Endolysins as tools to eradicate pneumococcal biofilms and development of protective immunity
内溶素作为根除肺炎球菌生物膜和发展保护性免疫的工具
基本信息
- 批准号:10587285
- 负责人:
- 金额:$ 90.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-12-09 至 2023-11-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAnimal ModelAnimalsAntibiotic ResistanceAntibioticsAntibodiesAntibody FormationAntibody ResponseAntibody-mediated protectionAntigensAntimicrobial ResistanceApoptosisAutomobile DrivingBacteremiaBacteriaBacterial ProteinsBacteriophagesBenchmarkingBiochemicalBiochemistryBiologicalBiological AssayBiophysicsCell DeathCell Death InductionCellsCessation of lifeChildCoculture TechniquesCountryDeveloping CountriesDevelopmentDisadvantagedDiseaseEffectivenessElderlyEnzymesEpitheliumExtracellular MatrixFatality rateGenerationsGoalsGram-Positive BacteriaHealthHealth Care CostsHumanImmunityImmunizeImmunologic TechniquesImmunologicsIn VitroIndividualInflammationLeadLungLytic PhaseMacrophageMass Spectrum AnalysisMicrobial BiofilmsModelingMolecularMusN-Acetylmuramoyl-L-alanine AmidaseNasopharynxNecrosisNoseOral mucous membrane structureOrganismOtitis MediaPeptidoglycanPharyngeal structurePhosphotransferasesPneumococcal ColonizationPneumococcal InfectionsPneumoniaPolymersPolysaccharidesPopulationPredispositionPropertyProteinsProteomicsProxyResearchResistanceRoleSafetySerotypingSinusitisSpecificityStreptococcus pneumoniaeStreptococcus pneumoniae plY proteinTechnologyTestingTherapeuticTissuesToxic effectToxinTransgenic MiceVaccinesWorld Health Organizationantimicrobialaspiratecellular developmentcommunity acquired pneumoniaeffectiveness evaluationeffectiveness testingendolysinextracellularimmunogenicin vivomembermucosal vaccinenext generationnovelopportunistic pathogenoral commensalpoint of carepreventresistant strainresponsesingle-cell RNA sequencingsugartooltranscriptomics
项目摘要
Project Summary
Streptococcus pneumoniae (Spn, the pneumococcus) are Gram-positive bacteria and the leading cause of
community-acquired pneumonia worldwide. The World Health Organization estimates >1.6 million deaths are
the result of Spn infection each year, with children and the elderly being the most susceptible populations. Major
problems of pneumococcal disease include the acquisition of antimicrobial resistance and the global spread of
resistant clones. In addition, these problems are magnified by the major disadvantages of the current capsular
polysaccharide-based vaccines, such as serotype specificity and the resulting incomplete coverage. An
emerging way to address the growing antimicrobial resistance problem is the use of bacteriophage endolysins.
These enzymes are capable of degrading the bacterial peptidoglycan, killing and dispersing biofilm bacteria and
its matrix. In preliminary studies, we have developed a chimeric derivative of the well characterized Cpl-1
endolysin that displays >100-fold increase in antimicrobial activity, termed ClyX-1. We also show the ability of
this new endolysin to lyse planktonic Spn, and importantly we also observed that ClyX-1 was able to kill biofilm
Spn, as well as disperse the biofilm matrix. In addition, we have shown that upon Spn nasopharyngeal
colonization, activation of programmed necrosis, i.e. necroptosis, leads to development of antigen-specific
antibodies. Of note, treatment of colonized mice with ClyX-1 further promoted necroptosis activation, suggesting
endolysin treatment may enhance development of protective immunity against Spn. Herein, we aim to address
three overall hypotheses: a) that endolysins are efficient pneumococcal anti-biofilm agents, b) that endolysins
can be an effective way to prevent Spn colonization in a serotype-independent manner, and c) that intranasal
treatment with endolysins promotes protective immunity, to prevent re-colonization and severe disease. We will
use a combination of in vitro and in vivo studies with static and dynamic biofilms, mice, biochemistry (characterize
and benchmark pneumococcal endolysins), transgenic mice (to define the role of programmed cell death in
protective immunity), molecular and immunological techniques and next generation technologies (proteomics,
single cell transcriptomics) to establish better understanding of the effects of endolysin treatments against
pneumococcal disease in vivo and test their effectiveness in development of long-term serotype-independent
protective immunity.
项目总结
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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Norberto Gonzalez Juarbe其他文献
Norberto Gonzalez Juarbe的其他文献
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{{ truncateString('Norberto Gonzalez Juarbe', 18)}}的其他基金
Development of novel protein-based vaccine formulations to prevent pneumococcal colonization and disease
开发新型蛋白质疫苗制剂以预防肺炎球菌定植和疾病
- 批准号:
10057035 - 财政年份:2020
- 资助金额:
$ 90.1万 - 项目类别:
Development of novel protein-based vaccine formulations to prevent pneumococcal colonization and disease
开发新型蛋白质疫苗制剂以预防肺炎球菌定植和疾病
- 批准号:
10264136 - 财政年份:2020
- 资助金额:
$ 90.1万 - 项目类别:
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