Roles of alternative splicing in infectious diseases: from hosts, pathogens to their interactions

Abstract

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.

Genome-wide association analysis of the resistance to infectious hematopoietic necrosis virus in two rainbow trout aquaculture lines confirms oligogenic architecture with several moderate effect quantitative trait loci

“…However, it contains multiple genes encoding for the spliceosome sub-units 2 and 5. Alternative splicing has been recently implicated as a component of host-pathogen interactions in human and other mammals (Boudreault et al, 2019;Chauhan et al, 2019;Rotival et al, 2019;Yamaguchi et al, 2022;Lyu et al, 2023), including direct interactions between viral proteins and sub-unit 5 (U5) (Boudreault et al, 2022a;Boudreault et al, 2022b). Thus, it is plausible that variants of the spliceosome subunits may have an impact on the host-pathogen interactions after IHNV infection, and potentially may be the causative variant or variants for resistance to IHNV infection that was detected on chromosome Y QTL.…”