Discuss how PAMPs are recognized
The immune system functions as a defence against opportunistic microbes. It as well necessitates the capability of detecting between self and non-self molecules to make sure that an immune response is not raised against the organisms own tissues. This discrimination is partly realized by the identification of a pathogens chemical motifs by the host receptors. As a result, latent, potential, or probable pathogens have tailored various ways to overcome the immune systems of the host, while the host responds with a novel defence (Grennan 2006, p. 810). PAMPs or pathogen associated molecular patterns are molecules associated with groups of pathogens, which are identified by cells of innate immune system. These molecules can as well be referred to as minute molecular motifs conserved in a class of microbes. Pathogen associated molecular patterns are recognized by Toll-like receptors (TLRs) as well as other pattern recognition receptors referred to as pathogen recognition receptors(PRRs) in both animals and plants (Ausubel 2005, p. 975).
These receptors activate both the innate and acquired immune responses and thus protect the organism from infections, through recognition of some conserved non-self molecules. An endotoxin found on the cell wall of a bacterium (Lipopolysaccharide) is considered to be prototypical PAMP and is specifically identified by Toll-like receptor 4, an innate immune system recognition receptor. Apart from lipopolysaccharides, other PAMPs comprise of lipoteichoic acid, from gram positive bacteria, bacterial flagellin, and nucleic acid variants usually associated with viruses, such as double stranded RNA (dsRNA). Though the word PAMP is relatively novel, the idea that molecules resulting from microbes ought to be distinguished by receptors from multicellular organisms has been held for a number of decades, and references to an endotoxin receptor are available in much of the older literature (Ausubel 2005, p. 977).
Over the years, the term PAMP has been under criticism by some immunologists on the basis that a large number of microbes, not only pathogens, express the molecules detected. Therefore the term MAMP (microbe associated molecular pattern) has been suggested. A virulence signal which is able to bind to a pathogen receptor in combination with a MAMP has been suggested as one way to constitute a PAMP. In plant immunology, the terms PAMP and MAMP are often treated interchangeably, considering them as the very first step in plant immunity (Ausubel 2005, p. 979).
Mechanism of Immune Recognition
Immune recognition is a unique mechanism and is mediated between products encoded in dissimilar genomes. Besides, the selective advantage imposed through immune recognition on the host genome normally implies a selective disadvantage to the pathogen genome. This conflict of interests directs evolution of non specific immunity toward identification of invariant molecular components of the infectious agents (Janeway 1989, p.6). Molecular structures which are imperative for microbes survival are never subject to variability in the sense that mutations upsetting these structures are mortal, lethal, and deadly for microbes. Molecular structure conservation means that they are shared by groups of pathogens. For instance, the generic structure of lipopolysaccharide is shared by the entire class of gram negative bacteria (Janeway 1989, p.6).
A receptor which would identify the conserved lipid A of lipopolysaccharide would therefore be capable of detecting the presence of any gram negative bacteria. This example exemplifies another characteristic of innate immune recognition, where the targets of recognition mechanism represent molecular patterns called pathogen associated molecular patterns (PAMPs), rather than other particular structures (Janeway 1989, p.10). Host organisms have developed receptors which can specifically identify or recognize pathogen associated molecular patterns that include both pattern recognition receptors (PRRs) and Toll-like receptors (TLRs). This evolutionary strategy of host organisms not only prevents the generation of microbial escape mutants, but permits a limited number of germline encoded receptors to identify a great array of molecular structures linked to pathogens as well. Additionally, it ought to be emphasized that PAMPs recognition by Toll-like receptors and PRRs not only permits the adaptive immune response to discriminate between non-self and self, but also between pathogen associated non-self and innocuous non-self (Janeway 1989, p.10).
