Cui Tao, Li Weihui, Liu Lei, Huang Qiaoyun, He Zheng-Guo
National Key Laboratory of Microbiology, Huazhong Agricultural University, Wuhan, 430070, China.
PLoS One. 2016 Jan 22;11(1):e0147612. doi: 10.1371/journal.pone.0147612. eCollection 2016.
Pathogens usually evade and manipulate host-immune pathways through pathogen-host protein-protein interactions (PPIs) to avoid being killed by the host immune system. Therefore, uncovering pathogen-host PPIs is critical for determining the mechanisms underlying pathogen infection and survival. In this study, we developed a computational method, which we named pairwise structure similarity (PSS)-PPI, to predict pathogen-host PPIs. First, a high-quality and non-redundant structure-structure interaction (SSI) template library was constructed by exhaustively exploring heteromeric protein complex structures in the PDB database. New interactions were then predicted by searching for PSS with complex structures in the SSI template library. A quantitative score named the PSS score, which integrated structure similarity and residue-residue contact-coverage information, was used to describe the overall similarity of each predicted interaction with the corresponding SSI template. Notably, PSS-PPI yielded experimentally confirmed pathogen-host PPIs of human immunodeficiency virus type 1 (HIV-1) with performance close to that of in vitro high-throughput screening approaches. Finally, a pathogen-host PPI network of human pathogen Mycobacterium tuberculosis, the causative agent of tuberculosis, was constructed using PSS-PPI and refined using filtration steps based on cellular localization information. Analysis of the resulting network indicated that secreted proteins of the STPK, ESX-1, and PE/PPE family in M. tuberculosis targeted human proteins involved in immune response and phagocytosis. M. tuberculosis also targeted host factors known to regulate HIV replication. Taken together, our findings provide insights into the survival mechanisms of M. tuberculosis in human hosts, as well as co-infection of tuberculosis and HIV. With the rapid pace of three-dimensional protein structure discovery, the SSI template library we constructed and the PSS-PPI method we devised can be used to uncover new pathogen-host PPIs in the future.
病原体通常通过病原体与宿主的蛋白质-蛋白质相互作用（PPI）来逃避和操纵宿主免疫途径，以避免被宿主免疫系统杀死。因此，揭示病原体与宿主的PPI对于确定病原体感染和存活的潜在机制至关重要。在本研究中，我们开发了一种计算方法，命名为成对结构相似性（PSS）-PPI，用于预测病原体与宿主的PPI。首先，通过详尽探索蛋白质数据银行（PDB）数据库中的异源蛋白复合物结构，构建了一个高质量且无冗余的结构-结构相互作用（SSI）模板库。然后，通过在SSI模板库中搜索与复杂结构的PSS来预测新的相互作用。一个名为PSS分数的定量评分，整合了结构相似性和残基-残基接触覆盖信息，用于描述每个预测相互作用与相应SSI模板的整体相似性。值得注意的是，PSS-PPI产生了经实验证实的1型人类免疫缺陷病毒（HIV-1）与宿主的PPI，其性能与体外高通量筛选方法相近。最后，使用PSS-PPI构建了人类病原体结核分枝杆菌（结核病的病原体）与宿主的PPI网络，并基于细胞定位信息通过过滤步骤进行了优化。对所得网络的分析表明，结核分枝杆菌中丝氨酸/苏氨酸蛋白激酶（STPK）、ESX-1和PE/PPE家族的分泌蛋白靶向参与免疫反应和吞噬作用的人类蛋白。结核分枝杆菌还靶向已知调节HIV复制的宿主因子。综上所述，我们的研究结果为结核分枝杆菌在人类宿主中的存活机制以及结核病和HIV的合并感染提供了见解。随着三维蛋白质结构发现的快速发展，我们构建的SSI模板库和设计的PSS-PPI方法未来可用于揭示新的病原体与宿主的PPI。
