TUBERCULOSIS, HIV AND SURFACTANT APOPROTEINS

结核病、艾滋病毒和表面活性剂脱辅基蛋白

• 批准号: 6527336
• 负责人: William J Martin
• 金额: $ 31.92万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-10 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6527336
• 关键词: HIV infections; Mycobacterium tuberculosis; alveolar macrophages; bacteria infection mechanism; clinical research; diagnostic respiratory lavage; gene targeting; human immunodeficiency virus; human subject; laboratory mouse; phagocytosis; protein binding; pulmonary surfactants; respiratory protein; secondary infection; tuberculosis

DESCRIPTION (Adapted from the Applicant's Abstract): Pulmonary tuberculosis remains a serious world-wide problem. Mycobacterium tuberculosis (MTB) causes pulmonary infection by first being inhaled into the alveolar spaces where it attaches and enters alveolar macrophages (AM) to survive and replicate. The ability of MTB to use AM as a "safe habitat" is central to its survival during the earliest stages of infection. Studies from this laboratory indicate that bronchoalveolar lavage (BAL) fluid from HIV subjects contains a factor that promotes attachment of MTB to AM. This factor was shown to be surfactant protein A (SP-A). Preliminary data indicate that SP-D is also elevated in the HIV BAL fluid and can also promote MTB attachment to AM. Interestingly, two conditions associated with a marked elevation of SP-A and SP-D include HIV disease and silicosis; both conditions are associated with an increased risk for tuberculosis. Thus, the hypothesis is: SP-A/SP-D mediates attachment of MTB to AM in HIV-infected subjects facilitating MTB growth and survival in the alveolar spaces. The Specific Aims of this proposal include: 1 Determine molecular site(s) and characteristics of SP-A/SP-D binding to MTB; 2. Determine if: a)SP-A/SP-D mediated attachment of MTB to AM in vivo impairs AM immune response and/or facilitates MTB growth and b) prevention of SP-A/SP-D mediated attachment of MTB to AM in vivo blocks these effects suggesting a cause-effect mechanism; 3.) Determine if: a) SP-A/SP-D mediated attachment of MTB to AM in vivo impairs AM immune response and/or facilitates MTB growth and b) prevention of SP-A/SP-D- mediated attachment of MTB to AM in vivo blocks these effects suggesting a cause-effect mechanism; 4) Determine how human BAL fluid from normal and HIV-infected individuals influences MTB attachment to AM, the AM cytotoxic response and growth of MTB inside AM. If successful, these studies will result in the development of fundamentally new approaches to the study of pulmonary tuberculosis in HIV subjects. The opportunity to determine the specific site of SP-A or SP-D binding to MTB may provide insights that suggest novel therapeutic strategies in the future.

描述(改编自申请者摘要)：肺部 结核病仍然是一个严重的世界性问题。分枝杆菌 结核病(MTB)首先被吸入体内，从而导致肺部感染 附着并进入肺泡巨噬细胞(AM)的肺泡腔 以求生存和繁殖。MTB使用AM作为“安全工具”的能力 栖息地“是其在早期阶段生存的核心 感染。该实验室的研究表明，支气管肺泡 HIV患者的灌洗液(BAL)中含有一种促进 将MTB连接到AM这一因子被证明是表面活性蛋白质。 A(SP-A)。初步数据显示，在HIV感染者中，SP-D也升高 BAL液体，还可以促进MTB与AM的附着有趣的是，两个 与SP-A和SP-D显著升高相关的情况包括HIV 疾病和矽肺；这两种情况都与 患肺结核的风险。因此，假设是：SP-A/SP-D在 HIV感染者结核分枝杆菌与AM的附着促进结核分枝杆菌生长 以及在肺泡腔内存活。这项建议的具体目的 包括：1确定SP-A/SP-D分子位置(S)及性质 与结核杆菌的结合；2.确定：A)SP-A/SP-D介导的结核杆菌附着 体内TO AM损害AM免疫反应和/或促进结核分枝杆菌生长和 B)在体内阻断SP-A/SP-D介导的MTB与AM的附着 这些影响暗示了一种因果机制；确定是否：a) SP-A/SP-D介导的MTB与AM的体内黏附损害AM免疫 应对和/或促进结核分支杆菌的增长和b)预防SP-A/SP-D- 体内介导的MTB与AM的附着可阻断这些效应 一个因果机制；4)决定人类BAL液体如何从正常和 HIV感染者影响结核分枝杆菌对AM的附着，AM具有细胞毒性 AM中MTB的反应和成长如果成功，这些研究将 导致了研究的全新方法的发展 HIV感染者中的肺结核。有机会确定 SP-A或SP-D与MTB结合的特定位置可提供以下见解 在未来提出新的治疗策略。