Human TLR 8 senses UR / URR motifs in bacterial and mitochondrial RNA

Abstract

Toll-like receptor (TLR) 13 and TLR2 are the major sensors of Gram-positive bacteria in mice. TLR13 recognizes Sa19, a specific 23S ribosomal (r) RNA-derived fragment and bacterial modification of Sa19 ablates binding to TLR13, and to antibiotics such as erythromycin. Similarly, RNase A-treated Staphylococcus aureus activate human peripheral blood mononuclear cells (PBMCs) only via TLR2, implying single-stranded (ss) RNA as major stimulant. Here, we identify human TLR8 as functional TLR13 equivalent that promiscuously senses ssRNA. Accordingly, Sa19 and mitochondrial (mt) 16S rRNA sequence-derived oligoribonucleotides (ORNs) stimulate PBMCs in a MyD88-dependent manner. These ORNs, as well as S. aureus-, Escherichia coli-, and mt-RNA, also activate differentiated human monocytoid THP-1 cells, provided they express TLR8. Moreover, Unc93b1−/−- and Tlr8−/−-THP-1 cells are refractory, while endogenous and ectopically expressed TLR8 confers responsiveness in a UR/URR RNA ligand consensus motif-dependent manner. If TLR8 function is inhibited by suppression of lysosomal function, antibiotic treatment efficiently blocks bacteria-driven inflammatory responses in infected human whole blood cultures. Sepsis therapy might thus benefit from interfering with TLR8 function.

Streptococci Engage TLR13 on Myeloid Cells in a Site-Specific Fashion

“…With respect to TLR repertoire and function, humans are similar to cattle, which are widely accepted as the original host of GBS (37). It remains to be established whether TLR13 equips mice with specific resistance to bacteria or whether it takes over the role of TLR8, which was recently identified as a sensor for bacterial RNA in human myeloid cells (38)(39)(40). The latter seems likely, because mononuclear cells from mice and humans use the TLR signaling partners IRAK4 and MyD88 for the optimal response to streptococci and staphylococci (41).…”

Cathelicidin Insufficiency in Patients with Fatal Leptospirosis

“…The defect in production of antimicrobial peptides was not a global innate immune dysfunction, as we found no significant differences in other antimicrobial transcripts or serum proteins (elastase, resistins, and defensins) between survivors and fatal cases. We identified differences in abundances in only two Toll-like Receptors: TLR8 (can detect single-stranded bacterial RNA) [40, 41], which was elevated in fatal cases likely due to higher bacterial loads, and TLR7 (senses bacterial RNA in phagosomes) [42, 43], which was less abundant in fatal cases, possibly due to fewer phagocytic cells.…”

Розвиток Імунної Відповіді При Стафілококовій Пневмонії (Частина 2)

“…[55] установили, что высво-бождаемая при деградации золотистого стафило-кокка одноцепочечная РНК взаимодействует с ре-цептором TLR8 клеток макроорганизма. Согласно данным Bjarte Bergstrøm и соавт.…”