**4.2 Leishmaniasis**

*Toll-like Receptors*

stimulatory molecules [29].

**4. Protozoan infections**

**4.1 Malaria**

adapter-like). Then, IRAK-4 phosphorylates IRAK-1 [26] which in turn phosphorylates IRAK-2. IRAK-2 ubiquitinates TRAF6 (tumor necrosis factor receptorassociated 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 (interferonregulatory 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-

Different protozoan (Plasmodium, Leishmania, Trypanosoma, Toxoplasma, and Entamoeba) PAMPs induced pathogenic reactions through TLR signaling pathway.

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 *Plasmodium* are responsible for human malarial infection. Among *Plasmodium falciparum*, *Plasmodium vivax*, *Plasmodium ovale,* and *Plasmodium malariae*, *P. falciparum* is the deadliest. Recently, another species named *Plasmodium knowlesi* has been found to infect humans [30]. In the early presymptomatic stage, a very low level of plasmodium can induce inflammatory response [31]. The innate immune genes such as TLRs, PRRs, and inflammatory cytokines are already upregulated, and these lead to elevate the level of TNF, IFN, and IL-12 from plasmodium-infected peripheral blood mononuclear cells (PBMCs) up to 48 h of infection [32, 33]. These inflammatory responses are associated with the pathophysiological condition and clinical symptoms of

malaria including anemia, cerebral malaria, and ultimate death [34]. Cerebral malaria is caused due to overexpression and binding of adhesion molecules such as intracellular adhesion molecule 1 (ICAM-1), vascular cellular adhesion molecule 1 (VCAM-1), endothelial/leukocyte adhesion molecule (ELAM-1), and CD36 [35] on brain endothelial cell receptors. Thus, inflammatory response leads to sequestration of infected red blood cells in host brain [36]. Furthermore, TNF and IFN suppress hematopoiesis and lead to anemia during malarial infection [37]. The potential immunomodulators of the malarial parasites are: (1) plasmodial glycosylphosphatidylinositol (GPI) anchors, (2) hemozoin, and (3) plasmodial DNA. All of these three molecules are referred as "malaria toxin" released during schizogony and cause inflammation and

Homodimer of TLR4 and heterodimer of TLR1/TLR2 and TLR4/TLR6 can bind to GPIs released during erythrocytic phase of *P. falciparum* infection [40]. GPI induces TLR-mediated proinflammatory cytokines (TNFα and IL-1) [41] and

**66**

symptoms of malaria [38, 39].

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., *L. major*, *L. mexicana*, and *L. guyanensis*), mucocutaneous (i.e., *L. amazonensis* and *L. braziliensis*), or visceral leishmaniasis (*L. donovani* and *L. chagasi*) [54]. Several reports indicate that few Leishmania-derived molecules could interact with innate immune receptors (TLRs) of host and result in inflammatory

**Figure 2.** *TLR signaling during Plasmodium infection.*

response. This inflammation effectively deprives parasites from the host by inducing efficient adaptive responses.

