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• W1995653973 abstract "The innate immunity plays a critical role in host protection against pathogens and it relies amongst others on pattern recognition receptors such as the Toll-like receptors (TLRs) and the nucleotide-binding oligomerization domains proteins (NOD-like receptors, NLRs) to alert the immune system of the presence of invading bacteria. Since their recent discovery less than a decade ago, both TLRs and NLRs have been shown to be crucial in host protection against microbial infections but also in homeostasis of the colonizing microflora. They recognize specific microbial ligands and with the use of distinct adaptor molecules, they activate different signalling pathways that in turns trigger subsequent inflammatory and immune responses that allows a immediate response towards bacterial infections and the initiation of the long-lasting adaptive immunity. In this review, we will focus on the role of the TLRs against bacterial infections in humans in contrast to mice that have been used extensively in experimental models of infections and discuss their role in controlling normal flora or nonpathogenic bacteria. We also highlight how bacteria can evade recognition by TLRs. The human body is constantly exposed to microbes that usually only colonize the host harmlessly, but that may cause infectious diseases, sometimes leading to fatal outcomes. To control the resident colonizing microflora, as well as to fight pathogens, the human body has developed a variety of host defence mechanisms that in most cases effectively prevent the development of invasive microbial diseases. These defence mechanisms comprise physical or anatomical (skin, mucosal lining), mechanical (ciliated cells from the respiratory tracts, tight junctions) and biochemical barriers (tears or saliva containing antimicrobial lysozyme) as well as two inducible immune defence systems: the innate and the adaptive immune systems. These two systems are sequentially activated during infection and work cooperatively to eradicate the microbial agent. The innate immune system is the first line of host defence towards microbial infections, whilst the adaptive immune system is elicited later, about 4–7 days postinfection and includes a specific and long-lasting immunity that is based on the rearrangement and the clonal expansion of a random repertoire of antigen receptors (TCR and BCR) on lymphocytes. In this review, we will focus on the early innate responses and the role of the Toll-like receptors (TLRs). The innate immune system gives protection to a broad variety of pathogens and is based on a limited repertoire of germline-encoded receptors called pattern recognition receptors (PRRs) because they recognize conserved microbial components known as pathogen-associated molecular patterns (PAMPs). The PRRs include amongst others the members of the TLRs family and the nucleotide-binding oligomerization domain proteins (NOD-like receptors, NLRs) [1, 2]. Here, we will primarily discuss the role of TLRs in host protection against bacterial infections. The Toll receptors are evolutionary conserved and homologous receptors are found in plants, insects, worms (Caenorhabditis elegans) and vertebrates. The first member of this family, named Toll was initially identified in the fruit fly, Drosophila melanogaster [3]. This receptor has been shown to be responsible for the embryogenic dorsoventral development of fruit flies and to play an important role in the protection against fungi in adult flies [4]. The TLRs are the mammalian homologues of Toll and totally, 13 mammalian TLRs have been identified so far; 10 human (TLR1–10) and 12 murine (TLR1–9 and TLR11–13) receptors, of which some are homologues [5]. TLRs are type I transmembrane proteins that are characterized by an extracellular leucin-rich domain (LRR) and an intracellular or cytoplasmic domain homologous to the interleukin-1 receptor (IL-1R) and therefore called Toll/IL-1 receptor (TIR) domain [6, 7]. The homology between TLRs and IL-1R is restricted to their cytoplasmic domain, whilst their extracellular domains are remarkably different. Whereas IL-1R has an immunoglobulin-like structure, TLRs contain LRR. The LRR domains consist of 19–25 tandem repeats where each repeat has a length of 24–29 amino acids. These