TUBERCULOSIS, HIV AND SURFACTANT APOPROTEINS

描述（改编自申请人摘要）：肺 肺结核仍然是一个严重的世界性问题。 分枝杆菌 结核病（MTB）通过首先吸入 附着并进入肺泡巨噬细胞（AM）的肺泡腔 来生存和复制 MTB将AM用作“安全”的能力 栖息地”是其生存的核心，在最早的阶段， 感染 这个实验室的研究表明， 来自HIV受试者的灌洗液（BAL）含有促进 将MTB连接到AM。 该因子被证明是表面活性蛋白 A（SP-A）。 初步数据表明，SP-D也在HIV感染者中升高。 并且还可以促进MTB附着到AM。 有趣的是，两个 与SP-A和SP-D显著升高相关的疾病包括HIV 疾病和矽肺;这两种情况都与增加 肺结核的风险。 因此，假设：SP-A/SP-D介导 HIV感染者中MTB与AM的附着促进MTB生长 以及在肺泡中的存活率。 本提案的具体目标 包括：1.确定SP-A/SP-D分子位置和特性 与MTB结合; 2. 确定是否：a）SP-A/SP-D介导的MTB附着 在体内对AM的作用损害AM免疫应答和/或促进MTB生长， B）在体内阻断SP-A/SP-D介导的MT B与AM的附着 这些影响表明了因果机制; 3.）确定是否：a） SP-A/SP-D介导的MTB与AM的体内粘附损害AM免疫 响应和/或促进MT B生长和B）预防SP-A/SP-D- MTB与AM的介导的体内连接阻断了这些作用，这表明 因果机制; 4）确定人BAL液如何从正常和 HIV感染个体影响MTB与AM的附着，AM细胞毒性 AM内MTB的反应和生长。 如果成功，这些研究将 导致发展从根本上新的方法来研究 艾滋病毒感染者中的肺结核。 有机会确定 SP-A或SP-D与MTB结合特异性位点可以提供如下见解， 提出了未来新的治疗策略。

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.