Lipophosphoglycan (LPG) occurs as a surface protein of *L. major*, *L. mexicana*, *L. aethiopica*, and *L. tropica* and acts as a major ligand for TLR-mediated host immune response. LPG's secreted form is structurally similar to membrane bound form with differences in sugar types of glycan and in number of phosphorylated oligosaccharide repeats. Membrane bound LPG induces ROS production and Th2 cell differentiation, whereas soluble LPG causes Th1-promoting cytokine production [55]. Inside NK cells, LPG of *L. tropica* induces TNFα, IFNγ, nitric oxide (NO), and reactive oxygen species (Th1 response) release via TLR2 upregulation and stimulation [56, 57]. TLR2 can also induce immune response by altering TLR9 expression [58]. However, in case of *L. braziliensis* and *L. amazonensis*, parasite could decrease IL-12 production, increase IL-10 production by TLR2-mediated p38 MAPK inhibition in macrophages, and thus increase pathogenesis. TLR2/TLR4 dimerization induces the expression of SOCS-1 and SOCS-3 (suppressor of cytokine signaling protein) by LPG [59]. A protein structurally related to silent information regulator 2 (SIR2) family could activate B lymphocytes, major histocompatibility complex (MHC) II, CD40 and CD86 (costimulatory molecules) overexpression, DC maturation, and TNFα and IL12 secretion through TLR2 [60]. HO-1 (heme oxygenase-1) mediated inhibition of TLR2, 4, 5, and 9 (but not TLR3) association with their adaptor proteins resulted in downregulation of TNFα and IL-12 production in *L. chagasi* and *L. donovani* infection [61]. This inflammatory imbalance occurs due to MAPKp38 phosphorylation inhibition and ERK 1/2 phosphorylation activation in macrophages. In addition, *L. donovani*, *L. mexicana* (expressed p8 proteoglycolipid complex), and *L. major* suppressed TLR4 activation by releasing TGFβ that activates A20, a complex deubiquitinating enzyme, through SRC homology region-2 domain containing phosphatase-1 (SHP-1) and IRAK inactivation [62]. Proteoglycolipid complex (P8), host-derived Apolipoprotein E (ApoE), and four glycolipids of *L. pifanoi* amastigote were the ligands of TLR4 and control the parasite [55]. P8 activates TLR4 of parasitophorous vacuole, which induces IL1 and TNFα production and aids in phagocytosis of *L. pifanoi*. At early stage of infection, neutrophil-derived serine protease and elastase results in parasite death, but at later stage, bone marrow derived macrophages (M2b macrophage) phagocytose neutrophil and helps in *L. major* replication by Th2-type response [63]. *L. panamensis* infection results in TNF α production through TLR-1, TLR-2, TLR-3, and TLR-4 pathway in human primary macrophages [64], metacyclic promastigote of *L. mexicana* induce phosphorylation of MAP kinases (ERK, p38, and JNK) through TLR4 and MФ(bone marrow-derived macrophages), iNOS, cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), NO, and arginase-1 are act as the inflammatory response mediators [65]. Leishmania parasites grow inside the phagolysosome of the host cells, which reflect that endosomally localized TLRs are also involved in pathogenesis [66]. In case of *L. donovani* infection, TLR7 activates IRF-5 and induces Th1 responses of host [67]. Cytosine-phosphate-guanosine motifs in DNA of *L. major* induce TLR9-mediated NK cell activation and IL12 production from bone marrowderived DC [68, 69]. Recent reports show that viral RNA present in *L. guyanensis* (LRV1-Lg), *L. major* (LRV2-Lmj) [70], and *L. aethiopica* (LRV2-Lae) serves as a ligand for TLR3 [71]. TLR3 produces NO and TNFα during *L. donovani* infection and mediates leishmanicidal activity [72] (**Figure 3**).

#### **4.3 Trypanosomiasis**

The protozoan parasites of the genus *Trypanosoma* cause a group of disease in several vertebrates, called trypanosomiasis or trypanosomosis. In humans,

**69**

*TLR Signaling on Protozoan and Helminthic Parasite Infection*

*Trypanosoma brucei gambiense* and *Trypanosoma brucei rhodesiense* cause African trypanosomiasis or sleeping sickness (transmitted by tsetse fly), and *Trypanosoma* 

Triatominae bugs) [73]. All of these parasites cause millions of death per year in both sub-Saharan African and Latin American countries. The disease remains asymptomatic for several years and ultimately affects the central nervous system,

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 *T. cruzi* trypomastigote membrane activates MAPK (by phosphorylation) and IkB (inhibitor of NF-κB), which triggers TLR2-mediated cytokine production by macrophages [76]. A TLR2-TLR6 and CD14 complex recognize the free GPI (glycoinositophospholipids containing ceramide) from *T. cruzi* parasite (epimastigote) [77]. Tc25, a *T. cruzi* derived protein, induces TLR2-mediated proinflammatory cytokine release from host cells [78]. However, role of GPI anchors VSGs of *T. brucei* Trypomastigotes in specific TLR-mediated macrophage activation and proinflammatory cytokine (TNFα, IL-6, and NO) production have not been elucidated yet [79]. *T. cruzi* and *T. brucei* genomic DNA (contains unmethylated CpG motifs) have TLR9-mediated TNFα and IFNα/β stimulation and penetration