domains are responsible for the recognition of PAMPs from bacteria and parasites but also from fungi and viruses [8-12]. At least one ligand for each TLR has been identified so far (Fig. 1 and Table 1). Schematic representation of the Toll-IL-1R superfamily. IL-1 receptor (IL-1R) and the Toll-like receptors (TLRs) share a common signalling pathway via recruitment of an adaptor molecule to their homologous cytoplasmic domain called TIR (Toll/IL-1 receptor domain). The extracellular domain of the IL-1R has an immunoglobulin-like structure whilst TLRs have leucine-rich repeat motifs (LRR). The extracellular domains of TLRs, the LRRs, are responsible for the recognition of pathogen-associated molecular patterns. TLR4 is the most extensively studied PRR and it recognizes a variety of ligands (mannan from yeast, host heat shock proteins and fibrinogen and envelope proteins from virus, pneumolysin, a cytotoxin from Streptococcus pneumoniae) but is mostly known as the lipolysaccharide (LPS) receptor [13]. TLR2 also recognizes a broad range of ligands, such as bacterial lipopeptides, yeast zymosan, parasite and viral proteins and lipoteichoic acid (LTA) from Gram-positive bacteria. The variety of ligands recognized is believed to be due to heterodimer formation of TLR2 with two other TLRs, TLR1 or TLR6, which can discriminate subtle changes in the ligand structure [14-16]. The heterodimer of TLR1/TLR2 has been suggested to recognize triacylated lipoproteins, whilst TLR2/TLR6 recognizes diacylated lipoproteins [16, 17]. TLR5 detects a conserved domain on flagellin monomers, the main structural protein that forms the flagella on Gram-negative bacteria. Flagella are bacterial motor organelles responsible for virulence, chemotaxis, adhesion and invasion of host surfaces [18]. TLR9 recognizes nucleic acids such as hypomethylated CpG, motifs, which are common amongst prokaryotic DNA and absent in eukaryotic genomes [14, 19]. Moreover, TLR9 has been shown to be activated by hemozoin, a haeme containing degradation product of haemoglobin generated in erythrocytes infected by malaria parasites [20]. TLR3, TLR7 and TLR8 recognize nucleic acids like TLR9, but single-stranded (ss) and double-stranded (ds) RNA rather than DNA [21-23]. The expression of TLRs differ with cell types and cellular localization where some have been found to be expressed primarily extracellularly (TLR1, TLR2, TLR4, TLR5, TLR6 and TLR11) and others intracellularly (TLR3, TLR7, TLR8 and TLR9) on numerous myeloid cells (macrophages, dendritic cells, neutrophils, T and B cells) but also on nonmyeloid cells (epithelial cells, fibroblasts). Gram-positive bacteria have a thick multilayer cell wall consisting mainly of peptidoglycan (PG), a polymer of carbohydrates (N-acetylmuramic acid and N-acetylglucosamine) cross-linked through peptide bonds that surrounds the cytoplasmic membrane [24, 25]. The Gram-positive cell wall contains polyalcohols called teichoic acid, some of which are lipid-linked to form lipotechoic acids (Fig. 2). Lipoteichoic acids are anchored in the cytoplasmic membrane via lipid moieties, whereas wall teichoic acids (WTA) are covalently bound to the PG (Fig. 2). Due to the presence of phosphodiester bonds between teichoic acid monomers, teichoic acids give the Gram-positive cell wall an overall negative charge. Many Gram-positive pathogens, however, such as Streptococcus pyogenes and S. pneumoniae express teichoic acids that are d-alanylated, decreasing the net negative surface charge thereby increasing resistance to cationic antibacterial peptides present in the host [26, 27]. Teichoic acids of S. pneumoniae also contain choline residues providing binding sites for a series of choline-binding proteins [28, 29]. Purified WTA is not inflammatory, whereas purified LTA is moderately inflammatory through its diacylated moiety being recognized by TLR2/TLR6 [30-33]. Recent data, however, suggest that lipoproteins of Staphylococcus aureus might be more dominant TLR2 ligands when compared with LTA [34]. Schematic pictures of Gram-positive and Gram- negative cell wall in relation to Toll-like receptor recognition. In the Gram-positive and Gram- negative bacterial cell walls, the inner membrane (IM) or cytoplasmic membrane is composed of a double layer of phospholipids and lipoproteins (LP). A thick layer of peptidoglycan (PG) covers the IM of Gram-positive bacteria whilst a thinner layer is found in the periplasmic space (PS) in Gram-negative bacteria. In Gram-positive bacteria, lipotechoic acids are attached via its lipid moiety anchored to the cytoplasmic membrane. In Gram- negative bacteria, an additional membrane, the outer membrane (OM) mainly composed by lipopolysaccharide (LPS), phospholipids, proteins (i.e. porins) and lipoproteins (LP) covers the PS. Gram-negative cell walls are more complex than their Gram-positive counterpart (Fig. 2). They consist of a thin PG layer adjacent to the cytoplasmic membrane and an outer membrane of lipopolysaccharides (LPS), phospholipids and proteins, which face into the external environment [24, 35]. Lipopolysaccharide, the main component of the outer leaflet of the outer membrane, is highly charged and confers an overall negative charge to the Gram- negative cell wall. The chemical structure of the outer membrane LPS is often unique to specific bacterial strains (i.e. subspecies) and is responsible for many of the antigenic properties of these strains. The outer membrane of Gram-negative bacteria also contains channel proteins called porins that allow passive transport of many ions, sugars and amino acids across the outer membrane. The cytoplasmic and the outer membranes are separated by the periplasmic space, which contains the PG layer (Fig. 2). LPS, also known as endotoxin, is the most studied PAMP of Gram-negative bacteria (Fig. 2) [35]. This structure protects the bacteria from bile salts, hydrophobic antibiotics and complement activation, and is crucial for bacterial survival. LPS is generally composed of an O-linked polysaccharide, which is attached to the lipid A moiety via the core polysaccharide (Fig. 2). With the exception of Neisseria meningitidis, LPS is crucial for the viability and growth of the bacteria [36-38]. The classical lipid A has a monophosphorylated or biphosphorylated disaccharide backbone, which has been acylated with fatty acids. Lipid A anchors LPS to the outer membrane via its fatty acids. The classical lipid A of Escherichia coli is hexa-acylated. Lipid A is the active component of LPS. This component is probably the most potent immunostimulatory molecule of all the PAMPs and is responsible for most of the acute inflammatory response to bacterial LPS observed during endotoxic shock [39]. The level of lipid A acylation is critical to the immunostimulatory effects of LPS. Thus, penta-acylated LPS from a WaaN mutant of E. coli is much less potent than wild-type (wt) LPS in eliciting a proinflammatory cytokine response from cultured uroepithelial cells [40, 41]. Induction of innate immune responses by E. coli and purified LPS correlate with organ- and cell-specific expression of TLRs within the human urinary tract [40, 41]. Not all Gram-negative bacteria express similar LPS, and changes in the LPS and/or lipid A structure can occur during various environmental conditions, which can result in modulation of the host responses and may thereby confer specific advantages to certain bacterial species under changing environmental host conditions [35, 39]. For example, LPS from Porphyromonas gingivalis, an oral anaerobic bacterium, is less potent in eliciting an innate immune response than LPS from E. coli [42-44]. Moreover, clinical isolates of the gastric pathogen Helicobacter pylori expresses LPS that is penta-acylated and therefore not as immunostimulatory as LPS of many enteric commensals that produce hexa-acylated LPS [45]. Furthermore, Salmonella is able to downregulate the endotoxicity of its LPS by a lipid A deacetylase (PagL), which is under the global control of the PhoP/PhoQ regulon [46]. However, not only acylation, but also other modifications of the lipid A moiety (fatty acid composition, phosphate patterns) are crucial for host recognition [47-50]. LPS is recognized by TLR4 but TLR4 is not sufficient for the signalling [51]. It also requires accessory proteins. LPS binds first LPS-binding protein (LBP), which is an acute phase protein that circulates in the bloodstream and binds to glycosylphosphatidylinositol (GPI) linked coreceptor CD14, which is expressed on the cell surface. LPS is then transferred to a small accessory soluble protein, MD-2 that is also part of the TLR4 receptor complex [52]. The Gram-negative cell