HEMOGLOBIN-INDUCED VIRULENCE IN STREPTOCOCCUSPNEUMONIAE

肺炎链球菌中血红蛋白诱导的毒力

• 批准号: 10369595
• 负责人: Brian Akerley
• 金额: $ 19.44万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-10 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10369595
• 关键词: Antibiotic Resistance; Antigens; Bacteremia; Bacterial Adhesins; Binding; Binding Proteins; Blood Circulation; Cardiac Myocytes; Cells; Child; Childhood; Confocal Microscopy; Cues; Development; Disease; Environment; Epithelial Cells; Fibronectins; Functional disorder; Genes; Goals; Growth; Heart; Heart Injuries; Heme; Hemeproteins; Hemoglobin; Human; Immune response; In Vitro; Individual; Infection; Invaded; Iron; Lead; Life; Lung; Lung infections; Membrane Proteins; Meninges; Meningitis; Metals; Microbial Biofilms; Mutagenesis; Myocardium; Myoglobin; Nutrient; Otitis Media; Pathogenesis; Plasmin; Pleural; Pleural cavity; Pneumococcal Colonization; Pneumococcal Infections; Pneumococcal Pneumonia; Pneumococcal vaccine; Pneumonia; Process; Proteins; Regulatory Element; Reporting; Research; Role; Sepsis; Signal Transduction; Source; Streptococcus pneumoniae; Structural Protein; Surface; Testing; Toxin; Upper respiratory tract; Vaccination; Vaccine Antigen; Vaccines; Virulence; Work; burden of illness; experience; experimental study; extracellular; genetic approach; genetic regulatory protein; heart damage; human pathogen; in vivo; inhibitor; lung colonization; macrophage; mouse model; mutant; novel; receptor; receptor binding; respiratory colonization; response; reverse genetics; screening; transposon sequencing

1 Project summary 2 3 Streptococcus pneumoniae (Spn) colonizes the human upper airways of most children forming biofilms. Due 4 to mechanisms still not understood, nasopharyngeal carriage leads to invasive pneumococcal disease (IPD) 5 that kills more than one million individuals every year worldwide. IPD is characterized by colonization of the 6 lungs with subsequent translocation to the pleural cavity, and bloodstream, to cause lethal bacteremia. Once 7 in circulation, Spn translocates to the meninges causing meningitis or invades cardiomyocytes forming 8 intracellular biofilms that lead to cardiac damage. Although pneumococcal vaccination has reduced the 9 burden of disease, vaccines only target a subset of strains and have little to no impact against pneumococcal 10 bacteremia and meningitis. Efforts made in the last few years by this proposal's PIs have resulted in the 11 groundbreaking discovery that hemoglobin (Hb), a molecule that is accessible to Spn during carriage in the 12 upper airways and colonization of lung and heart, triggers the formation of robust biofilms and translocation 13 of pneumococci through human lung cells. These observations strongly support a new scientific premise that 14 Hb signaling is key to Spn colonization and disease processes. Our overarching goal is to identify the proteins 15 by which hemoglobin (Hb) triggers Spn virulence leading to the pathophysiology of pneumococcal disease 16 and to begin to describe the mechanism of Hb signaling in Spn. Specific Aim 1 will use a reverse genetic 17 approach to identify the proteins required for Hb to transduce a signal leading to the formation of biofilms, 18 and invasion of lung cells and cardiomyocytes. Whether this signal acts along with, or it is separated from, an 19 increased pool of intracellular iron will also be investigated. Specific Aim 2 will implement an agnostic 20 strategy (Tn-seq) to determine additional surface proteins and the regulators necessary for Hb signaling and 21 test key candidates defective in Hb signaling in vivo using murine models for pneumococcal colonization and 22 disease. At completion, this work will identify new proteins key for the pathophysiology of IPD, new antigens 23 for pneumococcal vaccines, and new targets for inhibitors that interfere with the establishment and 24 progression of IPD. 25 26 27 28 29 30