*Toxoplasma gondii*, an obligate intracellular apicomplexan parasite, is a leading cause of food borne disease in a wide range of worm-blooded animals worldwide [82]. *T. gondii* causes asymptomatic toxoplasmosis in healthy adults and produces severe toxoplasmic encephalitis in immune compromised people [83]. Moreover, it causes congenital toxoplasmosis in fetus leading to death and abortion [84]. Inside its intermediate host humans, mice, etc., *T. gondii* proliferates asexually to form

*cruzi* causes American trypanosomiasis or chagas disease (blood feeding

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

*TLR signaling induced by different Leishmania ligands.*

heart, and GI tract [74].

**Figure 3.**

**4.4 Toxoplasmosis**

of T cells in brain parenchyma [80, 81] (**Figure 4**).

tachyzoite and bradyzoite stages [85].

*TLR Signaling on Protozoan and Helminthic Parasite Infection DOI: http://dx.doi.org/10.5772/intechopen.84711*

*Toll-like Receptors*

efficient adaptive responses.

response. This inflammation effectively deprives parasites from the host by inducing

*L. aethiopica*, and *L. tropica* and acts as a major ligand for TLR-mediated host immune response. LPG's secreted form is structurally similar to membrane bound form with differences in sugar types of glycan and in number of phosphorylated oligosaccharide repeats. Membrane bound LPG induces ROS production and Th2 cell differentiation, whereas soluble LPG causes Th1-promoting cytokine production [55]. Inside NK cells, LPG of *L. tropica* induces TNFα, IFNγ, nitric oxide (NO), and reactive oxygen species (Th1 response) release via TLR2 upregulation and stimulation [56, 57]. TLR2 can also induce immune response by altering TLR9 expression [58]. However, in case of *L. braziliensis* and *L. amazonensis*, parasite could decrease IL-12 production, increase IL-10 production by TLR2-mediated p38 MAPK inhibition in macrophages, and thus increase pathogenesis. TLR2/TLR4 dimerization induces the expression of SOCS-1 and SOCS-3 (suppressor of cytokine signaling protein) by LPG [59]. A protein structurally related to silent information regulator 2 (SIR2) family could activate B lymphocytes, major histocompatibility complex (MHC) II, CD40 and CD86 (costimulatory molecules) overexpression, DC maturation, and TNFα and IL12 secretion through TLR2 [60]. HO-1 (heme oxygenase-1) mediated inhibition of TLR2, 4, 5, and 9 (but not TLR3) association with their adaptor proteins resulted in downregulation of TNFα and IL-12 production in *L. chagasi* and *L. donovani* infection [61]. This inflammatory imbalance occurs due to MAPKp38 phosphorylation inhibition and ERK 1/2 phosphorylation activation in macrophages. In addition, *L. donovani*, *L. mexicana* (expressed p8 proteoglycolipid complex), and *L. major* suppressed TLR4 activation by releasing TGFβ that activates A20, a complex deubiquitinating enzyme, through SRC homology region-2 domain containing phosphatase-1 (SHP-1) and IRAK inactivation [62]. Proteoglycolipid complex (P8), host-derived Apolipoprotein E (ApoE), and four glycolipids of *L. pifanoi* amastigote were the ligands of TLR4 and control the parasite [55]. P8 activates TLR4 of parasitophorous vacuole, which induces IL1 and TNFα production and aids in phagocytosis of *L. pifanoi*. At early stage of infection, neutrophil-derived serine protease and elastase results in parasite death, but at later stage, bone marrow derived macrophages (M2b macrophage) phagocytose neutrophil and helps in *L. major* replication by Th2-type response [63]. *L. panamensis* infection results in TNF α production through TLR-1, TLR-2, TLR-3, and TLR-4 pathway in human primary macrophages [64], metacyclic promastigote of *L. mexicana* induce phosphorylation of MAP kinases (ERK, p38, and JNK) through TLR4 and MФ(bone marrow-derived macrophages), iNOS, cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), NO, and arginase-1 are act as the inflammatory response mediators [65]. Leishmania parasites grow inside the phagolysosome of the host cells, which reflect that endosomally localized TLRs are also involved in pathogenesis [66]. In case of *L. donovani* infection, TLR7 activates IRF-5 and induces Th1 responses of host [67]. Cytosine-phosphate-guanosine motifs in DNA of *L. major* induce TLR9-mediated NK cell activation and IL12 production from bone marrowderived DC [68, 69]. Recent reports show that viral RNA present in *L. guyanensis* (LRV1-Lg), *L. major* (LRV2-Lmj) [70], and *L. aethiopica* (LRV2-Lae) serves as a ligand for TLR3 [71]. TLR3 produces NO and TNFα during *L. donovani* infection