wall also contains lipoproteins located either in the cytoplasmic or outer membrane. Particularly, lipoproteins from Borrelia burgdorferi, the agent of Lyme disease (LD) have been shown to activate inflammatory cells through TLR2 and TLR1 [53-55]. Peptidoglycan is a common component of both Gram-positive and Gram-negative bacteria (Fig. 2). TLR2 has been reported to recognize PG, however, this is controversial. Indeed, it has been suggested that PG purified directly from bacterial cultures may contain contaminations (such as LPS, LTA or covalently bound lipoproteins), which can account for the TLR2-dependent inflammatory responses observed [56-58]. Instead the intracellular NLRs have been shown to recognize muropeptides derived from the PG. NLR-stimulating ligands have also been shown to synergize the proinflammatory effects of TLR ligands and vice versa [59]. As, the NLRs are intracellular, muropeptides need to reach them in the cytosol for activation. It is therefore not surprising that the NLRs have been shown to play a particular role for defence against intracellular bacterial pathogens able to escape from the vacuolar compartment and replicate in the cytosol such as Shigella and Listeria monocytogenes [60, 61]. The primarily extracellular pathogen H. pylori has been proposed to deliver muropeptides to intracellular NLRs via its type IV secretion system encoded by the cag pathogenicity island, providing one explanation why cag-positive H. pylori are more proinflammatory than strains lacking this island [62]. Bacterial DNA contains hypomethylated CpG motifs, which are almost nonexistent in mammalian genomes. These CpG motifs are immunostimulatory via TLR9 recognition [14, 63]. As TLR9 is located intracellularly in the endosome, bacterial DNA must be taken up and transported to the endosome in order for it to interact with this receptor. Simultaneously, with the transport of CpG DNA from the early endosome to the endosome, TLR9 is recruited from the ER to CpG DNA-containing compartment [64]. In the endosome, the double-stranded DNA is cleaved into smaller single-stranded CpG motifs that will be recognized by TLR9. It was also shown that a small proportion of TLR9 is surface accessible on the plasma membrane after exposure to CpG DNA [64]. Flagellin is the main subunit protein of the flagellum [65, 66]. Different species of bacteria have different numbers and arrangements of flagella. For instance, Vibrio cholerae has only one flagellum whilst E. coli has several flagella expressed all around the bacteria and pointing in all directions. Flagellin monomers are recognized by TLR5 whilst the flagellum is not [18]. The amino acid residues responsible for TLR5 recognition have been defined and are located in a highly conserved region that is hidden in the flagellum but is accessible in the monomer [67, 68]. Some bacteria-specific ligands have also been described, such as porins or toxins. Porins are proteins that are prevalent in the outer membrane of Gram-negative bacteria, which act as a pore through which molecules can diffuse (Fig. 2). Porins from Neisseria meningitidis, Haemophilus influenzae type b and Shigella dysenteriae have been shown to be immunostimulatory molecules [69-71]. Porins from N. meningitidis are recognized by the heterodimer TLR1/TLR2, whilst the porin of S. dysenteriae signals via TLR2/TLR6 [72-74]. It has been suggested that the low percentage of protein homology (31%) between neisserial and Shigella porin accounts for the difference in the TLR recognition specificity [70]. Pneumolysin is a member of the thiol-activated cytolysin expressed by nearly all clinical isolates of S. pneumoniae [75]. Pneumolysin has several functional domains responsible for adherence to epithelial cells, cytolysis and complement activation and is therefore an important virulence factor. It has been suggested that TLR4 recognizes pneumolysin [76]. Upon recognition of their cognate ligands, TLRs dimerize and initiate a signalling cascade that leads to the activation of a proinflammatory response [6]. Ligand binding induces two signalling pathways, one is MyD88-dependent and the other is MyD88-independent inducing the production of proinflammatory cytokines and type I interferons (IFNs; Fig. 3) [7]. These two distinct responses are mediated via the selective usage of adaptor molecules