H. INFLUENZAE HMW ADHESION PROTEINS IN HOST IMMUNITY

中耳炎和其他疾病引起的非典型流感嗜血杆菌（NTHI）仍然是严重的健康问题，儿童在这个国家和世界其他地方。 该项目的长期目标是确定那些在保护性宿主免疫反应中重要的NTHI表面暴露的细菌抗原，并最终解决由这些抗原组成的疫苗是否能有效预防疾病的问题。 在以前的工作中，我们确定了HMW 1/HMW 2蛋白家族作为自然感染和定植后人血清抗体应答的主要靶点。 此外，我们证明了这些蛋白质在NTHI粘附到真核细胞中的关键作用。 关于这些蛋白质作为疫苗候选物的潜力，我们证明了用HMW 1/HMW 2混合物免疫龙猫提供对由同源菌株引起的实验性NTHI中耳炎的保护。 最后，在我们的初步研究中，我们证明了对HMW 1/HMW 2蛋白家族特异性的成人血清抗体介导对同源和异源菌株的调理吞噬活性。 我们建议在这些早期研究的基础上再接再厉，具体目标如下。 我们将表征针对HMW 1/HMW 2样蛋白产生的抗体对急性NTHI中耳炎儿童恢复期血清中开发的调理吞噬活性的贡献。 我们将绘制那些区域的HMW 1/HMW 2样蛋白，表达的抗体能够介导调理吞噬活性对同源和异源菌株识别的表位。 最后，我们将评估重组蛋白表达的抗体介导的调理吞噬活性对同源和异源菌株识别的表位，以提供对疾病的保护，在实验NTHI中耳炎的灰鼠模型的能力。 从这些研究中获得的知识将为HMW 1/HMW 2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于开发用于预防幼儿中不可分型流感嗜血杆菌中耳炎和其他疾病的疫苗的目标。

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.