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But what alerts the body to danger? How are foreign organisms detected? The discovery of microbial-sensing proteins called Toll-like receptors is helping to answer these questions and transform our understanding of the response to infection. A small number of Toll-like receptors can detect a broad range of human pathogens , as well as a variety of other molecules that indicate tissue damage, by a process called pattern recognition.

These receptors initiate two arms of the immune response — the innate and adaptive responses — that work together to fight infection in mammals. The innate response provides immediate protection.

However, it is relatively nonspecific in its mode of attack on pathogens, which results in damage to healthy tissue if the innate immune response lasts too long. The adaptive response, on the other hand, generates antibody-secreting B cells and cytotoxic T cells that are specific and efficient at targeting pathogen.

Unfortunately, this process takes longer to develop than the innate response. Because Toll-like receptors function as first responders to danger signals, they are centrally significant in research efforts to combat infectious and inflammatory disease.

New strategies for manipulating immune responses depend on understanding the cell biology of Toll-like receptors, including their structure, cell localization, signal transduction pathways, and expression patterns. The problem of microbial detection is part of a more general problem in cell biology: How can a cell obtain information about its environment? Even single-celled organisms must monitor their surroundings and respond to external signals to survive.

Our bodies are multicellular, and large numbers of cells need to communicate with one another and coordinate their activities to function as an integrated whole. The boundary of each cell is defined by the phospholipid bilayer of the plasma membrane, which acts as an effective barrier to most water-soluble molecules.

This boundary is not inert. The inclusion of proteins in the phospholipid bilayer makes the membrane a dynamic entity capable of sensing and interacting with the cellular environment. For example, membrane receptors bind and respond to specific molecules outside the cell, such as hormones, neurotransmitters, the extracellular matrix, and attachment molecules on other cells.

Proteins perform a wide range of biological functions because of their versatile structure. Linear chains of amino acids form proteins, and protein diversity arises from different amino acid combinations. Just as the twenty-six letters of the alphabet create a wide variety of words when combined, the twenty different amino acids create a variety of proteins when combined.

Each protein has a unique amino acid sequence that determines how the chain folds into a three-dimensional structure. The result is the tertiary structure or conformation of the protein, and it serves a unique, particular function. A receptor has a three-dimensional shape that enables it to bind with another molecule called a ligand which might be a hormone, a neurotransmitter, etc. The receptor and ligand bind with high affinity, meaning that the interaction is very strong, and with high specificity, meaning that binding is exclusive to the ligand or very similar molecules.

Human cells have only about 25, protein-encoding genes , so it is impossible to have a different gene and a different receptor for each species of virus , bacteria, protist, and fungus. How, then, can the body identify all species of pathogens that pose a danger, even those it has never encountered before? In , Charles Janeway proposed that cells use pattern recognition to detect pathogens Janeway In other words, receptors bind to structural shapes or patterns called PAMPs pathogen-associated molecular patterns that are present in whole groups of pathogens, but not the host.

According to Janeway's theory, receptors cannot identify a particular microbe with precision, but they can recognize it as a foreign organism. The first human pattern-recognition receptors were identified ten years after Janeway's proposal. The breakthrough was made possible by an earlier discovery in the fruit fly Drosophila.

German scientists originally identified the Toll gene as the site of mutations that generated bizarre-looking flies. They exclaimed that their results were " Toll!

A study reported that loss-of-function Toll mutations made Drosophila highly susceptible to fungal infections and that gain-of-function mutations led to increased production of certain antifungal proteins Lemaitre et al.

Comparisons of Toll mutations to mutations in other genes led to the conclusion that the Toll receptor plays a dominant role in detecting fungal infections and initiating the innate immune response. This exciting discovery provided researchers with the clue they needed to find human pathogen receptors. Figure 1: Receptors that detect infection Toll-like receptors TLRs recognize microbes by binding to pathogen-associated molecular patterns. Other pattern-recognition receptors for pathogens have been identified, such as: transmembrane C-type lectin receptors CLRs which detect fungi; secreted receptors collectins, ficolins, and pentaxins which activate innate defenses involving complement and phagocytosis; cytosolic RIGlike receptors RLRs which detect viruses; and cytosolic nucleotide-binding domain and leucine-rich repeat-containing receptors NLRs which detect pathogens and stress signals.

Figure Detail Scientists theorized that Toll-like receptors TLRs would initiate immune responses to pathogens because of their amino acid sequence similarities to Toll. But how could this theory be confirmed experimentally? Mouse models provided the necessary confirmation by enabling the function of TLRs to be studied in vivo in a whole organism. Mouse models are used to study a number of human inflammatory diseases, which are caused by an overactive innate immune response that leads to dangerous inflammation and tissue destruction.

For example, sepsis is a severe illness in which the bloodstream is overwhelmed with bacteria, causing inflammation throughout the body. It is responsible for the deaths of more than , people in the United States each year. Creating mouse models of sepsis involves injecting mice with bacteria to induce inflammation.

The severity of disease is then measured with controlled and standardized assays. Scientists have known for many years that isolated bacterial components, such as lipopolysaccharide LPS , can substitute for whole bacteria to induce sepsis. LPS is present in the cell walls of all Gram-negative bacteria, which represents a large group of pathogens.

In addition, Poltorak et al. Scientists now know that humans have at least ten different TLRs, and they collectively recognize a broad spectrum of pathogens Figure 1. TLRs 1, 2, 4, 5, and 6 bind to components of microbial cell walls and membranes unique to pathogens. The best characterized ligands are bacterial, including LPS and lipoteichoic acid from cell walls, lipoproteins from the cell membrane, and a structural component of bacterial flagella called flagellin.

