Neutralizing the GBS hemolytic lipid toxin

中和 GBS 溶血脂质毒素

• 批准号: 10647649
• 负责人: Lakshmi Rajagopal
• 金额: $ 82.33万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 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/10647649
• 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 Structure; Hemolysin; Hemolysis; Human; Immune; Immune Sera; Immunity; Immunization; Immunocompromised Host; Infection; Injury; Integration Host Factors; Intellectual functioning disability; Lipids; Macrophage; 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; aspirate; chemical synthesis; cytotoxic; diabetic; experimental study; human morbidity; human mortality; immunogenicity; improved; in utero; in vivo; in vivo Model; inhibiting antibody; 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

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 由于细菌感染导致的人类发病率和死亡率仍然是重大的公共卫生问题。 B族链球菌（GBS）或无乳链球菌在妊娠期间引起侵袭性感染 导致早产、死产或新生儿感染。此外，GBS也会导致 正常、老年、糖尿病和免疫功能低下的成年人。我们的研究表明，溶血素， GBS感染的关键毒力因子是着色的鸟氨酸鼠李糖脂，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后果， 成年人这项提案的目的是确定其他无毒类似物，可以防止毒素 使用小鼠感染模型在GBS感染期间的功能，以阐明宿主免疫机制 对于类似物介导的针对该GBS毒素的免疫重要的是，确定膜囊泡如何 加重GBS发病机制，以及抗体是否可以减弱其作用。总的来说，这些结果 目标对于预防人类GBS感染将是重要和相关的，并且将与其他目标相关。 病原体编码有毒脂质引起的疾病。