H. INFLUENZAE HMW ADHESION PROTEINS IN HOST IMMUNITY

H. 宿主免疫中的流感 HMW 粘附蛋白

• 批准号: 6191055
• 负责人: Stephen J. Barenkamp
• 金额: $ 25.9万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6191055
• 关键词: Haemophilus influenzae; Haemophilus influenzae vaccines; bacteria infection mechanism; bacterial antigens; bactericidal immunity; chinchilla; clinical research; epitope mapping; genetic strain; human tissue; infant human (0-1 year); laboratory mouse; laboratory rabbit; nonhuman therapy evaluation; opsonin; otitis media; preschool child (1-5); recombinant proteins; vaccine development; vector vaccine

Otitis media and other illnesses caused by nontypable Haemophilus influenzae (NTHI) remain significant health problems for children in this country and elsewhere in the world. The long-term objectives of this project are to identify those surface-exposed bacterial antigens of NTHI that are important in a protective host immune response and ultimately to address the question of whether or not a vaccine composed of such antigens would be effective in the prevention of disease. In previous work, we identified the HMW1/HMW2 family of proteins as major targets of the human serum antibody response following natural infection and colonization. Furthermore, we demonstrated a critical role for these proteins in adhesion of NTHI to eukaryotic cells. With respect to the potential of these proteins as vaccine candidates, we demonstrated that immunization of chinchillas with an HMW1/HMW2 mixture provided protection against experimental NTHI otitis media caused by the homologous strain. Finally, in our preliminary studies, we demonstrated that adult human serum antibodies specific for the HMW1/HMW2 family of proteins mediate opsonophagocytic activity against both homologous and heterologous strains. We propose to build on these earlier studies with the following specific aims. We will characterize the contribution of antibodies produced against the HMW1/HMW2- like proteins to the opsonophagocytic activity that develops in convalescent sera of children with acute NTHI otitis media. We will map those regions of the HMW1/HMW2-like proteins that express epitopes recognized by antibody capable of mediating opsonophagocytic activity against both homologous and heterologous strains. Finally, we will assess the ability of recombinant proteins that express epitopes recognized by antibodies mediating opsonophagocytic activity against homologous and heterologous strains to provide protection against disease in the chinchilla model of experimental NTHI otitis media. The knowledge gained from these studies will provide a clearer picture of the role of antibody to the HMW1/HMW2 proteins in host immunity and may move us closer to the goal of developing vaccines for prevention of nontypable Haemophilus influenzae otitis media and other diseases in young children.

对于这个国家和世界其他地方的儿童，由不可抑制的血液流感（NTHI）引起的中耳炎和其他疾病仍然是重大健康问题。 该项目的长期目标是确定在保护性宿主免疫反应中很重要的表面暴露的细菌抗原，并最终解决了该抗原疫苗是否有效的问题，可有效预防疾病。 在先前的工作中，我们将HMW1/HMW2蛋白质家族定为自然感染和定殖后人血清抗体反应的主要靶标。 此外，我们证明了这些蛋白质在NTHI对真核细胞的粘附中的关键作用。 关于这些蛋白作为候选疫苗的潜力，我们证明了用HMW1/HMW2混合物对龙猫进行免疫，为同源菌株引起的实验性NTHI耳炎提供了保护。 最后，在我们的初步研究中，我们证明了针对HMW1/HMW2蛋白质家族特异性的成年人类血清抗体，可介导对同源和异源性菌株的调查性毒素活性。 我们建议以以下特定目标在这些早期的研究基础上进行。 我们将表征针对HMW1/HMW2的蛋白质产生的抗体的贡献，这些蛋白质对急性NTHI耳炎培养基的疗养血清中产生的脑化古细胞活性。 我们将绘制HMW1/HMW2样蛋白的那些区域，这些蛋白表达表达能够介导对同源性和异源菌株的op子吞噬活性的抗体识别的表位。 最后，我们将评估通过介导对同源性和异源菌株介导的脑化古细胞活性识别的表达表达表现的重组蛋白的能力，以在实验性NTHI耳炎培养基的龙猫模型中提供保护疾病。 从这些研究中获得的知识将更清楚地了解抗HMW1/HMW2蛋白在宿主免疫中的作用，并可能使我们更接近开发疫苗以预防幼儿中预防不可抑制的嗜血型流感眼球炎和其他疾病的疫苗。