Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
Chin Med J (Engl). 2023 Apr 5;136(7):767-779. doi: 10.1097/CM9.0000000000002621.
Alternative splicing (AS) is an evolutionarily conserved mechanism that removes introns and ligates exons to generate mature messenger RNAs (mRNAs), extremely improving the richness of transcriptome and proteome. Both mammal hosts and pathogens require AS to maintain their life activities, and inherent physiological heterogeneity between mammals and pathogens makes them adopt different ways to perform AS. Mammals and fungi conduct a two-step transesterification reaction by spliceosomes to splice each individual mRNA (named cis -splicing). Parasites also use spliceosomes to splice, but this splicing can occur among different mRNAs (named trans -splicing). Bacteria and viruses directly hijack the host's splicing machinery to accomplish this process. Infection-related changes are reflected in the spliceosome behaviors and the characteristics of various splicing regulators (abundance, modification, distribution, movement speed, and conformation), which further radiate to alterations in the global splicing profiles. Genes with splicing changes are enriched in immune-, growth-, or metabolism-related pathways, highlighting approaches through which hosts crosstalk with pathogens. Based on these infection-specific regulators or AS events, several targeted agents have been developed to fight against pathogens. Here, we summarized recent findings in the field of infection-related splicing, including splicing mechanisms of pathogens and hosts, splicing regulation and aberrant AS events, as well as emerging targeted drugs. We aimed to systemically decode host-pathogen interactions from a perspective of splicing. We further discussed the current strategies of drug development, detection methods, analysis algorithms, and database construction, facilitating the annotation of infection-related splicing and the integration of AS with disease phenotype.
选择性剪接（AS）是一种进化上保守的机制，通过去除内含子并连接外显子来生成成熟的信使 RNA（mRNA），极大地提高了转录组和蛋白质组的丰富度。哺乳动物宿主和病原体都需要 AS 来维持其生命活动，而哺乳动物和病原体之间固有的生理异质性使它们采用不同的方式进行 AS。哺乳动物和真菌通过剪接体进行两步酯交换反应来剪接每个单独的 mRNA（称为顺式剪接）。寄生虫也使用剪接体进行剪接，但这种剪接可以发生在不同的 mRNA 之间（称为反式剪接）。细菌和病毒直接劫持宿主的剪接机制来完成这个过程。与感染相关的变化反映在剪接体行为和各种剪接调节剂（丰度、修饰、分布、运动速度和构象）的特征上，这进一步辐射到全局剪接谱的改变。具有剪接变化的基因富集在免疫、生长或代谢相关途径中，突出了宿主与病原体相互作用的途径。基于这些与感染相关的调节因子或 AS 事件，已经开发了几种靶向药物来对抗病原体。在这里，我们总结了感染相关剪接领域的最新发现，包括病原体和宿主的剪接机制、剪接调控和异常 AS 事件，以及新兴的靶向药物。我们旨在从剪接的角度系统解码宿主-病原体相互作用。我们进一步讨论了当前药物开发的策略、检测方法、分析算法和数据库构建，促进了感染相关剪接的注释和 AS 与疾病表型的整合。
