**2. Cells expressing TLRs**

TLRs, a major component of innate immunity, are Type-1 transmembrane glycoproteins present in both vertebrates and invertebrates [9]. Toll-like receptors are named due to their similarity with Drosophila Toll protein (Toll) [10]. All TLRs have a highly variable extracellular domain containing leucine-rich repeat (LRR) domain for ligand binding and intracellular TIR homology domain [11]. Toll-like receptors and interleukin-1 receptor together form "Interleukin-1 receptor/Toll-like receptor" superfamily whose all members have a common Toll-IL-1 receptor (TIR) domain [12]. Till date, 10 humans and 12 mice functional TLRs were identified. Although humans and mice have similar TLR1–9, TLR10 is nonfunctional in mice and TLR11–13 are lost in humans [13]. TLR1, TLR2, TLR4, TLR5, and TLR6 recognize extracellular PAMPs, which are expressed on cell surface, whereas TLR3, TLR7, TLR8, and TLR9 are expressed within endoplasmic reticulum (ER), endosomes, lysosomes, and endolysosomes and identify nucleic acids [14]. The presence of TLRs on specific intracellular vesicles restricts their activation by self-nucleic acids released by apoptotic cells [15]. TLR11 (a relative of TLR5) and TLR13 are expressed in intracellular vesicles [16], but cognate PAMP of TLR13 has not been identified yet [17]. **Table 1** shows the distribution of various TLRs in different cells.

TLRs can be classified on the basis of their recognized ligands—TLR1/TLR2 heterodimer (triacylated lipopeptides), TLR2/TLR6 heterodimer (diacylated lipopeptides), TLR4 (lipopolysaccharide), TLR3 (double-stranded RNA), TLR5


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**Figure 1.**

*TLR signaling pathway.*

*TLR Signaling on Protozoan and Helminthic Parasite Infection*

DCs) and Th2 cells (via IL-4 from B cell) [21, 23].

(flagellin), TLR 7/8 (single-stranded RNA), and TLR9 (unmethylated CpG motif) [18, 19]. These ligands for TLRs are of bacterial, viral, protozoan, fungal, and helminth membrane bound or endogenously released molecules such as hyaluronic acid, fibrinogen, fibronectin, b-defensins, heparan sulfate proteoglycans, heat

TLRs present on dendritic cells (DCs) [both myeloid DCs (mDCs) and plasmacytoid DCs (pDCs)], neutrophils, macrophages, natural killer (NK), and natural killer T (NKT) cells induce dendritic cell maturation, MHC molecule upregulation, and costimulatory molecule production (CD40, CD80, and CD86) [21, 22]. The cytokines released by TLR signaling ultimately activate Th1 cells (via IL-12 from

Toll-interleukin-1 receptor (TIR) domain is responsible for transducing the signal from TLRs to their adaptor proteins. The C-terminus of all TLRs, IL-1 and IL-18 and adaptor proteins of TLRs have this TIR domain. Six adaptor proteins involved in TLR signaling are MyD88 (myeloid differentiation factor 88), TIRAP (Toll-IL-1 receptor domain-containing adaptor protein) and MAL (MyD88 adapter-like), TRIF (TIR domain-containing adaptor inducing interferon-β) and TICAM-1, TRAM (TRIFrelated adaptor protein) and TICAM-2, SARM (sterile-α and HEAT/Armadillo motifs-containing protein) and MyD88-5, and BCAP (B Cell Adaptor for PI3K) [24]. TLR signaling occurs via two separate pathways: MyD88 (myeloid differentiation primary response protein)-dependent pathway and MyD88-independent pathway. MyD88-dependent pathway stimulates all TLRs except TLR-3, which gets stimulated by MyD88-independent pathway. However, in case of TLR4, both MyD88-dependent and independent pathways operate [25]. MyD88 (an adaptor molecule) activates IRAK-4 (interleukin-1 receptor-associated kinase-4) alone or in combination with TIRAP (Toll-IL-1 receptor domain-containing adaptor protein) or MAL (MyD88

shock proteins, nucleic acids, and synthetically derived molecules [20].

*DOI: http://dx.doi.org/10.5772/intechopen.84711*

**3. TLR signaling pathway**

#### **Table 1.**

*Different Toll-like receptors expressed by immune cells [7, 16].*

(flagellin), TLR 7/8 (single-stranded RNA), and TLR9 (unmethylated CpG motif) [18, 19]. These ligands for TLRs are of bacterial, viral, protozoan, fungal, and helminth membrane bound or endogenously released molecules such as hyaluronic acid, fibrinogen, fibronectin, b-defensins, heparan sulfate proteoglycans, heat shock proteins, nucleic acids, and synthetically derived molecules [20].