Lipophosphoglycan (LPG) occurs as a surface protein of *L. major*, *L. mexicana*,

**68**

**4.3 Trypanosomiasis**

and mediates leishmanicidal activity [72] (**Figure 3**).

The protozoan parasites of the genus *Trypanosoma* cause a group of disease in several vertebrates, called trypanosomiasis or trypanosomosis. In humans,

**Figure 3.** *TLR signaling induced by different Leishmania ligands.*

*Trypanosoma brucei gambiense* and *Trypanosoma brucei rhodesiense* cause African trypanosomiasis or sleeping sickness (transmitted by tsetse fly), and *Trypanosoma cruzi* causes American trypanosomiasis or chagas disease (blood feeding Triatominae bugs) [73]. All of these parasites cause millions of death per year in both sub-Saharan African and Latin American countries. The disease remains asymptomatic for several years and ultimately affects the central nervous system, heart, and GI tract [74].

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 *T. cruzi* trypomastigote membrane activates MAPK (by phosphorylation) and IkB (inhibitor of NF-κB), which triggers TLR2-mediated cytokine production by macrophages [76]. A TLR2-TLR6 and CD14 complex recognize the free GPI (glycoinositophospholipids containing ceramide) from *T. cruzi* parasite (epimastigote) [77]. Tc25, a *T. cruzi* derived protein, induces TLR2-mediated proinflammatory cytokine release from host cells [78]. However, role of GPI anchors VSGs of *T. brucei* Trypomastigotes in specific TLR-mediated macrophage activation and proinflammatory cytokine (TNFα, IL-6, and NO) production have not been elucidated yet [79]. *T. cruzi* and *T. brucei* genomic DNA (contains unmethylated CpG motifs) have TLR9-mediated TNFα and IFNα/β stimulation and penetration of T cells in brain parenchyma [80, 81] (**Figure 4**).

#### **4.4 Toxoplasmosis**

*Toxoplasma gondii*, an obligate intracellular apicomplexan parasite, is a leading cause of food borne disease in a wide range of worm-blooded animals worldwide [82]. *T. gondii* causes asymptomatic toxoplasmosis in healthy adults and produces severe toxoplasmic encephalitis in immune compromised people [83]. Moreover, it causes congenital toxoplasmosis in fetus leading to death and abortion [84]. Inside its intermediate host humans, mice, etc., *T. gondii* proliferates asexually to form tachyzoite and bradyzoite stages [85].

**Figure 4.** *Trypanosoma PAMPs and TLR signaling.*

TLR11 and TLR12 recognize *T. gondii* profiling (TgPRF) and induce IL12 and IFNα production in conventional dendritic cells (cDCs), macrophages, and plasmacytoid dendritic cells (pDCs). This IFNα induces IFNγ production from NK

**71**

*TLR Signaling on Protozoan and Helminthic Parasite Infection*

tion in different central nervous system cell types [85] (**Figure 5**).

