**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 *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 symptoms of malaria [38, 39].

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

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**Figure 2.**

*TLR signaling during Plasmodium infection.*

*TLR Signaling on Protozoan and Helminthic Parasite Infection*

derived molecules also induce Th2 response via IL-4-inducing factor (released by PI3K-Akt-NF-κB signaling) in DC [53].

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

**4.2 Leishmaniasis**

nitric oxide [42] release from macrophages. It also induces cerebral malaria at later course of infection [43]. Plasmodium 2-Cys peroxiredoxin also acts as a TLR4 ligand in monocyte and mast cells and causes cytokine production [44]. Hemozoin is released during each life cycle of *P. falciparum* infection and makes a complex with plasmodial DNA. This complex acts as a TLR9 ligand and leads to the production of proinflammatory cytokines (TNFα and IL-1β) [45]. Hemozoin DNA complex induces cerebral malaria by caspase 1-mediated inflammasome (NLRP3) formation by TLR9 in case of *P. chabaudi* infection [46] but is absent in *P. berghei* spoprozoite infection [47]. Although in case of both mice and humans, Plasmodium infection renders no TLR stimulation in dendritic cells. The infant exposed to TLR-mediated cytokine profiles (IL-10) is associated with higher risk of *P. falciparum* maternal infection during delivery [48]. RNA of *P. chabaudi* acts as a ligand for TLR7 and induces IFNγ, IL-10, IL-12, and TNF release at 24 h of infection [49]. In case of *P. vivax* infection, TLR5 and TLR7 hinder parasitic growth, but TLR9 is associated with high inflammation and cytokine production [50]. The 19 kDa C-terminal fragment of merozoite surface protein 1 (MSp1) in *P. vivax* acts as a ligand for TLR5 [51]. *P. yoelii* infection in peritoneal macrophages enhances TLR and parasite-specific immune response [52] (**Figure 2**). Other than Th1 response, malaria parasite-

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

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

nitric oxide [42] release from macrophages. It also induces cerebral malaria at later course of infection [43]. Plasmodium 2-Cys peroxiredoxin also acts as a TLR4 ligand in monocyte and mast cells and causes cytokine production [44]. Hemozoin is released during each life cycle of *P. falciparum* infection and makes a complex with plasmodial DNA. This complex acts as a TLR9 ligand and leads to the production of proinflammatory cytokines (TNFα and IL-1β) [45]. Hemozoin DNA complex induces cerebral malaria by caspase 1-mediated inflammasome (NLRP3) formation by TLR9 in case of *P. chabaudi* infection [46] but is absent in *P. berghei* spoprozoite infection [47]. Although in case of both mice and humans, Plasmodium infection renders no TLR stimulation in dendritic cells. The infant exposed to TLR-mediated cytokine profiles (IL-10) is associated with higher risk of *P. falciparum* maternal infection during delivery [48]. RNA of *P. chabaudi* acts as a ligand for TLR7 and induces IFNγ, IL-10, IL-12, and TNF release at 24 h of infection [49]. In case of *P. vivax* infection, TLR5 and TLR7 hinder parasitic growth, but TLR9 is associated with high inflammation and cytokine production [50]. The 19 kDa C-terminal fragment of merozoite surface protein 1 (MSp1) in *P. vivax* acts as a ligand for TLR5 [51]. *P. yoelii* infection in peritoneal macrophages enhances TLR and parasite-specific immune response [52] (**Figure 2**). Other than Th1 response, malaria parasitederived molecules also induce Th2 response via IL-4-inducing factor (released by PI3K-Akt-NF-κB signaling) in DC [53].
