Toll-like receptor 11
Toll-like receptor 11 (TLR 11) is a protein encoded by the gene TLR11. TLR 11 belongs to the Toll-like receptor (TLR) family and the Interleukin-1 receptor/Toll-like receptor superfamily. By recognizing molecular patterns present on microbes, it helps propagate a host immune response. TLR 11 plays a fundamental role in both the innate and adaptive immune responses, through the activation of Tumor necrosis factor-alpha, the Interleukin 12 (IL-12) response, and Interferon-gamma (INF-gamma) secretion. TLR 11 specifically mounts an immune response to two different microbes: Toxoplasma gondii (T. gondii) and uropathogenic Escherichia coli (E. coli).
Structure and Localization
Proteins in the TLR family are pattern-recognition receptors whose task is to alert the immune system of foreign invaders. These foreign invaders may be bacteria, viruses, fungi, or parasites. Every TLR has three domains that compose its overall structure: a leucine-rich repeat (LRR) region, a transmembrane domain, and a Toll/Interleukin-1 receptor (TIR) domain. The LRR region of TLR 11 interacts with the T. gondii profilin and uropathogenic E. coli. It is positioned outside the cell and is thus an extracellular domain. The transmembrane domain mounts TLR 11 to the cell membrane and connects the LRR region to the TIR domain. Lastly, the TIR domain resides on the cytosolic side of the cell. Its job is to initiate a signal that will activate the Toll pathway in the cell. The ultimate end of the Toll pathway is the expression of genes by the transcription factors NF-κB and AP-1.
Many mammals, including humans, have the TLR 11 gene. But only some species’ TLR 11 can successfully code for the functional protein that is able to play an active role in the innate immune response. Human TLR 11 contains stop codons, meaning functional TLR 11 protein is not found in humans. All the collective knowledge about the function and immunopathology of TLR 11 has come from experiments in other animals, often mice.
Experiments on mouse TLR 11 both in vivo and in vitro have revealed much about the biological role of TLR 11. TLR 11 has a primary role as a “sentinel” for the innate immune system. Like all TLRs, TLR 11 distinguishes between self molecules and non-self molecules. When an infection of T. gondii or uropathogenic E. coli reaches a host cell expressing TLR 11 on its surface, the LRR region binds to the pathogen and activates the Toll pathway through the TIR domain. The transcription factor NF-kappa B at the end of the pathway transcribes pro-inflammatory cytokines (such as IL-12) and chemokines. Activation of the Toll pathway also results in the expression of co-stimulatory molecules on dendritic cells, which then go on to activate naïve CD4 cells in the lymph nodes.
TLR 11 and T. gondii
T. gondii is a apicomplexan parasite that can cause infection in humans. The parasite can live in many mammals and birds, but it carries out the sexual part of its lifecycle in cats. Feline feces from infected cats or undercooked meat from infected livestock contain T. gondii oocysts. Ingesting these could lead to Toxoplasmosis, a disease which at its worst can cause encephalitis or miscarriage as the disease is passed from mother to fetus.
T. gondii and other apicomplexan parasites rely on actin-dependent gliding motility in order to gain access to the body. This form of cellular motion requires profilin, an actin filament binding protein that helps restructure the actin cytoskeleton. Without profilin, T. gondii can still grow and replicate, but it loses the ability to pass through cell layers and biological barriers in order to carry out infection. Thus profilin is a conserved, essential protein for T. gondii infection efficacy.
Profilin from T. gondii is a critical parasite ligand for TLR 11. It preferentially induces IL-12 production in dendritic cells that communicate with natural killer cells and cytotoxic T cells. In one study, mice bred to not express TLR 11 (knock-out mice) did not mount the IL-12 response upon profilin stimulation. Dendritic cells in the knock-out mice also failed to migrate to lymph nodes, halting the initiation of the adaptive immune response.
Furthermore, mice lacking the TLR 11 gene are susceptible to pancreatitis, fat cell necrosis, and increased inflammatory reactants. Pancreatitis is also a pathological response in humans to T. gondii infection. Wild-type mice are able to produce an immune response, marked by IL-12 and IFN-gamma production that is unseen in humans, who lack a functional TLR 11 protein.
TLR 11 and uropathogenic E. coli
Uropathogenic E. coli is a bacterium that causes urinary tract infections. The infection begins with colonization in the urethra. The infection typically ascends and can reside primarily in the bladder or the kidneys, though the latter is more threatening due to the possibility of transmission of pathogens to the blood stream.
TLR 11 is expressed in mouse kidney and bladder epithelial cells, the cells that line the urinary tract and protect the underlying tissue. In another study of TLR 11 in mice, exposure of human uropathogenic E. coli bacteria to mouse cells expressing TLR 11 resulted in NF-kappa B activation. While the bladders from both wild-type and knockout mice were almost equally infected, the kidneys of the mice without TLR 11 had 10,000 times more bacteria and showed a greater inflammatory response than the normal mouse kidneys. TLR 11 appears to recognize a pattern on uropathogenic E. coli and can prevent ascending infection.
It is important to note that mice as a species do not grapple with urinary tract infections like humans do, unless some part of their TLR 11 immune response is made non-functional. With functional TLR 11, humans might not succumb to urinary tract infections so readily.
- ↑ 1.0 1.1 Zhang D et al (March 2004). “A Toll-like Receptor That Prevents Infection by Uropathogenic Bacteria”. Science 303, 1522-6 http://www.sciencemag.org/cgi/content/full/303/5663/1522
- ↑ 2.0 2.1 Yarovinsky F et al (June 2005). "TLR11 Activation of Dendritic Cells by a Protozoan Profilin-Like Protein'". Science 308, 1626-9http://www.sciencemag.org/cgi/content/full/308/5728/1626
- ↑ 3.0 3.1 Yarovinsky F, Hieny S, and Sher A (2008). “Recognition of Toxoplasma gondii by TLR11 Prevents Parasite-Induced Immunopathology”. The Journal of Immunology 181, 8478-84http://www.jimmunol.org/cgi/content/full/181/12/8478
- ↑ Lauw FN, Caffrey DR, and Golenbock DT (October 2005). “Of mice and men: TLR11 (finally) finds profilin”. TRENDS in Immunology 26 (10), 509-11http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6W7H-4GX0CDP-2&_user=145269&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000012078&_version=1&_urlVersion=0&_userid=145269&md5=88ae7942cd568a0afdc39d04adc4224e
- ↑ Janeway, CA Jr., Travers P, Walport M, and Shlomchik M, 2005, Immunobiology: The Immune System in Health and Disease, Garland Science Publishing, New York, 823 p.
- ↑ Plattner F et al (February 2008). “Toxoplasma Profilin Is Essential for Host Cell Invasion and TLR11-Dependent Induction of an Interleukin-12 Response”. Cell Host & Microbe 3, 77-87http://www.cell.com/cell-host-microbe/retrieve/pii/S1931312808000267