Different Toll-like receptors expressed by immune cells [7, 16].
Abstract
Toll-like receptors (TLRs), a major component of innate immune system, are expressed as membrane or cytosolic receptors on neutrophils, monocytes, macrophages, dendritic cells (DCs), B lymphocytes, Th1, Th2, and regulatory T lymphocytes. It recognizes pathogen-associated molecular patterns (PAMPs) and Toll-interleukin1 (IL-1) receptor (TIR) of various invading pathogens. Downstream signaling of TLRs activates NF-κB, which acts as a transcription factor of pro-inflammatory cytokines, chemokines, and costimulatory molecules. A balance between pro- and anti-inflammatory cytokine protects host body from infectious agents and also induces the healing process. Some of parasitic infections by protozoans and helminths such as Malaria, Leishmaniasis, Trypanosomiasis, Toxoplasmosis, Amoebiasis, Filariasis, Schistosomiasis, Ascariasis, Taeniasis, and Fasciolosis are the leading cause of death and economic loss in both developing and developed nations. Frequent exposure to parasites, immigration, refugee resettlement, increasing immunodeficiency, climate change, drug resistance, lack of vaccination, etc. are the major cause of emerging and re-emerging of the above-stated diseases. However, TLR activation by parasites could stimulate antigen presenting cells and ultimately clear the pathogens by phagocytosis. So, a better understanding of host-parasite interaction in relation to TLR signaling pathway will improve the controlling method of these pathogens in immunotherapy.
Keywords
- Toll-like receptors
- pathogen-associated molecular patterns
- protozoan parasite
- helminth infection
1. Introduction
Increasing cases of parasitic infections (due to protozoans and helminths) and high rate of mortality are the greatest problem of today’s world. Some of these diseases such as Malaria, Filariasis, Trypanosomiasis, Leishmaniasis, Toxoplasmosis, Amoebiasis, Ascariasis, Schistosomiasis, and Taeniasis affect over half a billion people worldwide and cause economic loss in both developing and developed countries [1]. Overpopulations, migration of people into large urban areas, and unhygienic environment are the main reasons for making these diseases epidemic [2]. However, the tragedy is that only 5% of total health expenditure was given for research work on parasitic diseases [3]. Currently, there is no effective vaccine available for these major problems. So, a better understanding of pathogenesis during infection, resistance mechanism of pathogens, host protective immune response initiation, and progression is needed for developing effective vaccines or therapeutic interventions [4].
Among the two types of vertebrate immune system, innate immunity provides the first line of defense against parasites. Previous studies stated innate immunity as nonspecific response, and it induces the acquired immunity (slower and specific response) by providing pathogens to T and B cells [5]. However, recent evidence proved that innate immune system also had a great degree of specificity and can provide host defense against invading parasites. This is because of the presence of five classes of pattern recognition receptors: TLRs (Toll-like receptors), C-type lectin receptors, NOD-like receptors (nucleotide-binding oligomerization domain leucine-rich repeat-containing receptors), RIG-I (retinoic acid inducible gene I protein) helicase receptors, and cytosolic dsDNA sensors [6, 7]. Among them, TLRs form a bridge between innate and adaptive immunity and play a very important role in parasite eradication. TLRs recognize specific pathogen-associated molecular patterns (PAMPs) in pathogens and initiate opsonization, phagocytosis, pro-inflammatory and anti-inflammatory response, and apoptosis [7, 8].
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.
Cells | Expressing TLRs |
---|---|
Neutrophils | TLR 1, 2, 4, 5, 6, 7, 8 |
Monocytes/macrophages | TLR 1, 2, 4, 5, 6, 7, 8 |
Myeloid dendritic cells | TLR 2, 3, 4, 7, 8 |
Plasmacytoid dendritic cells (PDCs) | TLR 1, 6, 7, 9 |
B lymphocytes | TLR 1, 3, 6, 7, 9, 10 |
T lymphocytes (Th1/Th2) | TLR 2, 3, 5, 9 |
T lymphocytes (regulatory) | TLR 2, 5, 8 |
Peripheral blood mononuclear cell (PBMC) | TLR 2, 4, 5, 7, 8, 9 |
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 (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].
3. TLR signaling pathway
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 DCs) and Th2 cells (via IL-4 from B cell) [21, 23].
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 (TRIF-related 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 adapter-like). Then, IRAK-4 phosphorylates IRAK-1 [26] which in turn phosphorylates IRAK-2. IRAK-2 ubiquitinates TRAF6 (tumor necrosis factor receptor-associated factor 6) and induces two signaling pathways: (1) AP-1 (activator protein 1) activation via MAK 4/7 (mitogen-activated protein kinase) phosphorylation and (2) TAK1 (transforming growth factor-β-activated kinase 1) activation ultimately leads to MAPK (mitogen-activated protein kinase) and IKK complex [27] stimulation and nuclear factor κB (NF-κB) translocation inside the nucleus via degradation of its inhibitor. Both AP-1 and NF-κB induce the expression of pro-inflammatory cytokines and chemokines. A different MyD88-dependent pathway stimulates TLR 7, 8, and 9, which acts as a ligand for viral nucleic acids. MyD88-associated IRAK1 (interleukin-1 receptor-associated kinase-1) phosphorylates IRF7 (interferon-regulatory factor-7), which regulates Type I interferon expression [28]. TLR signaling through MyD88-independent pathway occurs via two adaptor molecules—TRIF (Toll-IL-1 receptor domain-containing adaptor inducing interferon-β) and TRAM (TRIF-related adaptor molecules) (Figure 1). This induces Type 1 interferon by IRF-3 (interferon-regulatory factor-3), NF-κB activation, and expression of co-stimulatory molecules [29].
