Genomic and immunological comparisons of M africanum and M tuberculosis

描述(申请者提供)：在获得首届国际研究发展奖期间，De Jong博士于2003年移居冈比亚。她的目的是确定特别适合传播和空化的结核分枝杆菌菌株；然而，非洲分枝杆菌和结核分枝杆菌的偶然分裂使她能够比较结核分枝杆菌复合体中两个在系统发育上截然不同的成员之间的传播、空化和其他表型。分析表明：1)感染和接触非洲支原体的患者对早期分泌抗原6(ESAT-6)的免疫反应迟钝，这与非洲支原体的发展有关 2)非洲支原体在HIV感染者中更普遍，这表明非洲支原体是一种更具机会性的感染；3)非洲支原体在2年的随访中不太可能在家庭接触者中发展为疾病。这些观察结果导致德容博士推测，与结核分枝杆菌相关的遗传差异导致非洲分枝杆菌从感染到疾病的能力减弱，而这种能力因逃避免疫反应而增强，这一点得到了补偿。反过来，她假设非洲分枝杆菌的潜伏感染提供了一定程度的免疫接种，以对抗结核分枝杆菌疾病。她现在建议通过对基因组和体外差异的研究来检验这些假说 转录组，以及在结核病病例及其家庭接触者中使用非洲分枝杆菌和结核分枝杆菌特异性抗原的免疫学研究。此外，她计划更详细地描述对非洲分枝杆菌和结核分枝杆菌的免疫反应。考虑到艾滋病毒/结核病的混合感染，她将把冈比亚和几内亚比绍艾滋病毒患者在抗结核治疗前后的CD4计数与他们痰中培养的分枝杆菌基因相关联。这将证明非洲支原体的疾病是在较低的CD4计数下发生，还是仅仅是免疫抑制程度更高。非洲分枝杆菌感染为了解结核分枝杆菌感染提供了一个重要的模型。结合来自全序列的信息，在活动性感染中优先表达的基因，以及免疫流行病学数据，可能会导致对结核分枝杆菌感染的发病机制的重要见解，这与加强我们诊断和控制这种疾病的工具有关。结核病是由一组相关细菌引起的，其中一种在西非非常常见。这项拟议的研究试图解释为什么这种名为非洲分枝杆菌的细菌在艾滋病毒感染者中更常见，以及为什么一种新的诊断测试在这种类型的结核病患者中效果不佳。

DESCRIPTION (provided by applicant): During the first International Research Development Award, Dr. de Jong moved to the Gambia in 2003. Her intention was to identify M. tuberculosis strains particularly well suited for transmission and cavitation; however a fortuitous split between M. africanum and M. tuberculosis allowed her to compare transmission, cavitation, and other phenotypes between two phylogenetically distinct members of the M. tuberculosis complex. This analysis showed that 1) both patients infected with and contacts of M. africanum have a blunted immune responses to Early Secretory Antigen 6 (ESAT-6),which has relevance to the development of diagnostic tests and vaccines; 2) M. africanum is more prevalent in HIV infected people, suggesting M. africanum behaves as a more opportunistic infection, 3) M. africanum is less likely to progress to disease in household contacts during the 2 year follow-up. These observations led Dr. de Jong to hypothesize that genetic differences relative to M. tuberculosis result in M. africanum's weakened ability to progress from infection to disease, and that this is compensated by increased persistence due to evasion of the immune response. In turn, she hypothesizes that latent infection with M. africanum provides a degree of immunization against disease with M. tuberculosis. She now proposes to test these hypotheses with studies on differences in the genome and ex vivo transcriptome, as well as immunological studies using antigens specific to M. africanum and M. tuberculosis in TB cases and their household contacts. Moreover, she plans to characterize the immune response to M. africanum and M. tuberculosis in more detail. Looking at HIV/TB co-infection, she will correlate the CD4 counts of HIV patients in the Gambia and Guinea- Bissau before and after antitubercular therapy with the mycobacterial genotype cultured from their sputum. This will demonstrate if disease with M. africanum occurs at lower CD4 counts or if it is simply more immunosuppressive. M. africanum infection provides an important model for understanding M. tuberculosis infections. Combining information from the full sequences, the genes preferentially expressed in active infection, and the immuno-epidemiologic data will likely lead to important insights into the pathogenesis of M. tuberculosis infection with relevance to enhancing our tools for the diagnosis and control of this disease. Tuberculosis is caused by any of a group of related bacteria, one of which is very common in West-Africa. The proposed research tries to explain why this bacterium, M. africanum, is more common in HIV infected people, and why a new diagnostic test does not work as well in people with this type of tuberculosis.