The Roles of TLRs in Innate and Acquired Immune Response
The defence of the host organism against the invading microbial pathogens is induced by the immune system that consists of two components acquired immunity and innate immunity. Both components recognize the microbial pathogens as non-self and hence trigger the immune system to eradicate them. Today, both innate and acquired components of immune system have been characterized independently and the major research interest in immunology has been restricted to acquired immunity. In this immunity, T and B lymphocytes use antigen receptors, such as T-cell receptors and immunoglobulins to recognize non-self (Takeda and Akira 2005, p. 1). The mechanisms through which these antigen receptors identify foreign antigens have been extensively analyzed and the main mechanisms like clonality, memory, and diversity have been well characterized. However, these receptors exist only in vertebrates and according, the mechanism for non-self recognition in less advanced organisms is not fully understood. In addition, the mammalian innate immune system has not been well researched on. Consequently, innate immune cells of mammals, such as dendritic cells and macrophages are known to be activated by microbial components like lipopolysaccharide from gram negative, a receptor liable for recognition remains unknown (Takeda and Akira 2005, p. 1).
Toll-like receptors are germline encoded type 1 transmembrane receptors that are expressed on various cell types comprising dendritic cells and macrophages. They function as pattern recognition receptors, activating innate immunity by recognizing PAMPs that are unique to microbes and imperative for their survival (Carpenter and ONeill 2007, p.1891). Therefore, TLRs provide both instantaneous protective responses against pathogens as well as the acquired response by stimulation of dendritic cells recruitment and maturations (Muzio et al 2000, p. 453). Toll-like receptor triggering leads to nuclear factor kappa B-mediated activation of inflammatory genes. More than ten TLRs have been demonstrated and described in humans and agonists have been defined for nine of them. Toll-like receptors can function as heterodimers or homodimers, mounting the repertoire of specificities. TLR1, TLR2, and TLR6 are activated by any microbial product as well as peptidoglycan, TLR3 by double stranded RNA (dsRNA), TLR4 by LPS, TLR5 by flagellin, imidazoquinolines triggers both TLR7 and TLR8, and TLR9 is activated by CpG DNA (Campos et al 2001, p. 419).
TLRs Recognition of Microorganisms
Toll-like receptors being membrane bound molecules recognize microbial products within or on the surface of extracellular compartments of cells. Thus, intracellular recognition of invading microbial pathogens seems to involve a TLR independent system. Recent evidence shows that nucleotide binding oligomerization domain (NOD) family of proteins plays a substantial function in the recognition of pathogenic microbes. It has previously been indicated that TLR2 is capable of recognizing peptidoglycan (Takeuchi et al 1999, p. 443). However, peptidoglycan (PGN) contains a thick layer which is made up of overlapping lattice of 2 sugars that are cross linked by bridges of amino acids, and thus the exact structure of PGN which is recognized by TLR2 remains unknown. Nucleotide binding oligomerization was originally recognized as a molecule which is related to apotosis regulator, Apaf-1. It encompasses a caspase recruitment domain (CARD), a C-terminal domain, and a NOD domain.
Recent researches by a number of scientists have illustrated that over expression of NOD1 enables 293 cells to respond to peptidoglycan preparation (Girardin 2003, p. 1584). Therefore, NOD1 may play an essential role in sensing intracellular gram negative bacterial infections. Though, TLR2 has been reported to identify peptidoglycan, it is probable that TLR2 recognizes lipopeptide or lipoprotein contaminants trapped in the layers of PGN mesh. The viral identification is as well mediated by TLR dependent and independent mechanisms. TLR3 mediated recognition of dsRNA or viruses leads to TRIF dependent activation of interferon regulatory factor 3 (IRF-3) and nuclear factor kappa B. However, dsRNA or viruses are recognized in a TLR3 independent manner, as the impairment of responsiveness to dsRNA or viruses in TLR3 scarcity is only partial. RIG-1 is recognized as a molecule which is responsible for recognition of viruses and mediates 1RF-3 activation (Figure 1).