cells. *T. gondii* infection also induces IFNβ production in inflammatory monocytes (IMs) and TLR4-mediated phagocytic uptake of the parasite [86]. Endosomal TLRs (TLR3, TLR7, and TLR9) stimulate IL12 production in human PBMCs in response to DNA and mRNA of *T. gondii* tachyzoites when the cells were primed with IFNγ [87]. GPIs present in parasite membrane aggravate TLR2- and TLR4-mediated TNFα production in inflammatory response [88]. In some cases, tachyzoites differentiate into bradyzoites inside the central nervous system and cause neurological and behavioral abnormalities [89]. TLR2 signaling pathway makes chronic inflamma-

*Entamoeba histolytica* is a protozoan parasite, which causes amebiasis in humans. It is one of the deadliest diseases after malaria and causes almost 40,000–100,000 deaths per year in underdeveloped countries [90]. The clinical symptoms include diarrhea, dysentery, pain in lower abdomen, and liver abscess, which occur due to invasion of amoeba in host lung, heart, brain, skin, genital, etc. [91]. The lipophosphopeptidoglycan (LPPG) present on the surface of *E. histolytica* induces TLR2- and TLR4-mediated NF-κB activation and cytokine (IL-8, IL-10, IL-12p40, and TNFα) release from human monocytes [92]. The Gal/GalNAc lectin (Gal-lectin), a surface molecule of *E. histolytica,* upregulates cytokines and TLR2 genes via NF-κB and MAP kinase activation in macrophages and dendritic cells [93]. TLR9 recognizes *E. histolytica* genomic DNA and helps in TNFα production in macrophages [94]

Although several studies were conducted on TLR signaling in response to intracellular parasites, only a few examination reflects the interaction of helminths

Lymphatic filariasis (commonly called elephantiasis), caused by three species of nematode parasites, *Wuchereria bancrofti*, *Brugia malayi*, and *B. timori*, is a major health problem in tropical countries. During initial stage, infection remains asymptomatic. Acute condition displays local inflammation of skin, lymph nodes, and lymphatic vessels, which ultimately leads to edema in chronic condition [95]. Wolbachia, an intracellular symbiotic bacterium of filarial nematode, is the major mediator of inflammatory response in case of lymphatic filariasis and onchocerciasis [2]. WSP protein in outer membrane of *Wolbachia* sp. induces TLR2- and

In case of chronic infection, filarial nematode downregulates host immune response via TLR4-mediated T cell apoptosis [97]. Live microfilariae of *B. malayi* can downregulate mRNA and protein expression of TLR1, TLR2, TLR4, and TLR9 and activate TLR2 upon antigen stimulation on B cells and monocytes [98]. In DCs, live microfilariae and microfilarial antigen (MF Ag) diminish IL-12, IFNα, and cytokine production via inhibition of NF-κB complex formation [99]. Microfilariae infective stage (L3) of *B. malayi* also shows partial inhibition of Langerhans cells (LCs) that lead to CD4+ T cell proliferation [100]. Circulating B cells (called Breg) express TLR2 and TLR4 and maintain a worm favorable condition via induction of Treg, IL-10, and filarial-specific IgG. However, Breg-mediated response causes

TLR4-mediated inflammation in macrophages and DCs [96].

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

**4.5 Amoebiasis**

(**Figure 5**).

with TLRs.

**5.1 Filariasis**

**5. Helminth infections**

**Figure 5.** *Toxoplasma and Entamoeba induced TLR signaling pathway.*

*TLR Signaling on Protozoan and Helminthic Parasite Infection DOI: http://dx.doi.org/10.5772/intechopen.84711*

cells. *T. gondii* infection also induces IFNβ production in inflammatory monocytes (IMs) and TLR4-mediated phagocytic uptake of the parasite [86]. Endosomal TLRs (TLR3, TLR7, and TLR9) stimulate IL12 production in human PBMCs in response to DNA and mRNA of *T. gondii* tachyzoites when the cells were primed with IFNγ [87]. GPIs present in parasite membrane aggravate TLR2- and TLR4-mediated TNFα production in inflammatory response [88]. In some cases, tachyzoites differentiate into bradyzoites inside the central nervous system and cause neurological and behavioral abnormalities [89]. TLR2 signaling pathway makes chronic inflammation in different central nervous system cell types [85] (**Figure 5**).

