Qian Xu, Nguyen Duc T M, Li Yaojun, Lyu Jianxin, Graviss Edward A, Hu Tony Y
Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, 77030, USA; Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, Wenzhou Medical University, Wenzhou, 325035, PR China.
HMRI Molecular Tuberculosis Laboratory, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Houston, TX, 77030, USA.
Tuberculosis (Edinb). 2016 Dec;101S:S109-S118. doi: 10.1016/j.tube.2016.09.022. Epub 2016 Sep 28.
There is an urgent need for methods that can rapidly and accurately assess therapeutic responses in patients with active tuberculosis (TB) in order to predict treatment outcomes. Exposure to bacterial pathogens can rapidly activate the plasma contact system, triggering the release of bradykinin (BK) and its metabolite desArg-bradykinin (DABK) to induce inflammation and innate immune responses. We hypothesized that serum BK and DABK levels might act as sensitive immune response signatures for changes in Mycobacterium tuberculosis (Mtb) burden, and therefore examined how serum levels of these markers corresponded with anti-TB therapy in a small cohort of active TB cases.
Nanotrap Mass-Spectrometry (MS) was used to analyze serial blood specimens from 13 HIV-negative adults with microbiologically confirmed active TB who were treated with first-line anti-TB chemotherapy. MS signal for BK (m/z 1060.5) and DABK (m/z 904.5) serum peptides were evaluated at multiple time-points (before, during, and after treatment) to evaluate how BK and DABK levels corresponded with disease status.
Serum BK levels declined from pretreatment baseline levels during the early stage anti-TB therapy (induction phase) and tended to remain below baseline levels during extended treatment (consolidation phase) and after therapy completion. BK levels were consistent with induction phase sputum culture conversions indicative of decreased Mtb burden reflecting good treatment responses. Serum DABK levels tended to increase during the induction phase and decrease at consolidation and post-therapy time points, which may indicate a shift from active disease to chronic inflammation to a disease free state. Elevated BK and DABK levels after treatment completion in one patient may be related to the subsequent recurrent TB disease.
Our pilot data suggests that changes in the circulating BK and DABK levels in adult TB patients can be used as potential surrogate markers of the host response both early and late in anti-TB treatment for both pulmonary and extrapulmonary TB patients. We will further exploit these host-response signatures in the future as biomarkers in combination with other clinical and microbiologic tools which may improve treatment efficacy and facilitate the development of host-directed therapy.
迫切需要能够快速、准确评估活动性肺结核（TB）患者治疗反应的方法，以预测治疗结果。接触细菌病原体可迅速激活血浆接触系统，触发缓激肽（BK）及其代谢产物去精氨酸缓激肽（DABK）的释放，从而诱导炎症和固有免疫反应。我们推测血清BK和DABK水平可能作为结核分枝杆菌（Mtb）负荷变化的敏感免疫反应标志物，因此在一小群活动性肺结核病例中研究了这些标志物的血清水平与抗结核治疗的相关性。
采用纳米陷阱质谱（MS）分析13例经微生物学确诊为活动性肺结核的HIV阴性成人患者的系列血标本，这些患者接受一线抗结核化疗。在多个时间点（治疗前、治疗期间和治疗后）评估BK（m/z 1060.5）和DABK（m/z 904.5）血清肽的MS信号，以评估BK和DABK水平与疾病状态的相关性。
在抗结核治疗早期（诱导期），血清BK水平从治疗前基线水平下降，在延长治疗期（巩固期）及治疗结束后往往维持在基线水平以下。BK水平与诱导期痰培养转阴一致，表明Mtb负荷降低，反映出良好的治疗反应。血清DABK水平在诱导期趋于升高，在巩固期和治疗后时间点降低，这可能表明从活动性疾病向慢性炎症再到无病状态的转变。一名患者治疗结束后BK和DABK水平升高可能与随后的结核病复发有关。
我们的初步数据表明，成人肺结核患者循环中BK和DABK水平的变化可作为肺内和肺外结核病患者抗结核治疗早期和晚期宿主反应的潜在替代标志物。未来，我们将进一步利用这些宿主反应标志物作为生物标志物，结合其他临床和微生物学工具，这可能会提高治疗效果并促进宿主导向治疗的发展。