Figure 1 TLR Dependent Independent Recognition of Microbial Constituents
(Yoneyama 2004 730)
TLRs and Phagocytosis
The process of phagocytosis is an essential step for defence of the host against microbial invaders, as it activates both degradation of pathogens and resultant presentation of pathogen derived peptide antigen. Recognition of pathogens by Toll-like receptors results in expression of genes, such as co-stimulatory molecules and inflammatory cytokines. Phagocytosis mediated antigen when presented together with Toll-like receptor dependent gene expression of co-stimulatory molecule and inflammatory cytokines, instruct development of antigen-specific adaptive or acquired immunity (Figure 2). Thus, it is of great interest to characterize the correlation between TLRs and phagocytosis process. For instance, in absence of MyD88 (a common adaptor in TLR signalling) or TLR2TLR4, phagocytosis of bacteria comprising Salmonella typhimurium, Staphylococcus aureus, and Escherichia coli has been shown to be impaired because of impaired phagosome maturation. Several studies indicate that Toll-like receptor-mediated MyD88 dependent activation of p38 is needed for maturation of phagosome.
Figure 2 Adaptive Innate Immunity
(Takeda Akika 2000 8)
TLR Signalling Pathways
TLRs stimulation by microbial components or products triggers expression of a number of genes which are involved in the hosts immune responses (Takeuchi et al 2000, p. 113). The molecular mechanisms through which Toll-like receptors elicit gene expression are today being elucidated by analyses of TLR mediated signalling pathways. Microbial identification of TLRs assists dimerization of TLRs. Toll-like receptor 2 is shown to form a heterophilic dimer with either TLR1 or TLR6, but in other usual cases TLRS are alleged to form homodimers. TLRs dimerization triggers activation of signalling pathways that emanate from a cytoplasmic Toll Interleukin-1 Receptor domain (TIR). A TIR domain containing adaptor MyD88, was shown to be important for stimulation of inflammatory cytokines, such as Tumour necrosis facto-alpha (TNF-) and interleukin 12 (IL-12) through all Toll-like receptors (Takeuchi et al 2000, p. 113). However, specific TLRs activation results in slightly dissimilar patterns of gene expression profiles. For instance, activation of Toll-like receptor-3 and 4 signalling pathways leads to induction of type 1 interferons, but activation of TLR2 and TLR5 mediated pathways does not (Doyle 2002, p. 251). TLR7, TLR8, and TLR9 signalling pathways as well results in induction of type 1 interferons by mechanism distinct from TLR3 or 4 mediated induction. Therefore, its crystalline clear that Toll-like receptors activation leads to expression of several genes that are later involved in the immune response of the host (Figure 3).
Figure 3 Toll-like Receptor Signalling Pathways
(Hemmi et al 20033059 Beutler 2004 259)
Interaction between TLRs and Dendritic cells (DCs)
Dendritic cells express a collection of PRRs on the surface, which can specifically interact with pathogen associated molecular patterns, including mannose receptors, Toll-like receptors, and c-type lectins. Dissimilar DCs subsets could express different TLRs. For instance, mouse spleen CD8 DCs are indicated to express Toll-like-2, 3, 4, and 9 and encompass a greater Ag presentation ability than CD8- which express TLR-2, 3, 4, 5, 7, and 9 (Liu 2006, p.214 ). It has been discovered that DCs utilize a number of TLRs in detecting several characteristics of a pathogen at the same time and transmit the information regarding the nature of the microbial pathogens (danger signals) to direct an immune response tailored to the threat. Therefore, Toll-like receptor-induced signals could serve as one of the mechanisms of self or non-self discrimination (Figure 4). Triggering of distinct TLRs on DCs can induce dissimilar cytokine profiles leading to specific activation status of dendritic cells. For instance, TLR-associated molecule MyD88 signals are able to activate downstream TRAF6 stimulation, and this is followed by activation of nucleic factor kappa B (Liu 2006, p. 214). This may perhaps result in production of different sets of cytokines and render DCs with ability to promote generation of Th1, Th2 plus other T-helper cell subsets as well as cytotoxic T cells.
