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个项目摘要 2 3肺炎链球菌（SPN）在大多数形成生物膜的儿童的人类上呼吸道上定居。到期的 4对于仍不清楚的机制，鼻咽托架导致侵入性肺炎球菌疾病（IPD） 5每年在全球杀死超过一百万个人。 IPD的特征是定植 6个肺随后易位到胸膜腔和血液，引起致命菌血症。一次 7在循环中，SPN转移到引起脑膜炎或侵入心肌细胞的脑膜上 8导致心脏损伤的细胞内生物膜。尽管肺炎球菌疫苗接种降低了 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。在过去几年中，该提议的PI所做的努力导致了 11开创性的发现，血红蛋白（HB），这是一种在运输过程中SPN访问的分子 12上呼吸道和肺和心脏的定殖，触发了强大的生物膜的形成 通过人肺细胞的13个肺炎球菌。这些观察结果强烈支持一个新的科学前提 14 HB信号传导是SPN定植和疾病过程的关键。我们的总体目标是识别蛋白质 15血红蛋白（Hb）触发SPN毒力导致肺炎球菌病的病理生理学 16并开始描述SPN中HB信号的机理。特定目标1将使用反向遗传 17识别HB所需的蛋白质传递信号所需的蛋白质的方法，导致形成生物膜， 18和肺部细胞和心肌细胞的入侵。该信号是与或与之分离的 19还将研究增加细胞内铁的池。具体目标2将实施不可知论 20策略（TN-SEQ）确定HB信号传导和 21测试关键候选者在体内使用鼠模型进行肺炎球菌定植和 22疾病。完成后，这项工作将确定IPD病理生理学的新蛋白质密钥 23用于肺炎球菌疫苗，以及干扰机构和抑制剂的新靶标 24 IPD的进展。 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