Mycobacterium tuberculosis (Mtb), the bacterium that causes tuberculosis (TB), causes 10 million infections and 1.5 million deaths per year worldwide. The success of Mtb as a human pathogen is directly related to its ability to suppress host responses, which are critical for clearing intracellular pathogens. Emerging evidence suggests that key response pathways may be regulated by a novel class of small non-coding RNA, called tRNA-derived fragments (tRFs). tRFs can complex with Argonaute proteins to target and degrade mRNA targets, similarly to miRNAs, but have thus far been overlooked in the context of bacterial infections.
We generate a novel miRge2.0-based tRF-analysis tool, tRFcluster, and use it to analyze independently-generated and publicly available RNA-sequencing datasets to assess tRF dysregulation in host cells following infection with Mtb and other intracellular bacterial pathogens.
We find that Mtb and Listeria monocytogenes drive dramatic tRF dysregulation, whereas other bacterial pathogens do not. Interestingly, Mtb infection uniquely increased the expression of mitochondria-derived tRFs rather than genomic-derived tRFs, suggesting an association with mitochondrial damage in Mtb infection.
tRFs are dysregulated in some, but not all, bacterial infections. Biased dysregulation of mitochondria-derived tRFs in Mtb infection suggests a link between mitochondrial distress and tRF production.
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Mycobacterium tuberculosis infection drives mitochondria-biased dysregulation of host tRNA-derived fragments.