Figure 4 TLRs in Control of Self Non-self Ag Presentation by DCs
(Liu 2006 215)
The major role of Toll-like receptors in the immune system is recognition of pathogen associated molecular patterns (PAMPs). The result of this pathogenic recognition is the killing and subsequent elimination of the pathogens by the acute inflammatory response as well as the presentation of antigens to adaptive immune system cells (Basset 2003, p. 21). Therefore, TLRs is very substantial in both components of immune system (innate immunity and acquired or adaptive immunity).
These receptors activate both the innate and acquired immune responses and thus protect the organism from infections, through recognition of some conserved non-self molecules. An endotoxin found on the cell wall of a bacterium (Lipopolysaccharide) is considered to be prototypical PAMP and is specifically identified by Toll-like receptor 4, an innate immune system recognition receptor. Apart from lipopolysaccharides, other PAMPs comprise of lipoteichoic acid, from gram positive bacteria, bacterial flagellin, and nucleic acid variants usually associated with viruses, such as double stranded RNA (dsRNA). Though the word PAMP is relatively novel, the idea that molecules resulting from microbes ought to be distinguished by receptors from multicellular organisms has been held for a number of decades, and references to an endotoxin receptor are available in much of the older literature (Ausubel 2005, p. 977).
Over the years, the term PAMP has been under criticism by some immunologists on the basis that a large number of microbes, not only pathogens, express the molecules detected. Therefore the term MAMP (microbe associated molecular pattern) has been suggested. A virulence signal which is able to bind to a pathogen receptor in combination with a MAMP has been suggested as one way to constitute a PAMP. In plant immunology, the terms PAMP and MAMP are often treated interchangeably, considering them as the very first step in plant immunity (Ausubel 2005, p. 979).
Mechanism of Immune Recognition
Immune recognition is a unique mechanism and is mediated between products encoded in dissimilar genomes. Besides, the selective advantage imposed through immune recognition on the host genome normally implies a selective disadvantage to the pathogen genome. This conflict of interests directs evolution of non specific immunity toward identification of invariant molecular components of the infectious agents (Janeway 1989, p.6). Molecular structures which are imperative for microbes survival are never subject to variability in the sense that mutations upsetting these structures are mortal, lethal, and deadly for microbes. Molecular structure conservation means that they are shared by groups of pathogens. For instance, the generic structure of lipopolysaccharide is shared by the entire class of gram negative bacteria (Janeway 1989, p.6).
A receptor which would identify the conserved lipid A of lipopolysaccharide would therefore be capable of detecting the presence of any gram negative bacteria. This example exemplifies another characteristic of innate immune recognition, where the targets of recognition mechanism represent molecular patterns called pathogen associated molecular patterns (PAMPs), rather than other particular structures (Janeway 1989, p.10). Host organisms have developed receptors which can specifically identify or recognize pathogen associated molecular patterns that include both pattern recognition receptors (PRRs) and Toll-like receptors (TLRs). This evolutionary strategy of host organisms not only prevents the generation of microbial escape mutants, but permits a limited number of germline encoded receptors to identify a great array of molecular structures linked to pathogens as well. Additionally, it ought to be emphasized that PAMPs recognition by Toll-like receptors and PRRs not only permits the adaptive immune response to discriminate between non-self and self, but also between pathogen associated non-self and innocuous non-self (Janeway 1989, p.10).
The Roles of TLRs in Innate and Acquired Immune Response
The defence of the host organism against the invading microbial pathogens is induced by the immune system that consists of two components acquired immunity and innate immunity. Both components recognize the microbial pathogens as non-self and hence trigger the immune system to eradicate them. Today, both innate and acquired components of immune system have been characterized independently and the major research interest in immunology has been restricted to acquired immunity. In this immunity, T and B lymphocytes use antigen receptors, such as T-cell receptors and immunoglobulins to recognize non-self (Takeda and Akira 2005, p. 1). The mechanisms through which these antigen receptors identify foreign antigens have been extensively analyzed and the main mechanisms like clonality, memory, and diversity have been well characterized. However, these receptors exist only in vertebrates and according, the mechanism for non-self recognition in less advanced organisms is not fully understood. In addition, the mammalian innate immune system has not been well researched on. Consequently, innate immune cells of mammals, such as dendritic cells and macrophages are known to be activated by microbial components like lipopolysaccharide from gram negative, a receptor liable for recognition remains unknown (Takeda and Akira 2005, p. 1).
