
负责人:Carlos J Orihuela
-
依托单位:
Mechanism of PsrP mediated adhesion
-
批准号:8423395
-
项目类别:
-
资助金额:$23.94万
-
财政年份:2009
-
负责人:Carlos J Orihuela
-
依托单位:
Age-associated Toll-like receptor dysfunction in the lungs
-
批准号:7790552
-
项目类别:
-
资助金额:$15.07万
-
财政年份:2009
-
负责人:Carlos J Orihuela
-
依托单位:
Mechanism of PsrP mediated adhesion
-
批准号:7654374
-
项目类别:
-
资助金额:$27.83万
-
财政年份:2009
-
负责人:Carlos J Orihuela
-
依托单位:
Mechanism of PsrP mediated adhesion
-
批准号:8204783
-
项目类别:
-
资助金额:$25.47万
-
财政年份:2009
-
负责人:Carlos J Orihuela
-
依托单位:
Age-associated inflammation increases susceptibility to pneumococcal infection
-
批准号:7385278
-
项目类别:
-
资助金额:$15.51万
-
财政年份:2007
-
负责人:Carlos J Orihuela
-
依托单位:
Age-associated inflammation increases susceptibility to pneumococcal infection
-
批准号:7502167
-
项目类别:
-
资助金额:$15.2万
-
财政年份:2007
-
负责人:Carlos J Orihuela
-
依托单位:
海外基金