Abstract

Alternative splicing of pre-mRNAs expands a single genetic blueprint to encode multiple functionally diverse protein isoforms. Viruses have previously been shown to interact with, depend on, and alter host splicing machinery. The consequences however incited by viral infection on the global alternative slicing (AS) landscape are under appreciated. Here we investigated the transcriptional and alternative splicing profile of neuronal cells infected with a contemporary Puerto Rican Zika virus (ZIKVPR) isolate, the prototypical Ugandan ZIKV (ZIKVMR) isolate and dengue virus 2 (DENV2). Our analyses revealed that ZIKVPR induced significantly more differential changes in expressed genes compared to ZIKVMR or DENV2, despite all three viruses showing equivalent infectivity and viral RNA levels. Consistent with the transcriptional profile, ZIKVPR induced a higher number of alternative splicing events compared to ZIKVMR or DENV2, and gene ontology analyses highlighted alternative splicing changes in genes associated with mRNA splicing. All three viruses modulated alternative splicing with ZIKVPR having the largest impact on splicing. ZIKV alteration of the transcriptomic landscape during infection caused changes in cellular RNA homeostasis, which might dysregulate neurodevelopment and function leading to neuropathologies such as microcephaly and Guillain-Barre syndrome associated with the ZIKV infection.