recruited to the TIR domains of the TLRs after ligand recognition and binding. Four adaptor molecules have been identified so far, MyD88, TIR-associated protein (TIRAP), also called MyD88-adaptor-like (Mal), TIR domain- containing adaptor protein-inducing IFN-β (TRIF) also known as TIR domain-containing molecule 1 (TICAM-1) and TRIF-related adaptor molecules (TRAM), also named TIR domain containing molecule 2 (TICAM-2) [77-81]. MyD88 and TIRAP are responsible for the induction of proinflammatory genes and TRIF and TRAM for the induction of the IFNs. One additional adaptor molecule has been found the sterile alpha and HEAT/Armadillo motifs (SARM). Its function in the TLR signalling is not fully understood, even though it was reported that it acts as a negative regulator of TRIF-dependent TLR signalling [82, 83]. Toll-like receptor (TLR) signalling. Ligand binding to their cognate TLRs induces two signalling pathways, the MyD88-dependent and the MyD88-independent pathways. Four adaptor proteins [MyD88, TIRAP (Mal), TRIF (TICAM-1) and TRAM (TICAM-2)] selectively activate these two signalling pathways leading either to the production of proinflammatory cytokines or type I interferons (IFNs). All TLRs, except TLR3, signal through MyD88 [84]. Upon ligand recognition, MyD88 is recruited and associates with the cytoplasmic domain of the TLRs via homophilic interaction between the TIR domains. Then IL-1R-associated kinase 4 (IRAK-4) and IRAK-1 are recruited and activated by phosphorylation. Activated IRAK-4 phosphorylates IRAK-1, which subsequently associates with TNFR-associated factor 6 (TRAF6) [85]. TRAF6 activates transforming growth factor (TGF)-β-activating kinase 1 (TAK1). TAK1 phosphorylates IKK-b and MAP kinase kinase 6 (MKK 6) leading to the degradation of I-κB and thereby leading to the nuclear translocation of NF-κB which results in the induction of genes involved in inflammatory responses. Activation of the MyD88-dependent pathway results also in the activation of MAPKs such as p38 and JNK, which leads to the activation of AP-1. In addition to NF-κB and AP-1, the MyD88-dependent pathway can activate a third transcription factor IRF-5. Upon ligand stimulation, IRF-5 can also translocate into the nucleus and bind to IFN-stimulated response elements (ISRE) motifs in the promoter region of cytokines genes. In addition to MyD88, TLR2 and TLR4 needs a second adaptor molecule, TIRAP/Mal in order to signal. It was recently demonstrated that TIRAP/Mal is recruited to the plasma membrane through its phoshatidylinositol 4,5-bisphosphate-binding domain, where it then can promote delivery of MyD88 to activated TLR4 [86]. TLR7 and TLR9 activation does not only lead to the induction of proinflammatory cytokines, but can also cause the induction of IFN-α in a MyD88-dependent manner. This is specific to plasmacytoid dendritic cells (pDC) that are expressing high levels of TLR7 and TLR9 and are capable of producing high levels of IFN-α. Upon ligand stimulation, a complex consisting of MyD88, IRAK-4, IRAK-1 and TRAF6 is formed at the TIR domain of TLR7 and TLR9 and then the transcription factor IRF-7 is also recruited to this complex. The activation of IRF-7 by phosphorylation leads to its translocation to the nucleus and induction of the IFN response. TLR3 and TLR4 activation triggers the induction of a type I IFN response leading to the induction of IFN-α and IFN inducible genes. Whilst TLR3-mediated signalling only requires the adaptor molecule TRIF, TLR4-mediated signalling needs in addition to TRIF another adaptor protein, TRAM. TRAM is considered as a bridging adaptor between TLR4 and TRIF. TRIF interacts with both receptor-interacting protein 1 (RIP1) and TRAF6 and cooperatively with these two proteins activates NF-κB to induce expression of proinflammatory cytokines [87]. Furthermore, TRIF activates also TRAF family members-associated NF-κB activator (TANK) binding kinase 1 (TBK1) via TRAF3. In turn, TBK1 phosphorylates directly two transcription factors, IRF-3 and IRF-7 allowing them to translocate into the nucleus and induce IFN-α and IFN inducible genes [88]. In viral infections, the induction of type I IFNs has recently been shown to be primarily due to the recognition of double-stranded RNA, which is a sign of replicating viruses. The retinoic acid inducible gene I (RIG-I) with