Wareham Alice S, Tree Julia A, Marsh Philip D, Butcher Philip D, Dennis Mike, Sharpe Sally A
Public Health England, Microbiology Services, Porton Down, Salisbury, United Kingdom.
Department of Medical Microbiology, St. George's Hospital Medical School, London, United Kingdom.
PLoS One. 2014 Feb 4;9(2):e88149. doi: 10.1371/journal.pone.0088149. eCollection 2014.
Tuberculosis (TB) remains a major global public health problem. The only vaccine, BCG, gives variable protection, especially in adults, so several new vaccines are in clinical trials. There are no correlates of protective immunity to TB; therefore vaccines progress through lengthy and expensive pre-clinical assessments and human trials. Correlates of protection could act as early end-points during clinical trials, accelerating vaccine development and reducing costs. A genome-wide microarray was utilised to identify potential correlates of protection and biomarkers of disease induced post-BCG vaccination and post-Mycobacterium tuberculosis challenge in PPD-stimulated peripheral blood mononuclear cells from cynomolgus macaques where the outcome of infection was known. Gene expression post BCG-vaccination and post challenge was compared with gene expression when the animals were naïve. Differentially expressed genes were identified using a moderated T test with Benjamini Hochberg multiple testing correction. After BCG vaccination and six weeks post-M. tuberculosis challenge, up-regulation of genes related to a Th1 and Th17 response was observed in disease controllers. At post-mortem, RT-PCR revealed an up-regulation of iron regulatory genes in animals that developed TB and down-regulation of these genes in disease controllers, indicating the ability to successfully withhold iron may be important in the control of TB disease. The induction of a balanced Th1 and Th17 response, together with expression of effector cytokines, such as IFNG, IL2, IL17, IL21 and IL22, could be used as correlates of a protective host response.
结核病仍然是一个重大的全球公共卫生问题。唯一的疫苗卡介苗提供的保护效果不一,尤其是在成年人中,因此几种新疫苗正在进行临床试验。目前尚无针对结核病的保护性免疫相关指标;因此,疫苗要经过漫长且昂贵的临床前评估和人体试验。保护性相关指标可作为临床试验中的早期终点,加速疫苗研发并降低成本。利用全基因组微阵列来识别来自食蟹猕猴的经PPD刺激的外周血单核细胞中卡介苗接种后和结核分枝杆菌攻击后诱导的疾病的潜在保护性相关指标和生物标志物,这些猕猴的感染结果是已知的。将卡介苗接种后和攻击后的基因表达与动物未接触病原体时的基因表达进行比较。使用带有Benjamini Hochberg多重检验校正的适度t检验来识别差异表达基因。在卡介苗接种后以及结核分枝杆菌攻击六周后,在疾病控制者中观察到与Th1和Th17反应相关的基因上调。在尸检时,RT-PCR显示患结核病的动物中铁调节基因上调,而在疾病控制者中这些基因下调,这表明成功保留铁元素的能力可能对结核病的控制很重要。诱导平衡的Th1和Th17反应,以及效应细胞因子如IFNG、IL2、IL17、IL21和IL22的表达,可作为宿主保护性反应的相关指标。