Toll-like receptors are germline encoded type 1 transmembrane receptors that are expressed on various cell types comprising dendritic cells and macrophages. They function as pattern recognition receptors, activating innate immunity by recognizing PAMPs that are unique to microbes and imperative for their survival (Carpenter and ONeill 2007, p.1891). Therefore, TLRs provide both instantaneous protective responses against pathogens as well as the acquired response by stimulation of dendritic cells recruitment and maturations (Muzio et al 2000, p. 453). Toll-like receptor triggering leads to nuclear factor kappa B-mediated activation of inflammatory genes. More than ten TLRs have been demonstrated and described in humans and agonists have been defined for nine of them. Toll-like receptors can function as heterodimers or homodimers, mounting the repertoire of specificities. TLR1, TLR2, and TLR6 are activated by any microbial product as well as peptidoglycan, TLR3 by double stranded RNA (dsRNA), TLR4 by LPS, TLR5 by flagellin, imidazoquinolines triggers both TLR7 and TLR8, and TLR9 is activated by CpG DNA (Campos et al 2001, p. 419).
TLRs Recognition of Microorganisms
Toll-like receptors being membrane bound molecules recognize microbial products within or on the surface of extracellular compartments of cells. Thus, intracellular recognition of invading microbial pathogens seems to involve a TLR independent system. Recent evidence shows that nucleotide binding oligomerization domain (NOD) family of proteins plays a substantial function in the recognition of pathogenic microbes. It has previously been indicated that TLR2 is capable of recognizing peptidoglycan (Takeuchi et al 1999, p. 443). However, peptidoglycan (PGN) contains a thick layer which is made up of overlapping lattice of 2 sugars that are cross linked by bridges of amino acids, and thus the exact structure of PGN which is recognized by TLR2 remains unknown. Nucleotide binding oligomerization was originally recognized as a molecule which is related to apotosis regulator, Apaf-1. It encompasses a caspase recruitment domain (CARD), a C-terminal domain, and a NOD domain.
Recent researches by a number of scientists have illustrated that over expression of NOD1 enables 293 cells to respond to peptidoglycan preparation (Girardin 2003, p. 1584). Therefore, NOD1 may play an essential role in sensing intracellular gram negative bacterial infections. Though, TLR2 has been reported to identify peptidoglycan, it is probable that TLR2 recognizes lipopeptide or lipoprotein contaminants trapped in the layers of PGN mesh. The viral identification is as well mediated by TLR dependent and independent mechanisms. TLR3 mediated recognition of dsRNA or viruses leads to TRIF dependent activation of interferon regulatory factor 3 (IRF-3) and nuclear factor kappa B. However, dsRNA or viruses are recognized in a TLR3 independent manner, as the impairment of responsiveness to dsRNA or viruses in TLR3 scarcity is only partial. RIG-1 is recognized as a molecule which is responsible for recognition of viruses and mediates 1RF-3 activation (Figure 1).
Figure 1 TLR Dependent Independent Recognition of Microbial Constituents
(Yoneyama 2004 730)
TLRs and Phagocytosis
The process of phagocytosis is an essential step for defence of the host against microbial invaders, as it activates both degradation of pathogens and resultant presentation of pathogen derived peptide antigen. Recognition of pathogens by Toll-like receptors results in expression of genes, such as co-stimulatory molecules and inflammatory cytokines. Phagocytosis mediated antigen when presented together with Toll-like receptor dependent gene expression of co-stimulatory molecule and inflammatory cytokines, instruct development of antigen-specific adaptive or acquired immunity (Figure 2). Thus, it is of great interest to characterize the correlation between TLRs and phagocytosis process. For instance, in absence of MyD88 (a common adaptor in TLR signalling) or TLR2TLR4, phagocytosis of bacteria comprising Salmonella typhimurium, Staphylococcus aureus, and Escherichia coli has been shown to be impaired because of impaired phagosome maturation. Several studies indicate that Toll-like receptor-mediated MyD88 dependent activation of p38 is needed for maturation of phagosome.