These TLRs cannot distinguish self-nucleic acids those of the host cell on structural differences alone, and recognition of foreign nucleic acids those of the pathogen largely depends on the location in the cell. All these ligands play an essential role in the microbe, and the microbe cannot eliminate or modify them to evade detection.

Scientists have found TLRs in lower animals, such as the nematode C. Other pattern-recognition receptors for pathogens are also being identified Figure 1.

Drosophila and the nematode C. The receptors cross the membrane a single time and have an extracellular domain that extends outside the membrane and a cytoplasmic domain that extends into the cytoplasm. Panel B shows a molecular ribbon diagram of a TLR homodimer embedded in a plasma membrane. The two identical TLR proteins are colored red and blue. The extracellular domain of the each TLR protein folds into a semicircular shape, and the cytoplasmic domain folds into several coils.

Panel C shows that the signal transduction pathways that occur after activation of Toll and Toll-like receptors are conserved in the mouse, Drosophila , and C. Human TLRs are — amino acids long and consist of extracellular, transmembrane, and cytoplasmic domains.

The extracellular domain houses the ligand-binding site, and TLRs generally function as homodimers associations of two identical proteins. In fact, many ligands with distinct PAMPs exist, and the list of known ligands keeps growing.

Scientists have deduced the three-dimensional structure of TLRs with x-ray crystallography example, Figure 2b. The analysis of protein tertiary structure is a complicated puzzle, and figuring out the structure of something like a TLR is always a significant accomplishment. For TLRs, the precise molecular details reveal how ligand-receptor interactions emerge from the properties of atoms within the receptor Jin et al.

This information explains the specificity of a receptor and permits design of chemical agonists, which mimic the ligand's function, or chemical antagonists, which block the ligand's action. For example, chemists can use the molecular structure of TLR4 and its interaction with LPS to infer the best design for TLR4 antagonists, which can be treatments for certain inflammatory disorders, including sepsis Park et al.

TLRs 1, 2, 4, 5, and 6 are located primarily in the plasma membrane, where they interact with components of microbial pathogens that come into contact with the cell. In contrast, TLRs 3, 7, 8, and 9 are situated in the membranes of endosomes and lysosomes; the extracellular domain of the receptor and its ligand-binding site project into the interior of these organelles.

TLRs have complex expression patterns in different cell types. Thus, TLR10 may represent an immune marker for metabolic inflammation Sindhu et al. A high-glucose level could also induce TLR-2 and TLR-4 expression in retinal ganglion cells via increase in the secretion of pro-inflammatory factors in diabetic retinopathy Zhao et al.

Both of them inhibit MyDdependent pathway Brint et al. Although TLRs are essential elements in innate immune system and play a critical role in the host-defensive mechanism against microbes, overactivation of TLRs disrupts the immune homeostasis leading to excessive pro-inflammatory cytokines production that is no doubt involved in the pathogenesis of many autoimmune and inflammatory diseases.

Thus, inhibition of TLR signaling pathways has been predicted to be an effective therapeutic strategy to suppress unwanted, disease-associated inflammatory responses Gao et al. Accordingly, various therapeutic agents for inhibiting TLR signaling have been developed to control excessive inflammation; they can be classified as small molecule inhibitors, antibodies, oligonucleotides, lipid-A analogs, microRNAs, and new emerging nano-inhibitors Gao et al.

They are synthetic or naturally derived chemical weak bases that can inhibit TLR signaling by accumulation in the acidic intracellular compartments like endosomes and lysosomes leading to suppression of auto antigen presentation, blockade of endosomal TLR7, 8, and 9 signaling, and decrease in cytokine production Kuznik et al.

While HCQ has been found to ameliorate hypertension and aortic endothelial dysfunction Gomez-Guzman et al. They are designed to block the binding of ligands to the specific TLRs.

Blockade of TLR2 and 4 signaling by antagonistic antibodies decreases disease severity in sepsis models of Gram-positive and Gram-negative bacteria Daubeuf et al. It could successfully block cytokine release ex vivo and in vivo, prevent LPS-induced flu-like symptoms Monnet et al.

Accordingly, many of them have been developed particularly to treat inflammatory diseases associated with endosomal TLR activation, such as SLE Barrat et al. Recently, it was revealed that targeting of TLR7 and 9 signaling could be a novel strategy for treating the chronic inflammatory process associated with myasthenia gravis, an autoimmune neuromuscular disease Cavalcante et al. Varied forms of IMO, an immune modulatory oligonucleotide, could significantly reduce the expression of inflammatory genes in a mouse model of ILinduced psoriasis Suarez-Farinas et al.

They are small, endogenous non-coding RNAs with post-transcriptional regulatory functions to fine-tune gene expression Bartel, Gold nanoparticles GNPs have caught much attention in nanomedicine Pedrosa et al.

All researches done till now, in Egypt, have focused on the implications of TLRs in several diseases.

It was demonstrated that the genetic polymorphisms of TLR2 and TLR4 were not associated with asthma and allergic rhinitis, but significant association was found between these genetic variants and the disease severity in children Hussein et al. There was no significant association between TLR4 polymorphism and colorectal cancer CRC , but higher serum level of it was associated with a diagnostic prospect in CRC patients Bassuny, TLR4 levels were higher in T2DM patients and found to correlate well with the severity of albuminuria suggesting its possible role in the pathogenesis of diabetic nephropathy Fathy et al.

Increased TLR4 expression on T cells which associated with increased reactive oxygen species ROS generation has been shown to play pathogenic role in autistic children Nadeem et al. Based on the existing scientific literature, it is concluded that TLRs are the main elements in the innate orchestration of immune system. Working in TLRs area including their characterization, expression, ligands recognition, signaling, and implication in many diseases has significantly progressed in past years.

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