its helicase domain has been demonstrated to be an essential regulator for double-stranded RNA signalling that results in the activation of the transcriptional factors NF-κB as well as IRF-3 [89, 90]. The TLR signalling needs to be tightly regulated in order to be permissive for the resident microflora, to be restrictive for primary pathogens and to avoid excess inflammation, which can be deleterious for the tissue or organ [91]. The first and most basic level of regulation is directly linked to the TLR cellular localization as described above. For instance, the intracellular location of TLR9 allows an increased recognition of endocytosed viral DNA but also prevents recognition of self-DNA [92]. Furthermore, in organs like the gut, it was shown that normal primary enterocytes express low levels of TLR2 and TLR4, and the coreceptor MD-2 as well as the membrane-bound CD14 and that, in contrast to macrophages, TLR4 is not localized at the cell surface but rather at the Golgi apparatus requiring internalization of LPS via lipid rafts to activate signalling [93, 94]. Expression of membrane-bound CD14 is also absent from uroepithelial cells [95]. Besides their cellular localization, TLR signalling can be modulated by the selective usage of the adaptor molecules recruited to the TIR domains of the TLRs after ligand recognition and binding. The intracellular signalling cascade is also negatively regulated at various levels either by protein phosphorylation, degradation, interaction with inhibitory adaptor molecules or sequestration [91, 96]. Some of the main players in this immunomodulatory regulation are: (i) suppressor of cytokine signalling 1 (SOCS-1), (ii) Flightless I homologue (Fliih), (iii) ST2, (iv) Triad3A, (v) A20, (vi) IRAK-M, (vii) IRAK-1c, (viii) a short form of MyD88 (MyD88s) and (ix) β-arrestin [97-103]. MyD88s inhibits IL-1 and LPS-induced NF-κB activation. Indeed, MyD88s acts as a dominant negative form of MyD88 and replaces formation of MyD88 homodimers by MyD88s–MyD88 heterodimers. These heterodimers still recruit IRAK1 but inhibit phosphorylation of IRAK-1 via IRAK-4 and thereby inhibit downstream signalling [97]. ST2L is a type I transmembrane receptor composed of three extracellular immunoglobulin-like domains and an intracellular TIR domain that was shown to sequester MyD88 and Mal, but not TRIF or IRAK, which in turn negatively regulates IL-1R- and TLR4-mediated signalling. Another molecule, Fliih has been shown to act as negative regulator by interacting with MyD88. SOCS-1 mediates Mal degradation and thereby negatively regulates TLR signalling [104, 105]. Triad3A is a molecule that promotes the ubiquitination and degradation of TLR4 and TLR9 via binding the cytoplasmic domain of these two TLRs [99]. IRAK-M is a negative regulator that blocks IRAK-4 activation [101]. Similarly, Toll-interacting protein (Tollip) interacts with IRAK-1 and suppresses autophosphorylation of IRAK-1 [103]. It was suggested that Tollip regulates the intensity of the response to IL-1β and LPS [106]. IRAK-1c is a spliced variant of IRAK-1 that is nonfunctional because it cannot be phosphorylated by IRAK-4 but it maintains its ability to bind to MyD88 and TRAF-6. It therefore acts as a dominant negative form of IRAK-1. Whilst β-arrestin prevents oligomerization of TRAF6, which in turn inhibits the autoubiquitination of TRAF6; A20 removes the ubiquitin from TRAF6. However, both molecules inactivate the TLR signalling [102] [100]. In addition, TLR signalling can be downregulated by anti-inflammatory cytokines. For instance, it has been shown that TGF-β induces MyD88 degradation by the proteasome and suppresses the expression of TLR4 [107]. Whilst in vitro studies have highlighted the role of TLR for the recognition of specific bacterial ligands, in vivo studies were necessary to elucidate the role of individual TLRs in the recognition of the whole bacterium that can carry several ligands simultaneously. This task was facilitated by the creation of knock out animals in the different components of the TLR signalling pathway [13, 15, 84, 108-111]. The model of choice was the murine model and TLR-deficient mice were profoundly used [112]. In several instances, a deficiency in a single TLR had no significant effect on mice susceptibility to a pathogen even though it expressed the ligand for the