#### **4.5 Amoebiasis**

*Toll-like Receptors*

**Figure 4.**

*Trypanosoma PAMPs and TLR signaling.*

**70**

**Figure 5.**

*Toxoplasma and Entamoeba induced TLR signaling pathway.*

TLR11 and TLR12 recognize *T. gondii* profiling (TgPRF) and induce IL12 and IFNα production in conventional dendritic cells (cDCs), macrophages, and plasmacytoid dendritic cells (pDCs). This IFNα induces IFNγ production from NK

*Entamoeba histolytica* is a protozoan parasite, which causes amebiasis in humans. It is one of the deadliest diseases after malaria and causes almost 40,000–100,000 deaths per year in underdeveloped countries [90]. The clinical symptoms include diarrhea, dysentery, pain in lower abdomen, and liver abscess, which occur due to invasion of amoeba in host lung, heart, brain, skin, genital, etc. [91]. The lipophosphopeptidoglycan (LPPG) present on the surface of *E. histolytica* induces TLR2- and TLR4-mediated NF-κB activation and cytokine (IL-8, IL-10, IL-12p40, and TNFα) release from human monocytes [92]. The Gal/GalNAc lectin (Gal-lectin), a surface molecule of *E. histolytica,* upregulates cytokines and TLR2 genes via NF-κB and MAP kinase activation in macrophages and dendritic cells [93]. TLR9 recognizes *E. histolytica* genomic DNA and helps in TNFα production in macrophages [94] (**Figure 5**).

#### **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, *Wuchereria bancrofti*, *Brugia malayi*, and *B. timori*, is a major health problem in tropical countries. During initial stage, infection remains asymptomatic. Acute condition displays local inflammation of skin, lymph nodes, and lymphatic vessels, which ultimately leads to edema in chronic condition [95]. Wolbachia, an intracellular symbiotic bacterium of filarial nematode, is the major mediator of inflammatory response in case of lymphatic filariasis and onchocerciasis [2]. WSP protein in outer membrane of *Wolbachia* sp. induces TLR2- and TLR4-mediated inflammation in macrophages and DCs [96].

In case of chronic infection, filarial nematode downregulates host immune response via TLR4-mediated T cell apoptosis [97]. Live microfilariae of *B. malayi* can downregulate mRNA and protein expression of TLR1, TLR2, TLR4, and TLR9 and activate TLR2 upon antigen stimulation on B cells and monocytes [98]. In DCs, live microfilariae and microfilarial antigen (MF Ag) diminish IL-12, IFNα, and cytokine production via inhibition of NF-κB complex formation [99]. Microfilariae infective stage (L3) of *B. malayi* also shows partial inhibition of Langerhans cells (LCs) that lead to CD4+ T cell proliferation [100]. Circulating B cells (called Breg) express TLR2 and TLR4 and maintain a worm favorable condition via induction of Treg, IL-10, and filarial-specific IgG. However, Breg-mediated response causes

asymptomatic infection in initial stages but leads to secondary infection by bacteria and virus in filarial patients [92]. A phosphocholine-containing glycoprotein (ES-62) of *Acanthocheilonema viteae* (rodent filarial nematode) inhibits B and T lymphocyte activation. The secretory ES-62 inhibits TLR4-mediated IL-12 and TNFα production [101] (**Figure 6**).

#### **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]. *S. mansoni*, *S. intercalatum*, *S. haematobium*, *S. japonicum,* and *S. mekongi* are the five species of schistosomes that cause disease in humans. *S. mansoni*, *S. japonicum,* and *S. intercalatum* are responsible for intestinal schistosomiasis, while *S. haematobium* causes urinary schistosomiasis and is most important in terms of public health [102]. Fresh water snail of the genus *Bulinus* (*S. haematobium*), *Biomphalaria* (*S. mansoni*), and *Oncomelania* (*S. japonicum*) acts as an intermediate host of Schistosoma parasites [103].