Figure 2 Adaptive Innate Immunity
(Takeda Akika 2000 8)
TLR Signalling Pathways
TLRs stimulation by microbial components or products triggers expression of a number of genes which are involved in the hosts immune responses (Takeuchi et al 2000, p. 113). The molecular mechanisms through which Toll-like receptors elicit gene expression are today being elucidated by analyses of TLR mediated signalling pathways. Microbial identification of TLRs assists dimerization of TLRs. Toll-like receptor 2 is shown to form a heterophilic dimer with either TLR1 or TLR6, but in other usual cases TLRS are alleged to form homodimers. TLRs dimerization triggers activation of signalling pathways that emanate from a cytoplasmic Toll Interleukin-1 Receptor domain (TIR). A TIR domain containing adaptor MyD88, was shown to be important for stimulation of inflammatory cytokines, such as Tumour necrosis facto-alpha (TNF-) and interleukin 12 (IL-12) through all Toll-like receptors (Takeuchi et al 2000, p. 113). However, specific TLRs activation results in slightly dissimilar patterns of gene expression profiles. For instance, activation of Toll-like receptor-3 and 4 signalling pathways leads to induction of type 1 interferons, but activation of TLR2 and TLR5 mediated pathways does not (Doyle 2002, p. 251). TLR7, TLR8, and TLR9 signalling pathways as well results in induction of type 1 interferons by mechanism distinct from TLR3 or 4 mediated induction. Therefore, its crystalline clear that Toll-like receptors activation leads to expression of several genes that are later involved in the immune response of the host (Figure 3).
Figure 3 Toll-like Receptor Signalling Pathways
(Hemmi et al 20033059 Beutler 2004 259)
Interaction between TLRs and Dendritic cells (DCs)
Dendritic cells express a collection of PRRs on the surface, which can specifically interact with pathogen associated molecular patterns, including mannose receptors, Toll-like receptors, and c-type lectins. Dissimilar DCs subsets could express different TLRs. For instance, mouse spleen CD8 DCs are indicated to express Toll-like-2, 3, 4, and 9 and encompass a greater Ag presentation ability than CD8- which express TLR-2, 3, 4, 5, 7, and 9 (Liu 2006, p.214 ). It has been discovered that DCs utilize a number of TLRs in detecting several characteristics of a pathogen at the same time and transmit the information regarding the nature of the microbial pathogens (danger signals) to direct an immune response tailored to the threat. Therefore, Toll-like receptor-induced signals could serve as one of the mechanisms of self or non-self discrimination (Figure 4). Triggering of distinct TLRs on DCs can induce dissimilar cytokine profiles leading to specific activation status of dendritic cells. For instance, TLR-associated molecule MyD88 signals are able to activate downstream TRAF6 stimulation, and this is followed by activation of nucleic factor kappa B (Liu 2006, p. 214). This may perhaps result in production of different sets of cytokines and render DCs with ability to promote generation of Th1, Th2 plus other T-helper cell subsets as well as cytotoxic T cells.
Figure 4 TLRs in Control of Self Non-self Ag Presentation by DCs
(Liu 2006 215)
The major role of Toll-like receptors in the immune system is recognition of pathogen associated molecular patterns (PAMPs). The result of this pathogenic recognition is the killing and subsequent elimination of the pathogens by the acute inflammatory response as well as the presentation of antigens to adaptive immune system cells (Basset 2003, p. 21). Therefore, TLRs is very substantial in both components of immune system (innate immunity and acquired or adaptive immunity).
Categories:
0 коммент.:
Отправить комментарий