Abstract
Bacterial RNA serves an important function as activator of the innate immune system. In humans bacterial RNA is sensed by the endosomal receptors TLR7 and TLR8. Differences in the posttranscriptional modification profile of prokaryotic when compared with eukaryotic RNA allow innate immune cells to discriminate between “host” and “foreign” RNA. Ribose 2′-O-methylation is of particular importance and has been reported to antagonize TLR7/8 activation. Yet, the exact sequence context in which 2′-O-methylation has to occur to mediate its inhibitory activity remains largely undefined. On the basis of a naturally occurring 2′-O-methylated RNA sequence, we performed a systematic permutation of the methylated nucleotide as well as adjacent bases and hereby identify two minimal trinucleotide motifs within a 9-mer oligoribonucleotide that are necessary and sufficient to antagonize TLR7 and TLR8 activation, respectively. Given the growing interest in the development of inhibitors of nucleic acid-sensing TLRs for therapeutic purposes, these results will facilitate the rational design of such antagonists in the future.
Highlights
The innate immune system constitutes the first line of defense against invading pathogens by recognizing highly conserved pathogen-associated molecular patterns (PAMPs) through a limited set of germline encoded pattern recognition receptors (PRRs)
Due to these cell-type specific TLR expression and cytokine secretion profiles, bacterial RNA-induced TNF production within peripheral blood mononuclear cells (PBMCs) is commonly used as a read-out for TLR8-dependent monocyte activation, whereas IFN-α release within PBMCs serves as a marker for TLR7-dependent plasmacytoid dendritic cells (pDCs) activation
A short tRNA fragment derived from E. coli tRNATyr bearing a 2′-O-methylation at position G18 (Gm18) has previously been demonstrated to inhibit TLR7- and TLR8-mediated immunostimulation by a variety of stimulatory RNA species as efficiently as the respective full-length tRNA (Rimbach et al 2015)
Summary
Several studies identified 2′-O-methylation of the ribose, a modification which is more abundant in eukaryotic RNA, as a suppressor of TLR7 and TLR8 activation in human pDCs and monocytes, respectively (Robbins et al 2007; Sioud et al 2007; Hamm et al 2010; Vaishnaw et al 2010; Gehrig et al 2012; Jockel et al 2012; Kaiser et al 2014; Rimbach et al 2015). Inhibitory oligoribonucleotides (ORNs) might be used for therapeutic purposes in diseases associated with aberrant immune responses toward “self” RNA, for example, the autoimmune disease systemic lupus erythematosus
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
