GENE EXPRESSION IN MYCOBACTERIUM TUBERCULOSIS

结核病是人类最大的疾病之一，是全世界因单一传染病而死亡的主要原因。尽管结核病的发病率在美国再次开始下降，结核病仍然是这个国家的一个重大健康问题，最常影响老年人、无家可归者、艾滋病患者和来自结核病流行国家的移民。结核病的病原体结核分枝杆菌（Mycobacterium tuberculosis）在世纪前就已被发现，但对结核分枝杆菌的基本生理功能、遗传学和致病机制的了解还很有限。结核病现在才开始出现。我们已经确定了几个基因，表达的M。结核杆菌H37 Rv，当杆菌在培养物中的人巨噬细胞中生长时，其不被杆菌表达，但当它们在实验室肉汤培养物中生长时，其不被杆菌表达。我们推测，这些基因及其产物可能是重要的生存和增长的M。巨噬细胞中的结核病，并可能有助于结核杆菌的致病性。本研究拟（1）确定巨噬细胞表达的特定基因产物对巨噬细胞存活和生长的影响;通过对粘粒上似乎协同表达的基因（一种假定的反应调节基因）和mceD（一种已显示增强E.大肠杆菌在培养的巨噬细胞中的表达;（2）鉴定和表征M.结核分枝杆菌中，在吞噬作用后的早期、晚期以及在培养的人巨噬细胞中的整个生长过程中表达。

Tuberculosis, one of the great scourges of humankind, is the leading cause of death worldwide from a single infectious disease. Although the incidence of TB has again begun to decline in the U.S., TB remains a significant health problem in this country, most frequently affecting the elderly, the homeless, individuals with AIDS and immigrants from nations where TB is endemic. Although the causative agent of TB, Mycobacterium tuberculosis, was identified a century ago, knowledge about fundamental physiological capabilities, the genetics and the mechanisms of pathogenicity of M. tuberculosis is only now beginning to emerge. We have identified several genes which are expressed by M. tuberculosis H37Rv when the bacilli are growing in human macrophages in culture, but which are not expressed by the bacilli when they are growing in laboratory broth culture. We hypothesize that these genes and their products may be important in the survival and growth of M. tuberculosis in macrophages and may contribute to the pathogenicity of the tubercle bacilli. We propose to (1) determine the contribution of specific macrophage-expressed gene products to survival and growth of M. tuberculosis in macrophages by molecular and genetic characterization of genes on a cosmid that appear to be coordinately expressed, a putative response regulator gene, and mceD, a gene that has been shown to enhance survival of E. coli in cultured macrophages; and (2) to identify and characterize genes and gene products of M. tuberculosis that are expressed at early times after phagocytosis, at late times, and throughout growth in human macrophages in culture.