Cross-serotype protection against Streptococcus pneumoniae by induction of neutra

通过中性诱导对肺炎链球菌产生跨血清型保护

• 批准号: 8192027
• 负责人: Edward N Janoff
• 金额: $ 22.95万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8192027
• 关键词: Acute; Adherence; Adult; Alveolar; Alveolar Macrophages; Amino Acids; Antibodies; Archives; Bacteremia; Bacteria; Bacterial Pneumonia; Binding; Cells; Child; Cleaved cell; Complement; Data; Disease; Effectiveness; Enzymes; Epithelial; Epithelial Cells; Failure; Frequencies; Host Defense; Human; IgA-specific serine endopeptidase; IgA1; Immune; Immunocompetent; Immunoglobulin A; Immunoglobulin G; Infection; Mediating; Meningitis; Organism; Pathogenesis; Patients; Peptide Hydrolases; Persons; Phagocytes; Pneumococcal Infections; Pneumonia; Preparation; Proteins; Sampling; Serotyping; Serum; Site; Streptococcus pneumoniae; Structure of respiratory epithelium; Surface; Vaccination; Vaccine Antigen; Vaccines; Virulence Factors; base; capsule; immunogenic; killings; microbial; neutralizing antibody; neutrophil; pressure; prevent; respiratory; response; translational study

DESCRIPTION (provided by applicant): Effective vaccination against Streptococcus pneumoniae, the most common and serious cause of bacterial pneumonia in children and adults, is complicated by the high number of antigenically-distinct capsular serotypes that cause disease. Multiple capsular serotypes must be included in a vaccine, but failure to protect against one is failure of the vaccine. Moreover, disease- and vaccine-associated strains are shifting toward non-vaccine types in response to vaccine pressure. We propose to promote protection against colonization and subsequent invasive disease by S. pneumoniae with an immunogenic protein that is conserved among pneumococcal serotypes. This protein, IgA1 protease (IgA1P), likely contributes to microbial pathogenesis by subverting mucosal host defense. Indeed, we and others have shown that capsule-specific IgA supports killing of S. pneumoniae, and that the IgA1P of S. pneumoniae inhibits such IgA-dependent killing. Moreover, capsule-specific IgA cleaved by the protease enhances adherence to epithelial surfaces by modifying the bacterial surface, which may promote colonization and subsequent disease. In our preliminary studies, adults with pneumococcal bacteremia generated IgG antibodies that neutralize the proteolytic activity of IgA1P. We propose to characterize the diversity of the enzyme and the ability of and mechanisms by which IgG antibodies to IgA1P generated by the host inhibit the enzyme, and block protease-related inhibition of killing and enhancement of adherence. This early translational study will evaluate the feasibility of incorporating IgA1P as a protein vaccine antigen to facilitate cross-serotype protection against S. pneumoniae colonization, pneumonia and invasive disease. PUBLIC HEALTH RELEVANCE: The pneumococcus is the leading cause of bacterial pneumonia worldwide in children and adults. The infection starts in the upper airway where antibodies attempt to bind and inhibit bacterial virulence factors. The bacteria disarm these potentially protective local antibodies by producing an enzyme, IgA1 protease that cuts them in half. We propose to block the activity of IgA1 protease to enhance the effectiveness of local vaccines and of natural host defenses.

描述（由申请人提供）：针对肺炎链球菌的有效疫苗接种是儿童和成人细菌性肺炎最常见和严重的原因，这对引起疾病的抗原脱落囊膜血清型的数量很高。疫苗中必须包括多种囊型血清型，但未能防止一种疫苗是疫苗的失败。此外，疾病和疫苗相关的菌株响应疫苗压力而转向非疫苗类型。我们建议促进肺炎链球菌的侵袭性和随后的侵袭性疾病，其免疫原性蛋白在肺炎球菌血清型中保守。该蛋白质Iga1蛋白酶（IgA1p）可能通过颠覆粘膜宿主防御来导致微生物发病机理。实际上，我们和其他人表明，胶囊特异性IgA支持杀死肺炎链球菌，并且肺炎链球菌的IgA1p抑制了这种IgA依赖性杀害。此外，蛋白酶裂解胶囊特异性的IgA通过修饰细菌表面，从而增强了上皮表面的粘附，这可能促进定殖和随后的疾病。在我们的初步研究中，患有肺炎球菌菌血症的成年人产生了IgG抗体，可中和IgA1p的蛋白水解活性。我们建议表征酶的多样性以及宿主产生的IgA抗体IgG抗体抑制酶的能力和机制，并阻止蛋白酶与蛋白酶相关的抑制对杀害和增强依从性的抑制。这项早期翻译研究将评估将IgA1p作为蛋白质疫苗抗原的可行性，以促进针对肺炎链球菌定殖，肺炎和侵入性疾病的跨色谱保护。 公共卫生相关性：肺炎球菌是全世界细菌肺炎在儿童和成人中的主要原因。感染始于抗体试图结合和抑制细菌毒力因子的上部气道。细菌通过产生一种将它们切成两半的酶来解除这些潜在的保护性局部抗体。我们建议阻止IgA1蛋白酶的活性，以增强局部疫苗和自然宿主防御能力的有效性。