The aerobic, Gram-negative motile bacillus, Burkholderia pseudomallei is a facultative intracellular bacterium causing melioidosis, a critical disease of public health importance, which is widely endemic in the tropics and subtropical regions of the world. Melioidosis is associated with high case fatality rates in animals and humans; even with treatment, its mortality is 20-50%. It also infects plants and is designated as a biothreat agent. B. pseudomallei is pathogenic due to its ability to invade, resist factors in serum and survive intracellularly. Despite its importance, to date only a few effector proteins have been functionally characterized, and there is not much information regarding the host-pathogen protein-protein interactions (PPI) of this system, which are important to studying infection mechanisms and thereby develop prevention measures. We explored two computational approaches, the homology-based interolog and the domain-based method, to predict genome-scale host-pathogen interactions (HPIs) between two different strains of B. pseudomallei (prototypical, and highly virulent) and human. In total, 76 335 common HPIs (between the two strains) were predicted involving 8264 human and 1753 B. pseudomallei proteins. Among the unique PPIs, 14 131 non-redundant HPIs were found to be unique between the prototypical strain and human, compared to 3043 non-redundant HPIs between the highly virulent strain and human. The protein hubs analysis showed that most B. pseudomallei proteins formed a hub with human dnaK complex proteins associated with tuberculosis, a disease similar in symptoms to melioidosis. In addition, drug-binding and carbohydrate-binding mechanisms were found overrepresented within the host-pathogen network, and metabolic pathways were frequently activated according to the pathway enrichment. Subcellular localization analysis showed that most of the pathogen proteins are targeting human proteins inside cytoplasm and nucleus. We also discovered the host targets of the drug-related pathogen proteins and proteins that form T3SS and T6SS in B. pseudomallei. Additionally, a comparison between the unique PPI patterns present in the prototypical and highly virulent strains was performed. The current study is the first report on developing a genome-scale host-pathogen protein interaction networks between the human and B. pseudomallei, a critical biothreat agent. We have identified novel virulence factors and their interacting partners in the human proteome. These PPIs can be further validated by high-throughput experiments and may give new insights on how B. pseudomallei interacts with its host, which will help medical researchers in developing better prevention measures.

中文翻译：

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类鼻疽病原体伯克霍尔德氏菌和人类中宿主-病原体蛋白质相互作用的计算机预测揭示了新的毒力因子及其靶标。

需氧、革兰氏阴性运动杆菌、假鼻疽伯克霍尔德氏菌是一种兼性细胞内细菌，可引起类鼻疽，一种对公共卫生具有重要意义的严重疾病，在世界热带和亚热带地区广泛流行。类鼻疽与动物和人类的高病死率有关；即使进行治疗，其死亡率仍为20-50%。它还感染植物并被指定为生物威胁剂。B. 假鼻疽是致病性的，因为它能够侵入、抵抗血清中的因子并在细胞内存活。尽管它很重要，但迄今为止只有少数效应蛋白已被功能表征，并且关于该系统的宿主 - 病原体蛋白质 - 蛋白质相互作用（PPI）的信息并不多，这对于研究感染机制并制定预防措施很重要。我们探索了两种计算方法，即基于同源性的 interolog 和基于域的方法，以预测假鼻疽芽孢杆菌（原型和高毒力）和人类的两种不同菌株之间的基因组规模宿主-病原体相互作用 (HPI)。总共预测了 76 335 种常见 HPIs（两种菌株之间），涉及 8264 种人和 1753 种假鼻疽芽孢杆菌蛋白。在独特的 PPI 中，发现 14 131 个非冗余 HPI 在原型菌株和人类之间是独特的，而在高毒力菌株和人类之间则有 3043 个非冗余 HPI。蛋白质中心分析表明，大多数假鼻疽芽孢杆菌蛋白与与结核病相关的人类 dnaK 复合蛋白形成了一个中心，一种症状与类鼻疽相似的疾病。此外，发现宿主-病原体网络中的药物结合和碳水化合物结合机制过多，并且代谢途径经常根据途径富集被激活。亚细胞定位分析表明，大多数病原体蛋白质都针对细胞质和细胞核内的人类蛋白质。我们还发现了与药物相关的病原体蛋白质以及在假鼻疽芽孢杆菌中形成 T3SS 和 T6SS 的蛋白质的宿主靶点。此外，还对原型菌株和高毒菌株中存在的独特 PPI 模式进行了比较。目前的研究是关于在人类和假鼻疽芽孢杆菌（一种关键的生物威胁剂）之间开发基因组规模的宿主-病原体蛋白质相互作用网络的第一份报告。我们已经确定了人类蛋白质组中的新型毒力因子及其相互作用的伙伴。这些 PPI 可以通过高通量实验进一步验证，并可能对假鼻疽芽孢杆菌如何与其宿主相互作用提供新的见解，这将有助于医学研究人员制定更好的预防措施。