4. Protozoan infections
Different protozoan (Plasmodium, Leishmania, Trypanosoma, Toxoplasma, and Entamoeba) PAMPs induced pathogenic reactions through TLR signaling pathway.
4.1 Malaria
Malaria, one of the most life-threatening diseases of human history, has infected about 219 million people over 90 countries with around 1 million deaths per year. Plasmodium, an intracellular protozoan parasite, is the causative agent of malaria. It is transmitted by infected female Anopheles mosquito biting, and four species of
Homodimer of TLR4 and heterodimer of TLR1/TLR2 and TLR4/TLR6 can bind to GPIs released during erythrocytic phase of
4.2 Leishmaniasis
Leishmaniasis is one of the deadliest parasitic infections with an estimation of 200,000–400,000 worldwide infections each year. A protozoan parasite is the causative agent of this disease, which is transmitted to humans by the biting of female Phlebotomus sandfly. The pathology of this infection and causative parasitic species includes cutaneous (i.e.,
Lipophosphoglycan (LPG) occurs as a surface protein of
4.3 Trypanosomiasis
The protozoan parasites of the genus
TLR receptor plays an important role in internalization of the parasite through phagocytosis and induces immune response for parasite eradication from cells [75]. GPI anchored mucin-like glycoproteins (tGPI-mucin contains unsaturated alkylacylglycerol) of the
4.4 Toxoplasmosis
TLR11 and TLR12 recognize
4.5 Amoebiasis
5. Helminth infections
Although several studies were conducted on TLR signaling in response to intracellular parasites, only a few examination reflects the interaction of helminths with TLRs.
5.1 Filariasis
Lymphatic filariasis (commonly called elephantiasis), caused by three species of nematode parasites,
In case of chronic infection, filarial nematode downregulates host immune response via TLR4-mediated T cell apoptosis [97]. Live microfilariae of
5.2 Schistosomiasis
Schistosomiasis is a worldwide distributed parasitic disease caused by a flatworm, Schistosoma. It accounts for 260 million infected people in tropical and sub-tropical regions (Africa, South America, the Middle East, East Asia, and the Philippines) [102].
5.3 Taeniasis
The pork tapeworm (
TLR4 and TLR2 play an important role in developing murine NCC caused by
5.4 Ascariasis
Phospholipids from schistosomes and
5.5 Fasciolosis
6. Conclusion
In conclusion, induction of TLR signaling pathway by infectious pathogen recognition provides a better understanding of innate immune defense mechanism against this disease. Immunotherapy emerges as a promising therapeutic approach for parasitic infection treatment over the past few years. Although no effective drugs have emerged, vaccine adjuvants yield promising results due to induction of cellular immunity via TLR. Large scales of clinical studies were conducted for developing potent and well-tolerated adjuvants. The protozoan and helminth parasites can cause activation (to a small degree) and negative regulation (to a larger degree) of TLRs resulting in increasing or decreasing parasite burden [103]. TLR agonists or antagonists are small molecule mimics, natural ligands used for treating Type I allergy, cancer, and infectious diseases. MF59 (Novartis) and AS04 (GSK) are some examples of TLR4 agonist licensed for human use [124]. GLA (TLR4 ligand) and 3M-052 (TLR7/8) ligands are now in clinical trial. Recently, RTS,S/AS01, a recombinant chimeric protein (c-terminal of circumsporozoite antigen fused with HPB antigen, and “ASO1” refers to the adjuvant formulation MPL and QS21, a natural glucoside), is used for treating Malaria [125]. Several new drugs have been chemically synthesized for better understanding of the interaction of TLRs with their ligands. The knowledge from these studies will provide a greater opportunity for developing plant-derived new therapeutic drugs. So, major efforts are required for targeting TLRs in pathological conditions.
Acknowledgments
CF is thankful to the Head of the Department of Zoology, Visva-Bharati University, for extending the facilities for her research work. AM is thankful to Science & Engineering Research Board (SERB), Department of Science & Technology, Govt. of India, for her JRF fellowship (grant no. ECR/2017/001028). DC is thankful to DBT for JRF. SD thanks UGC, New Delhi, for SRF. The authors are thankful to Dr. Rakesh Kundu and Dr. Sandip Mukherjee for their technical assistance and constant encouragement.
Notes/thanks/other declarations
The authors thank the Head of the Department of Zoology, Visva-Bharati University, for providing the assistance in their research work.
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