Profiling proteome-scale antibody responses to M. tuberculosis proteins in sera of macaques infected with M. tuberculosis

Human infection with Mycobacterium tuberculosis results in a continuum of ill-defined, clinical manifestations with stable latent M. tuberculosis infection (LTBI) and severe active disease at the ends. Identifying different states of infection is of importance to tuberculosis (TB) control since risk of developing active disease varies among different asymptomatic states while infectiousness varies among patients with different bacterial burden. We investigated changes in proteome-scale antibody responses during disease progression in a non-human primate model of tuberculosis. We probed M. tuberculosis proteome microarrays with serial sera collected from three infection-outcome groups (active, reactivation, and latent). We found that each infection outcome is associated with characteristic changes in the antibody levels and number of antigenic targets, which suggested an association between antibody responses and bacillary burden. Additional proteome-scale serological profiling of > 400 human TB suspects established that antibody responses are positively associated with bacterial load. Thus tuberculosis-specific antibody levels and number of antigenic targets increases with disease progression. To investigate antibody responses during the course of infection, we probed M. tuberculosis proteome microarrays with serial sera collected from experimentally infected cynomolgus macaques. Based on infection outcome, the macaques were grouped into three classes; A) active disease (n = 4), B) latent infection (n=5) and C) reactivation disease (n = 5). Note that the macaques in the reactivation class developed signs of disease spontaneously without any experimental intervention. For each animal, we tested one pre-infection time point and approximately ten post-infection time points at one-month intervals.

结核分枝杆菌（Mycobacterium tuberculosis）感染人体后，会引发一系列表现各异的临床症状谱，两端分别为稳定的潜伏性结核分枝杆菌感染（LTBI）与严重的活动性结核病。明确感染的不同状态对于结核病（TB）防控至关重要：不同无症状感染状态下，进展为活动性疾病的风险存在差异；而不同菌负荷患者的传染性也各不相同。本研究针对结核病非人灵长类动物模型，探究了疾病进展过程中蛋白质组层面的抗体应答变化。我们使用从三类感染结局组（活动性感染、复发感染与潜伏感染）中收集的系列血清，对结核分枝杆菌蛋白质组芯片进行了检测。研究发现，每一类感染结局均与抗体水平及抗原靶标数量的特征性变化相关，这提示抗体应答与菌负荷存在关联。对400余名结核病疑似患者开展的额外蛋白质组血清学分析证实，抗体应答与细菌负荷呈正相关。因此，结核病特异性抗体水平及抗原靶标数量会随疾病进展而升高。为探究感染过程中的抗体应答情况，我们使用实验感染食蟹猴的系列血清，对结核分枝杆菌蛋白质组芯片进行了检测。根据感染结局，食蟹猴被分为三类：A）活动性疾病组（n=4）、B）潜伏感染组（n=5）以及C）复发疾病组（n=5）。需注意：复发疾病组的食蟹猴未接受任何实验干预，自发出现了疾病症状。针对每只实验动物，我们检测了1个感染前时间点的样本，以及约10个感染后按月采集的时间点样本。