Mukherjee Ishita, Chakraborty Abhijit, Chakrabarti Saikat
Structural Biology and Bioinformatics Division, Council for Scientific and Industrial Research (CSIR) - Indian Institute of Chemical Biology (IICB), Kolkata, West Bengal, India.
Parasit Vectors. 2016 Oct 21;9(1):557. doi: 10.1186/s13071-016-1842-5.
An active immune surveillance and a range of barriers to infection allow the host to effectively eliminate microbial pathogens. However, pathogens may use diverse strategies to subdue such host defences. For instance, one such mechanism is the use of leucine-rich repeat (LRR) proteins by pathogens (microbial) to cause infection. In this study, we aimed at identifying novel virulence factor(s) in Leishmania donovani, based on the possibility of lateral gene transfers of bacterial virulence factor(s) to L. donovani.
Rigorous homology searching protocols including Hidden Markov Model (HMM) and BLASTp based searches were employed to detect remote but significant similarities between L. donovani proteins and bacterial virulence factors.
We found that some L. donovani proteins are similar to internalin-A (Inl-A) protein of Listeria monocytogenes, a surface LRR protein that helps mediate host cell invasion by interacting with E-cadherin on the cell membrane. However, to date, no such invasion mechanism has been reported in Leishmania donovani, the causative agent of visceral leishmaniasis. Moreover, a comparative LRR motif analysis of L. donovani Inl-A-like proteins against the Inl-A protein of L. monocytogenes revealed existence of characteristic consensus LRR regions, suggesting a reliable evolutionary relationship between them. Further, through rigorous three dimensional (3D) modeling of L. donovani Inl-A-like proteins and subsequent molecular docking studies we suggest the probability of human E-cadherin binding with the L. donovani Inl-A-like proteins.
We have identified three potential candidates (UniProt ID: E9B7L9, E9BMT7 and E9BUL5) of Inl-A-like LRR containing proteins in L. donovani with the help of systematic whole genome sequence analysis. Thus, herein we propose the existence of a novel class of Inl-A-like virulence factor proteins in L. donovani and other Leishmania species based on sequence similarity, phylogenetic analysis and molecular modelling studies in L. donovani.
活跃的免疫监视和一系列感染屏障使宿主能够有效清除微生物病原体。然而，病原体可能会采用多种策略来战胜此类宿主防御。例如，一种这样的机制是病原体（微生物）利用富含亮氨酸重复序列（LRR）的蛋白质来引发感染。在本研究中，基于细菌毒力因子侧向基因转移至杜氏利什曼原虫的可能性，我们旨在鉴定杜氏利什曼原虫中的新型毒力因子。
采用包括隐马尔可夫模型（HMM）和基于BLASTp的搜索在内的严格同源性搜索协议，以检测杜氏利什曼原虫蛋白质与细菌毒力因子之间遥远但显著的相似性。
我们发现一些杜氏利什曼原虫蛋白质与单核细胞增生李斯特菌的内化素-A（Inl-A）蛋白相似，Inl-A是一种表面LRR蛋白，通过与细胞膜上的E-钙黏蛋白相互作用来帮助介导宿主细胞入侵。然而，迄今为止，在内脏利什曼病的病原体杜氏利什曼原虫中尚未报道过此类入侵机制。此外，对杜氏利什曼原虫Inl-A样蛋白与单核细胞增生李斯特菌的Inl-A蛋白进行的LRR基序比较分析揭示了特征性共有LRR区域的存在，表明它们之间存在可靠的进化关系。进一步地，通过对杜氏利什曼原虫Inl-A样蛋白进行严格的三维（3D）建模以及随后的分子对接研究，我们提出了人E-钙黏蛋白与杜氏利什曼原虫Inl-A样蛋白结合的可能性。
借助系统的全基因组序列分析，我们在杜氏利什曼原虫中鉴定出了三种含Inl-A样LRR的潜在候选蛋白（通用蛋白质数据库编号：E9B7L9、E9BMT7和E9BUL5）。因此，基于杜氏利什曼原虫中的序列相似性、系统发育分析和分子建模研究，我们在此提出在杜氏利什曼原虫及其他利什曼原虫物种中存在一类新型的Inl-A样毒力因子蛋白。
