A Novel Molecule Designed to Keep Bacteria out of the Urinary Tract

Abstract

So far 10 Toll-like receptors (TLR) that recognize distinct pathogen-associated molecular patterns have been reported in mammalian species. TLR represent of family of transmembrane proteins with an extracellular domain rich in leucine repeats and a cytoplasmic Toll/IL-1 receptor homology domain (1,2).Zhang browsed in the human and mouse genome databases provided by the National Center for Biotechnology Information to assess whether additional TLR beyond the 10 known members can be identified. This search in the mouse led to the recovery of a genomic sequence with an open reading frame encoding a hypothetical 907 amino acid protein with the characteristics of a toll receptor that the authors designated TLR-11. Using the cytoplasmic domain of TLR-11 cDNA as a probe, strong expression was found in the urinary tract (bladder) and kidney as well as liver, whereas expression was low in the spleen and absent in most blood cell types. In contrast, the known TLR-4 is expressed in urinary tract and bladder only but not in kidney (3).TLR-11 triggers activation of the central molecular inflammatory switches NF-B and AP-1, as shown with a stably transfected NF-B or AP-1 reporter construct. The search for stimulating agents led to surprising results. The known activating TLR ligands such as lipopolysaccharide, peptidoglycane, and polyinosinic:polycytidylic acid failed to activate NF-B in cells that were transfected with TLR-11, but uropathogenic Escherichia coli, even when heat-killed, were strongly stimulatory, suggesting that uropathogenic E. coli are a ligand for TLR-11. This assumption was corroborated further by the observation that mutant mice lacking TLR-11 were stimulated by lipopolysaccharide, peptidoglycane, and polyinosinic polycytidylic acid but failed to be stimulated by uropathogenic E. coli.After intraurethral infection with uropathogenic E. coli, bladders were infected both in wild-type and in knockout mice, but the kidneys were infected massively only in the knockout animals. Apparently, absence of TLR-11 rendered mice susceptible to renoparenchymal bacterial infection, leading to the conclusion that the function of TLR-11 is to recognize uropathogenic E. coli and to protect the kidney from ascending infection.Although this further finding is currently still preliminary, it is also of considerable interest that in the human genome (National Center for Biotechnology Information database), the authors noted that humans seem to fail to express full-length TLR-11 protein. The investigators pointed to the analogy with a stop codon in TLR-5, which renders certain individuals unable to respond to flagellated bacteria (4).Unless major species differences make extrapolations impossible, the exciting results suggest that this novel member of the Toll receptor family with unique specificities is crucial in the genesis of ascending urinary tract infection.

Toll-Like Receptors and Corneal Innate Immunity

“…to the mouse [17][18][19]. The TLRs have an extracellular domain containing leucine-rich repeats (LRRs) whereas the cytoplasmic domain shows a striking homology with that of the interleukin-1 receptor (IL-1R) and is referred to as the Toll/IL-1R (TIR) domain.…”

Toll-Like Receptors in Skin Infections and Inflammatory Diseases

“…Therefore, mouse TLR10 is non-functional[8]. In contrast, mouse TLR11 is functional and can be activated by uropathogenic bacteria, whereas a stop codon is present in the human TLR11 gene, resulting in lack of its translation[9]. Furthermore, TLRs 12–13 have only been found in mice.…”