1 项目概要 2 3 肺炎链球菌 (Spn) 定植于大多数儿童的人体上呼吸道，形成生物膜。到期的 4 鼻咽携带导致侵袭性肺炎球菌疾病（IPD）的机制尚不清楚 5 每年全世界有超过一百万人死亡。 IPD 的特点是定植 6 个肺部随后易位至胸膜腔和血流，导致致命的菌血症。一次 7 在循环中，Spn 易位至脑膜引起脑膜炎或侵入心肌细胞形成 8 导致心脏损伤的细胞内生物膜。尽管肺炎球菌疫苗接种已减少 9 疾病负担，疫苗仅针对一部分菌株，对肺炎球菌几乎没有影响 10菌血症和脑膜炎。该提案的 PI 在过去几年中所做的努力已取得成果 11 突破性发现血红蛋白 (Hb) 是一种在运输过程中可被 Spn 接触到的分子 12 上呼吸道以及肺和心脏的定植，触发强大的生物膜和易位的形成 13 种肺炎球菌通过人肺细胞传播。这些观察有力地支持了一个新的科学前提： 14 Hb 信号传导是 Spn 定植和疾病过程的关键。我们的首要目标是鉴定蛋白质 15 血红蛋白 (Hb) 触发 Spn 毒力，导致肺炎球菌疾病的病理生理学 参见图16并开始描述Spn中Hb信号传导的机制。具体目标 1 将使用反向遗传 17 鉴定 Hb 转导导致生物膜形成的信号所需的蛋白质的方法， 18、侵袭肺细胞和心肌细胞。该信号是否与某个信号一起作用，或者与其分离 19 细胞内铁库的增加也将被研究。具体目标 2 将实施不可知论 20 策略 (Tn-seq) 确定 Hb 信号传导所需的其他表面蛋白和调节因子 21 使用肺炎球菌定植小鼠模型测试体内 Hb 信号传导缺陷的关键候选物 22种疾病。完成后，这项工作将鉴定对 IPD 病理生理学至关重要的新蛋白质、新抗原 23 肺炎球菌疫苗，以及干扰建立和抑制的抑制剂的新靶标 24 IPD 进展。 25 26 27 28 29 30

项目成果

Prophylactic Inhibition of Colonization by Streptococcus pneumoniae with the Secondary Bile Acid Metabolite Deoxycholic Acid.

使用次级胆汁酸代谢物脱氧胆酸预防性抑制肺炎链球菌的定植。

• DOI: 10.1128/iai.00463-21
• 发表时间: 2021
• 期刊: Infection and immunity
• 影响因子: 3.1
• 作者: Vidal,JorgeE;Wier,MeaganN;AAngulo-Zamudio,Uriel;McDevitt,Erin;JopVidal,AnaG;Alibayov,Babek;Scasny,Anna;Wong,SandyM;Akerley,BrianJ;McDaniel,LarryS
• 通讯作者: McDaniel,LarryS

Oligopeptide Transporters of Nonencapsulated Streptococcus pneumoniae Regulate CbpAC and PspA Expression and Reduce Complement-Mediated Clearance.

• DOI: 10.1128/mbio.03325-22
• 发表时间: 2023-02-28
• 期刊: mBio
• 影响因子: 6.4

Effect of pneumococcal conjugate vaccine availability on Streptococcus pneumoniae infections and genetic recombination in Zhejiang, China from 2009 to 2019.

• DOI: 10.1080/22221751.2022.2040921
• 发表时间: 2022-12
• 期刊: Emerging microbes & infections
• 影响因子: 13.2
• 作者: Wu X;Zhao S;Jiang Y;Xiang X;Ge L;Chen Q;Wang Y;Vidal JE;Yu Y
• 通讯作者: Yu Y

The quorum sensing com system regulates pneumococcal colonisation and invasive disease in a pseudo-stratified airway tissue model.

群体感应通信系统在伪分层气道组织模型中调节肺炎球菌定植和侵袭性疾病。

• DOI: 10.1016/j.micres.2022.127297
• 发表时间: 2023
• 期刊: Microbiological research
• 影响因子: 6.7
• 作者: Kahlert,ChristianR;Nigg,Susanne;Onder,Lucas;Dijkman,Ronald;Diener,Liliane;Vidal,AnaGJop;Rodriguez,Regulo;Vernazza,Pietro;Thiel,Volker;Vidal,JorgeE;Albrich,WernerC
• 通讯作者: Albrich,WernerC