权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
Norberto Gonzalez Juarbe
金额：
$ 90.1万
依托单位：
J. CRAIG VENTER INSTITUTE, INC.
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：
https://reporter.nih.gov/project-details/10587285
关键词：
Address Animal Model Animals Antibiotic Resistance Antibiotics Antibodies Antibody Formation Antibody Response Antibody-mediated protection Antigens Antimicrobial Resistance Apoptosis Automobile Driving Bacteremia Bacteria Bacterial Proteins Bacteriophages Benchmarking Biochemical Biochemistry Biological Biological Assay Biophysics Cell Death Cell Death Induction Cells Cessation of life Child Coculture Techniques Country Developing Countries Development Disadvantaged Disease Effectiveness Elderly Enzymes Epithelium Extracellular Matrix Fatality rate Generations Goals Gram-Positive Bacteria Health Health Care Costs Human Immunity Immunize Immunologic Techniques Immunologics In Vitro Individual Inflammation Lead Lung Lytic Phase Macrophage Mass Spectrum Analysis Microbial Biofilms Modeling Molecular Mus N-Acetylmuramoyl-L-alanine Amidase Nasopharynx Necrosis Nose Oral mucous membrane structure Organism Otitis Media Peptidoglycan Pharyngeal structure Phosphotransferases Pneumococcal Colonization Pneumococcal Infections Pneumonia Polymers Polysaccharides Population Predisposition Property Proteins Proteomics Proxy Research Resistance Role Safety Serotyping Sinusitis Specificity Streptococcus pneumoniae Streptococcus pneumoniae plY protein Technology Testing Therapeutic Tissues Toxic effect Toxin Transgenic Mice Vaccines World Health Organization antimicrobial aspirate cellular development community acquired pneumonia effectiveness evaluation effectiveness testing endolysin extracellular immunogenic in vivo member mucosal vaccine next generation novel opportunistic pathogen oral commensal point of care prevent resistant strain response single-cell RNA sequencing sugar tool transcriptomics

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