*S. japonicum* eggs are deposited in the liver, lung, and intestinal wall of host, which induce granulomatous inflammation and progressive fibrosis. Th cells, natural killer (NK) cells, NKT cells, myeloid-derived suppressor cells (MDSCs), and macrophages are mainly involved in fight against *S. japonicum* and its eggs [104]. Expressions of TLR1, TLR3, TLR7, TLR8, and NF-κB are greatly repressed at the initial stage of schistosomiasis. TLR3 modulates Th2 response in lung in *S. mansoni* infection and in NK cells during *S. japonica* infection [105]. *S. mansoni* is known to attenuate Th1 responses (decrease IFN, TNF, IL-12, and NO) but to promote Th2 immune responses (increase IL-10 and TGF) [106]. Although TLR4 protects the host from Schistosoma infection, TLR2 favors the parasite growth [107]. Both SEA (soluble egg antigen) and ES products of *S. mansoni* act as a strong inducer of Th2 response [108]. It induces transcription of markers CD40 and CD86 and cytokines IFNβ, TNFα, and IL-12-p40 in mouse myeloid DCs [109]. Glycans present in *S. mansoni* induce Treg by TLR2-mediated DC differentiation and IL-10 secretion [110]. Schistosoma egg product LFNP III also stimulates IL-10 production

**73**

*TLR Signaling on Protozoan and Helminthic Parasite Infection*

from TLR2 and promotes Treg activation [111]. An immunomodulatory peptide, SJMHE1 of *S. japonicum*, induces TLR2-mediated Treg activation. The lysophosphatidylserine and glycolipids [112] of scistosome also activate TLR2 in DCs [113]

The pork tapeworm (*Taenia solium*) is a cestoda parasite transmitted to humans by feeding cystic larvae infected pork. Here, pig acts as an intermediate host, which swallows *T. solium* egg containing human stool and develops larva inside their body [114]. The cysticercosis cyst causes neurocysticercosis (NCC) in the nervous system, and adult taenia produces intestinal taeniasis in humans. Both are endemic in Latin America, sub-Saharan Africa, India, vast parts of China, and South East

TLR4 and TLR2 play an important role in developing murine NCC caused by *Mesocestoides corti* [116]. The carbohydrate of *T. crassiceps* induces TLR4- and TLR2-mediated cytokine release (IL-6 and IL-4) [117]. However, molecules derived from *T. sodium* did not induce TLR2- or TLR4-mediated cytokine release in human lymphocytes [118]. Both *T. solium* and *T. crassiceps* express several glycolipids (GSL-1) and phospholipids that may act as PAMPs. *T. crassiceps* expresses lysophosphatidylcholine [119], also present on Schistosome, and triggers TLR2 response. Although the mechanism of these molecules inducing TLR signaling has not yet been evaluated, the host may use a similar pathway of this parasite recognition

Phospholipids from schistosomes and *Ascaris* worm trigger TLR2, and lysophos-

*F. hepatica* tegumental antigens (FhTeg), *F. hepatica* ES, and ES-derived enzymes (thioredoxin peroxidase 2-Cys peroxiredoxin, fatty acid-binding protein) inhibit TLR4- and TLR3-mediated inflammatory response and facilitate parasite survival inside the host [122]. The protease activity of *F. hepatica* Cathepsin L1 (FheCL1) causes endosomal degradation of TLR3 and downregulates IL-1 production [123].

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

phatidylserine can activate DCs to induce Th2 and IL-10-producing Treg [121].

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

(**Figure 6**).

**5.3 Taeniasis**

Asia [115].

[120] (**Figure 6**).

**5.4 Ascariasis**

**5.5 Fasciolosis**

**6. Conclusion**

**Figure 6.** *TLR signaling pathway induced by Helminth pathogens.*

from TLR2 and promotes Treg activation [111]. An immunomodulatory peptide, SJMHE1 of *S. japonicum*, induces TLR2-mediated Treg activation. The lysophosphatidylserine and glycolipids [112] of scistosome also activate TLR2 in DCs [113] (**Figure 6**).
