Antibody profiles characteristic of tuberculosis state

描述(申请人提供)：大量证据支持宿主获得性免疫的表达可能导致结核分枝杆菌进入休眠状态，从而建立潜伏感染。随后免疫反应的损害可以使结核杆菌恢复繁殖并导致重新激活的疾病。我们观察到，在人类中，与活动性疾病相关的抗体谱与与潜伏感染相关的抗体谱不同。我们还发现，在小鼠中，宿主免疫的表达伴随着生长速度的明显变化和编码免疫优势抗原的细菌基因转录的变化。综上所述，这些数据导致了一种假设，即抗体谱在人类感染期间发生变化，可能与宿主免疫状态发生的细菌抗原组成变化有关。如果这一假设是正确的，抗体谱的变化可以成为细菌抗原变化和感染结局的间接标志。对这一假设的初步测试将在南非开普敦的一个地区进行，该地区的特点是结核病发病率高，艾滋病毒流行率相对较低。已经从四个诊断组的人那里获得了血清：活动性结核病、有和没有胸部X光异常的潜伏性结核分枝杆菌感染，以及未感染的对照组。提出了两个目标。首先，已建立的高通量方法将被用来产生一种适合血清学筛查的结核分枝杆菌200蛋白质微阵列芯片。其次，通过从上述四个诊断组中筛选带有血清的蛋白质微阵列，将识别出最具结核病状态特征的抗体图谱。这些抗体谱将与未来同一研究领域的纵向研究中结核分枝杆菌感染的结果相关。拟议的工作将导致确定进展为活动性结核病的血清学标志，这些标志在活动性疾病的临床或细菌学标志之前可被检测到。

DESCRIPTION (provided by applicant): A large body of evidence supports the idea that expression of host adaptive immunity may cause Mycobacterium tuberculosis to enter a dormant state that establishes latent infection. Subsequent impairment of the immune response can allow tubercle bacilli to resume multiplication and cause reactivation disease. We have observed that in humans the antibody profile associated with active disease differs from that associated with latent infection. We have also found that in mice expression of host immunity is accompanied by an apparent change in growth rate and by changes in transcription of bacterial genes encoding immunodominant antigens. Together, these data lead to the hypothesis that antibody profiles vary during human infection, presumably in relation to changes of bacterial antigen composition occurring in response to host immune status. If this hypothesis is correct, changes in antibody profiles can be an indirect marker of bacterial antigen change and infection outcome. An initial test of the hypothesis will be conducted in an area of Cape Town, South Africa characterized by high tuberculosis prevalence and relatively low HIV prevalence. Sera have already been obtained from persons in four diagnostic groups: active tuberculosis, latent M. tuberculosis infection with and without chest X-ray abnormalities, and uninfected controls. Two aims are proposed. First, established, high-throughput methods will be used to generate a >200-protein microarray chip of M. tuberculosis suited for serological screens. Second, antibody profiles most characteristic of tuberculosis state will be identified by screening the protein microarray with sera from the four, above-defined diagnostic groups. Those antibody profiles will be correlated with outcome of M. tuberculosis infection in future, longitudinal studies in the same study area. The proposed work will lead to identifying serological markers of progression to active tuberculosis that are detectable before clinical or bacteriological markers of active disease.