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

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.

From tuberculosis bedside to bench:UBE2B splicing as a potential biomarker and its regulatory mechanism

Alternative splicing(AS)is an important approach for pathogens and hosts to remodel transcriptome.However,tuberculosis(TB)-related AS has not been sufficiently explored.Here we presented the first landscape of TB-related AS by long-read sequencing,and screened four AS events(S100A8-intron1-retention intron,RPS20-exon1-alternaitve promoter,KIF13B-exon4-skipping exon(SE)and UBE2B-exon7-SE)as potential biomarkers in an in-house cohort-1.The validations in an in-house cohort-2(2274 samples)and public datasets(1557 samples)indicated that the latter three AS events are potential promising biomarkers for TB diagnosis,but not for TB progression and prognosis.The excellent performance of classifiers further underscored the diagnostic value of these three biomarkers.Subgroup analyses indicated that UBE2B-exon7-SE splicing was not affected by confounding factors and thus had relatively stable performance.The splicing of UBE2B-exon7-SE can be changed by heat-killed mycobacterium tuberculosis through inhibiting SRSF1 expression.After heat-killed mycobacterium tuberculosis stimulation,231 ubiquitination proteins in macrophages were differentially expressed,and most of them are apoptosis-related proteins.Taken together,we depicted a global TB-associated splicing profile,developed TB-related AS biomarkers,demonstrated an optimal application scope of target biomarkers and preliminarily elucidated mycobacterium tuberculosis-host interaction from the perspective of splicing,offering a novel insight into the pathophysiology of TB.