Widespread shortening of 3' untranslated regions and increased exon inclusion characterize the human macrophage response to infection

Changes in gene regulation have long been known to play important roles in both innate and adaptive immune responses. However, post-transcriptional mechanisms involved in mRNA processing have been poorly studied despite emerging examples of their role as regulators of immune defenses. We sought to investigate the role of mRNA processing in the cellular responses of human macrophages to live bacterial infections. We used mRNA-sequencing to quantify gene expression and isoform abundances in primary macrophages from 60 individuals, before and after infection with Listeria monocytogenes and Salmonella typhimurium. We show that immune responses to infection are accompanied by pervasive changes in isoform usage that lead to an overall increase in isoform diversity after infection. In response to both bacteria, we see global shifts towards (i) the inclusion of cassette exons and (ii) shorter 3' UTRs, with near-universal shifts towards usage of more upstream polyadenylation sites. Using individual-specific variation in RNA processing, we identify candidate splicing factors putatively regulating these post-infection patterns in trans. Finally, by profiling microRNA levels, we further show that 3' UTR regions with reduced abundance after infection are significantly enriched for target sites for specific miRNAs - including miR-146b, miR-3661, miR-151b, and miR-125a - that are up-regulated following infection. These results suggest that the prominent shift towards shorter 3' UTRs might be a cellular control mechanism to escape repression by immune-activated miRNAs. Overall, our results support concerted regulation of transcription and RNA processing in the control of gene regulatory programs engaged in the response to immune stressors.