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: 6374609
• 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/6374609
• 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.

中耳炎和由非典型流感嗜血杆菌（NTHI）引起的其他疾病仍然是该国和世界其他地方儿童的重大健康问题。该项目的长期目标是确定在保护性宿主免疫反应中重要的NTHI表面暴露的细菌抗原，并最终解决由此类抗原组成的疫苗是否有效预防疾病的问题。在之前的工作中，我们发现HMW1/HMW2家族蛋白是自然感染和定植后人类血清抗体反应的主要靶点。此外，我们证明了这些蛋白在NTHI粘附真核细胞中的关键作用。关于这些蛋白作为候选疫苗的潜力，我们证明了用HMW1/HMW2混合物免疫龙猫对同源菌株引起的实验性NTHI中耳炎介质具有保护作用。最后，在我们的初步研究中，我们证明了针对HMW1/HMW2蛋白家族的成人血清抗体介导了对同源和异源菌株的调理噬细胞活性。我们建议在这些早期研究的基础上，实现以下具体目标。我们将描述针对HMW1/HMW2样蛋白产生的抗体对急性NTHI中耳炎患儿恢复期血清中调理吞噬细胞活性的贡献。我们将绘制HMW1/ hmw2样蛋白的那些表达表位的区域，这些表位可以被抗体识别，能够介导对同源和异源菌株的调理噬细胞活性。最后，我们将在实验性NTHI中耳炎鼠模型中评估表达抗原表位的重组蛋白的能力，这些重组蛋白可被抗体识别，介导抗同源和异源菌株的抗噬细胞活性。从这些研究中获得的知识将为HMW1/HMW2蛋白抗体在宿主免疫中的作用提供更清晰的图像，并可能使我们更接近开发预防幼儿非分型流感嗜血杆菌中耳炎和其他疾病的疫苗的目标。