MUCOSAL IMMUNITY AND INFECTION

大多数感染涉及粘膜，要么作为实际的感染部位 感染或作为进入身体的门户。此计划项目 旨在调查这一疾病的性质、意义和预防措施 黏膜免疫反应对感染性疾病的治疗潜力 病原体。总体目标是加深对以下方面的了解： 免疫球蛋白A介导的防御机制及被动治疗效果 接种特异性IgA抗体，开发新的疫苗 预防选定的粘膜感染和某些免疫病理 粘膜免疫反应对感染的并发症。这项研究， 由具有基础科学和临床知识的研究人员进行 背景，将处理呼吸道感染和 由病毒、细菌和原生动物引起的胃肠道。这个 四个项目将侧重于重要人类疾病的动物模型和 粘膜IgA抗体在宿主防御中的作用。相关的人类 疾病有阿米巴病、幽门螺杆菌胃炎(被认为占大多数 消化性溃疡疾病)，以及与粘膜病毒相关的疾病 感染，包括IgA肾病。而传统的保护性 黏膜免疫球蛋白A的功能被认为是一种免疫排斥 屏障，一种基于体外研究的新提出的功能，即 中和粘膜上皮细胞内的病毒，现在将是 活体研究。第一个项目是阿米巴病，试图利用 有希望成为疫苗候选者的溶组织埃希氏菌成分 抗原，尤其是一种半乳糖抑制的黏附蛋白 对发病机制至关重要。这项研究将利用一种新的 恒河猴肠道阿米巴病模型。第二个项目，关于 幽门螺杆菌引起的胃炎也将调查有希望的候选对象 疫苗抗原，包括尿素酶。这项研究将利用 最近建立的无菌小鼠感染猫链球菌的模型。在 第三个项目，IgA抗体中和病毒的能力 细胞内研究将用于呼吸道感染和 肝脏。对于呼吸道感染，仙台病毒，一种天然的病原体 小鼠和导致人类感染的副流感病毒的近亲 呼吸道疾病，将使用；肝炎的研究将使用 小鼠肝炎病毒，一种类似于人类冠状病毒的冠状病毒。 IgA单抗对病毒的细胞内中和作用 重症联合感染患者气管上皮细胞和肝细胞的检测 免疫缺陷(SCID)小鼠。自IgA肾病以来，最常见的形式 肾小球肾炎，与上呼吸道暂时相关 疾病，第四个项目将寻求开发一种小鼠模型， 由呼吸道病毒(仙台)感染诱导，并模仿 人类疾病的本质。感染的这些特征和 导致IgA免疫复合体在体内沉积的宿主反应 并将肾炎和肾炎进行鉴别。

Most infections involve mucous membranes, either as the actual site of infection or as the portal of entry into the body. This Program Project is designed to investigate the nature, significance, and prophylactic and therapeutic potential of the mucosal immune response to infectious pathogens. The overall goals are to gain increasing insights into: mechanisms of defense mediated by IgA, therapeutic efficacy of passive administration of specific IgA antibody, development of new vaccines to prevent selected mucosal infections, and certain immunopathological complications of the mucosal immune response to infection. The research, to be performed by investigators with both basic science and clinical backgrounds, will deal with infections of the respiratory and gastrointestinal tracts caused by viruses, bacteria, and protozoa. The four projects will focus on animal models of important human diseases and the role of mucosal IgA antibodies in host defense. The relevant human diseases are amebiasis, H. pylori gastritis (thought to account for most cases of peptic ulcer disease), and diseases associated with mucosal viral infection, including IgA nephropathy. While the traditional protective function of mucosal IgA has been considered to act as an immune exclusion barrier, a newly proposed function based on studies in vitro, namely neutralization of viruses inside mucosal epithelial cells, will now be investigated in vivo. The first project, on amebiasis, seeks to exploit components of E. histolytica that are promising candidates for vaccine antigens, notably a galactose-inhibitable adherence protein that is critical to pathogenesis. This research will take advantage of a new baboon model of intestinal amebiasis. The second project, on Helicobacter-induced gastritis, will also investigate promising candidate vaccine antigens, including urease. The research will exploit the recently available model of H. felis infection of germ-free mice. In the third project, the ability of IgA antibodies to neutralize viruses intracellularly will be studied in infections of the respiratory tract and liver. For respiratory infection, Sendai virus, a natural pathogen of mice and a close relative of the parainfluenza viruses that cause human respiratory illnesses, will be used; the studies in hepatitis will employ mouse hepatitis virus, a coronavirus similar to human coronaviruses. Intracellular neutralization of virus by IgA monoclonal antibodies will be assessed in tracheal epithelial cells and hepatocytes in severe combined immunodeficient (SCID) mice. Since IgA nephropathy, the most common form of glomerulonephritis, is associated temporally with upper respiratory illness, the fourth project will seek to develop a mouse model that is induced by a respiratory viral (Sendai) infection and that mimics the essentials of the human disease. Those features of the infection and of the host response that lead to deposition of IgA immune complexes in the kidney and to nephritis will identified.