Neutralizing the GBS hemolytic lipid toxin

中和 GBS 溶血脂质毒素

基本信息

批准号：
10392131
负责人：
Lakshmi Rajagopal
金额：
$ 80.59万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
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：
2022-06-16 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10392131
关键词：
Adult Antibodies Antibody Formation Applications Grants Area Attenuated B-Lymphocytes Bacillus cereus Bacteria Bacterial Infections Bacteroides Biological Cell surface Cells Cerebral Palsy Clinical Cytotoxin Disease Elderly Erythrocytes Evaluation Genes Genus Mycobacterium Gram-Positive Bacteria Group Identifications Group Structure Hemolysin Hemolysis Human Immune Immune Sera Immunity Immunization Immunocompromised Host Infection Injury Integration Host Factors Intellectual functioning disability Lipids Mediating Membrane Meningitis Microbe Modeling Morbidity - disease rate Mus Names Neonatal Neurologic Newborn Infant Ornithine Pathogenesis Pathology Perinatal Pigments Placenta Pneumonia Pregnancy Premature Birth Prevention Propionibacterium Proteins Pseudomonas Public Health Reporting Research Seizures Sepsis Streptococcal Infections Streptococcus Group B T-Lymphocyte Toxic effect Toxin Umbilical Cord Blood Vaccinated Vaccination Vaccines Vesicle Virulence Factors Woman Work adverse outcome analog base chemical synthesis cytotoxic diabetic experimental study human morbidity human mortality immunogenicity improved in utero in vivo in vivo Model inhibiting antibody macrophage mast cell microbial mortality mouse model neonatal lung injury neutrophil pathogen pregnant prevent reproductive tract rhamnolipid screening stillbirth streptococcal group B hemolysin vaccine candidate vaccine response vaginal fluid

Adult Antibodies Antibody Formation Applications Grants Area Attenuated B-Lymphocytes Bacillus cereus Bacteria Bacterial Infections Bacteroides Biological Cell surface Cells Cerebral Palsy Clinical Cytotoxin Disease Elderly Erythrocytes Evaluation Genes Genus Mycobacterium Gram-Positive Bacteria Group Identifications Group Structure Hemolysin Hemolysis Human Immune Immune Sera Immunity Immunization Immunocompromised Host Infection Injury Integration Host Factors Intellectual functioning disability Lipids Mediating Membrane Meningitis Microbe Modeling Morbidity - disease rate Mus Names Neonatal Neurologic Newborn Infant Ornithine Pathogenesis Pathology Perinatal Pigments Placenta Pneumonia Pregnancy Premature Birth Prevention Propionibacterium Proteins Pseudomonas Public Health Reporting Research Seizures Sepsis Streptococcal Infections Streptococcus Group B T-Lymphocyte Toxic effect Toxin Umbilical Cord Blood Vaccinated Vaccination Vaccines Vesicle Virulence Factors Woman Work adverse outcome analog base chemical synthesis cytotoxic diabetic experimental study human morbidity human mortality immunogenicity improved in utero in vivo in vivo Model inhibiting antibody macrophage mast cell microbial mortality mouse model neonatal lung injury neutrophil pathogen pregnant prevent reproductive tract rhamnolipid screening stillbirth streptococcal group B hemolysin vaccine candidate vaccine response vaginal fluid

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项目摘要

PROJECT SUMMARY Human morbidity and mortality due to bacterial infections continue to remain significant public health concern. Group B Streptococcus (GBS) or Streptococcus agalactiae cause invasive infections during pregnancy leading to preterm births, stillbirths or infections in newborns. Furthermore, GBS also cause infections in the normal, elderly, diabetic and immuno-compromised adults. Our work has shown that the hemolysin, which is a key virulence factor for GBS infections is a pigmented ornithine rhamnolipid also known as granadaene. This hemolytic lipid toxin is cytotoxic to a number of host cells leading to adverse outcomes to newborns and adult humans. The objectives of this proposal are to identify additional nontoxic analogs that can prevent toxin function during GBS infections using murine models of infection, to elucidate host immune mechanisms important for analog mediated immunity against this GBS toxin, to determine how membrane vesicles exacerbate GBS pathogenesis and if antibodies can attenuate their effects. Collectively, the results from these aims will be important and relevant for prevention of GBS infections in humans and will be relevant to other diseases caused by pathogens encoding toxic lipids.

项目摘要由于细菌感染而引起的人类发病率和死亡率继续保持严重的公共卫生关注。 B组链球菌（GBS）或链球菌agalactiae在怀孕期间引起侵入性感染导致早产，死产或新生儿感染。此外，GB还引起感染正常，老年，糖尿病和免疫受损成年人。我们的工作表明，hemolysin，那是 GBS感染的关键毒力因子是色素的鸟氨酸鼠李糖脂，也称为granadaene。这种溶血性脂质毒素对许多宿主细胞具有细胞毒性，导致对新生儿的不良结果和成年人。该提案的目标是确定可以预防毒素的其他无毒类似物使用鼠类感染模型在GBS感染期间的功能，以阐明宿主免疫机制对于对这种GBS毒素的模拟介导的免疫力至关重要，以确定膜囊泡如何加剧GBS发病机理，抗体是否可以衰减其作用。总的来说，这些结果目的将与预防人类的GBS感染相关，并且与其他人有关由编码有毒脂质的病原体引起的疾病。