Abstract
Although inhaled tobramycin increases lung function in people with cystic fibrosis (pwCF), the density of P. aeruginosa in the lungs is only modestly reduced; hence, the mechanism whereby tobramycin improves lung function remains unclear. Previously, we demonstrated that P. aeruginosa secretes outer membrane vesicles (OMVs) that fuse with bronchial epithelial cells (HBECs), delivering small RNAs (sRNAs) that suppress the host immune response. Thus, we hypothesized that tobramycin modifies the sRNA content of OMVs leading to reduced inflammation and neutrophil-mediated lung damage. We found that tobramycin increased the amount of two 5′ tRNA-fMet halves in OMVs (Tobi-OMVs) and that Tobi-OMVs elicited less IL-8 secretion by CF-HBECs than control OMVs (ctrl-OMVs). A specific 5′ tRNA-fMet halves inhibitor reduced the ability of Tobi-OMVs to suppress IL-8 secretion. Tobi-OMVs were also less effective in stimulating KC secretion and neutrophil recruitment in mouse lungs compared to ctrl-OMVs. Tobramycin also reduced IL-8 and neutrophil abundance in bronchoalveolar lavage fluid obtained from pwCF. The 5′ tRNA-fMet halves reduced IL-8 secretion by an AGO2-mediated post-transcriptional regulatory mechanism. The clinical benefit of tobramycin is partly due to an increase in the secretion of 5′ tRNA-fMet halves in OMVs, leading to the attenuation of IL-8 and neutrophil-mediated CF lung damage.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
The authors have declared that no conflict of interest exists.