Human tRNA-Derived Small RNAs Modulate Host–Oral Microbial Interactions

Abstract

Coevolution of the human host and its associated microbiota has led to sophisticated interactions to maintain a delicate homeostasis. Emerging evidence suggests that in addition to small molecules, peptides, and proteins, small regulatory noncoding RNAs (sRNAs) might play an important role in cross-domain interactions. In this study, we revealed the presence of diverse host transfer RNA-derived small RNAs (tsRNAs) among human salivary sRNAs. We selected 2 tsRNAs (tsRNA-000794 and tsRNA-020498) for further study based on their high sequence similarity to specific tRNAs from a group of Gram-negative oral bacteria, including Fusobacterium nucleatum, a key oral commensal and opportunistic pathogen. We showed that the presence of F. nucleatum triggers exosome-mediated release of tsRNA-000794 and tsRNA-020498 by human normal oral keratinocyte cells. Furthermore, both tsRNA candidates exerted a growth inhibition effect on F. nucleatum, likely through interference with bacterial protein biosynthesis, but did not affect the growth of Streptococcus mitis, a health-associated oral Gram-positive bacterium whose genome does not carry sequences bearing high similarity to either tsRNA. Our data provide the first line of evidence for the modulatory role of host-derived tsRNAs in the microbial-host interaction.

Transfer RNA-Derived Fragments, the Underappreciated Regulatory Small RNAs in Microbial Pathogenesis

“…Selective human 5' tRNA halves identified in saliva have high sequence similarity to tRNAs of Fusobacterium nucleatum, an oral opportunistic pathogen. Co-culture of human 5' tRNA halves with F. nucleatum inhibits bacterial growth, likely through interference with bacterial protein biosynthesis (He et al, 2018). Several studies have also demonstrated that environmental stress increases cytosolic tRNA halves in microbes (Thompson et al, 2008;Garcia-Silva et al, 2010;Fricker et al, 2019;Raad et al, 2021); however, the function of 5' and 3' tRNA halves induced by stress remains elusive.…”

tRNA-Derived Small RNAs: Biogenesis, Modification, Function and Potential Impact on Human Disease Development

“…Of note, mammals maintain intricate symbiotic relationships with other eukaryotes (i.e., fungi) and with a plethora of prokaryotic organisms (representing the microbiota), all of which also maintain diverse molecular machineries for the production of tsRNAs. Interestingly, specific tsRNAs secreted into human saliva affected the growth of a key oral commensal and opportunistic pathogen Fusobacterium nucleatum [274]. Such observations pose exciting questions as to how tsRNAs produced in microbes could affect health and disease states of the mammalian host.…”

Extracellular RNA in viral–host interactions: Thinking outside the cell

“…Furthermore, tRNA and rRNA fragments are produced by a broad range of organisms and have been indicated to be important in the context of other parasite-host and microbial-host interactions (X. He et al, 2018;Lambertz et al, 2015).…”