missing TLR [10, 113-115]. These findings are usually explained by the redundancy in the system with several TLRs recognizing ligands on a given pathogen. TLR2 has been regarded as being the primary Gram-positive TLR and indeed, TLR2 has been proven critical for host protection in murine models of bacterial infection such S. aureus [116, 117] and L. monocytogenes [11, 118]. In a meningitis model of S. pneumoniae, TLR2 played a role as well, but in a pneumonia model, TLR2-deficient mice were only marginally affected [113, 119-123]. TLR2 has also been shown to be important for Gram-negative infections such as infections caused by Legionella pneumophila [124, 125] and Samonella [126, 127]. Using a calf model of gastroenteritis, it was recently demonstrated that Salmonella curli promoted the inflammatory response in the bowel, and that the likely receptor for this class of bacterial amyloids was TLR2 [127]. Moreover, in mice curliated E. coli were shown to mediate a more pronounced host response than noncurliated mutant bacteria as evidenced by a more significant blood pressure drop upon infection with curliated when compared with noncurliated E. coli [126]. Not much information is available for the role of TLR1 and TLR6 in vivo [15]. These two TLRs seem to be redundant or have a minor role in pneumococcal infections [113]. TLR4-deficient mice have been shown to be highly susceptible to many Gram-negative bacteria amongst others to Salmonella spp., H. influenzae and Klebsiella pneumoniae [128, 129]. Several inbred mice such as C3H/Hej or C57BL10/ScN have been shown to naturally harbour mutations in TLR4 ORF, which render them highly susceptible to Gram-negative infections. Using a mouse model of experimental urinary tract infection (UTI), it was shown that TLR4 is required for the immune response, including neutrophil recruitment in order to clear uropathogenic E. coli (UPEC) from the mucosa [130-132]. It was further demonstrated that in addition to LPS, the presence as well as the type of fimbriae expressed on the bacteria was necessary to trigger a TLR4-dependent response and neutrophil recruitment in the bladder. Indeed, LPS alone was not sufficient to trigger the immune response, as evidenced by the lack of response to infections by nonfimbriated E. coli [131, 133]. Interestingly, it is worth noticing that these fimbriae are also crucial for the initial attachment of the bacteria to the epithelial cell surfaces, which highlights the importance of coreceptors involved in the activation of a fully functional TLR signalling [134, 135]. This might explain how a limited number of the TLRs can recognize such a broad number of bacteria. For some Gram-negative infections such as acute lung infections caused by Pseudomonas aeruginosa, the role of TLR4 in host protection is not clear yet [136-139]. TLR4 has not only been suggested to play a role in host protection against Gram-negative bacteria, but also against Gram-positive bacteria and one study showed that TLR4-deficient mice might be more susceptible to Gram-positive colonization by S. pneumoniae [76]. However, these data have not been confirmed by others [113, 115, 123]. TLR5-deficient mice are unable to mount a response to purified flagellin, but are not more susceptible to Salmonella given intraperitoneally (i.p.) or to P. aeruginosa given intranasally (i.n.), possibly due to the activation of other TLRs [140]. MUC1 (in humans) and Muc1 (in mice) are membrane-bound mucins that interact with flagellin. Muc1-deficient mice were more capable of clearing P. aeruginosa from the airways and had a more pronounced proinflammatory response when compared with wt mice, suggesting that Muc1 has an immunosuppressive effect in Pseudomonas infections of the airways by interfering with flagellin interaction with TLR5 [141]. TLR7 recognizes viral ssRNA and so far, no bacterial ligands have been found. It is, however" @default.
• W1995653973 created "2016-06-24" @default.
• W1995653973 creator A5032587901 @default.
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• W1995653973 date "2007-06-01" @default.
• W1995653973 modified "2023-10-17" @default.
• W1995653973 title "Role of the innate immune system in host defence against bacterial infections: focus on the Toll-like receptors" @default.
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