**4.1 Parasitic protozoan infections**

Protozoan parasites are pathogens that have developed additional and sophisticated strategies to escape the immune attack of the host. This is because their life cycles generally involve several stages of specific antigenicity, which facilitates their survival and propagation within different cells, tissues, and hosts [51]. Frequently, the host is unable to eliminate protozoan infections, which often results in chronic disease or irreparable infections, in which the host continues to act as a reservoir of parasites, a cause of great concern due to their prevalence, morbidity and mortality [52, 53]. This host resistance to protozoa infections depends mainly on the development of a T helper type 1 (Th1) response and on the production of IL-12 by APCs [54]. Therefore, the classical reaction of the host to infections by protozoan parasites is the maturation of different subsets of DC, and in some cases, the activity of these cells leads to a response that is effective in controlling the infection [55].

Among the most important protozoan parasites are those that living in human blood and tissues, which can cause fatal diseases. The immune response against protozoan infections involves a strong innate immune response followed by predominantly a Th1 response. The innate immune system is comprised of several cell types, including DCs. Recognition of pathogens by these cell types leads to phagocytosis in some cases, and the production of pro-inflammatory cytokines, which assist in shaping the subsequent adaptive immune response (see **Figure 3**) [56].

During the parasitic protozoan infections different PRRs present in DCs are involved in the recognition PAMPs of parasites. In trypanosomiasis, the

#### **Figure 3.**

*Role of DCs in protozoan infections. Polarization of Th1 response through interactions between PAMPs and PRRs (TLR-2, -4, -9, -11 and -12), which in a signal-dependent manner (involving the activation of MAPKs p38/JNK and MyD88) induce the expression of Th1 cytokines such as IL-12, Il-6, IFN-*γ *and TNF-*α*. the PRRs from protozoa induce the presentation of antigens, the co-stimulation, and the expression of the cytokine IL-12, IFN-*γ *production by DCs during Ag presentation, by signaling pathway STAT-4. Description in the text. (figure created by Muñoz-Carrillo* et al*., with BioRender.com).*

#### *Role of Dendritic Cells in Pathogen Infections: A Current Perspective DOI: http://dx.doi.org/10.5772/intechopen.95551*

glycoinositolophospholipids (GIPLs) and glucosylphosphatidylinositol (GPI) anchors from Trypanosoma cruzi are recognized by TLR-4 and TLR-2, respectively, inducing the inflammatory cytokines production [57, 58]. Likewise, the DNA of *T. cruzi* stimulates the production of cytokines in a manner dependent on TLR-9 and synergizes with the GPI anchor of TLR-2 in the induction of cytokines [59], such as IL-12 by activation of the p38 pathway [60].

*Toxoplasma gondii* is a parasite that can infect any nucleated host cell, but it has a preference for cells of the immune system, including DCs [61]. Currently, the participation of TLRs in the recognition of *T. gondii* is not very clear. On the one hand, studies have shown that the soluble parasite extract (STAg) of *T. gondii* induces the production of IL-12 through the binding of *Toxoplasma profilin* (TgPRF) with TLR11 in DCs, signaling pathway MyD88 [62–65]. In fact, it has been shown that TgPRF is not required for the intracellular growth of *T. gondii*, but it is indispensable for host cell invasion and active egress from cells [65], and it is critical for the IL-12 production, especially in plasmacytoid DCs [66]. On the other hand, studies show that the absence of either TLR-2 or TLR-4 in DCs does not modify the production of IL-12 in response to STAg [62]. Other authors have reported the involvement of the TLR4-dependent signaling pathway in *T. gondii* independent of the MyD88 pathway [67]. However, reports have shown that mice deficient for TLR-2, TLR-4 or TLR-11 survive *T. gondii* infection, suggesting that *T. gondii* recognition may be associated with an additional signaling pathway MyD88-TLR-dependent. This additional signaling pathway could be by binding of TgPRF with TLR-12, since it has been observed that TLR-12-deficient mice succumb rapidly to *T. gondii* infection [62, 63, 66, 68]. On the other hand, *T. gondii* is capable to activate the JAK/STAT signaling pathway to facilitate survival within the host, blocking IFN-γ-mediated-STAT1 dependent proinflammatory gene expression in APCs. This is through sustained STAT-1 phosphorylation and nuclear translocation in bone marrow-derived DCs (BMDCs). However, in combination with IFN-γ, T. gondii simultaneously blocks IFN-γ-induced STAT-1 transcriptional activity avoiding the DCs activation by IFN-γ [69].

*Plasmodium falciparum* is capable to activate DCs through TLR-2 [58, 70, 71] and TLR-9, inducing the production of proinflammatory cytokines [72]. Depending on the DCs population that are activated during Plasmodium infection, it will be the type of cellular immune response that the host will mount against the infection. On the one hand, it has been observed that DCs subpopulations such as CD8+ CD11b− DC (located in the peripheral lymph nodes), mature (CD40+ ) spleen DC and (CD8α<sup>+</sup> CD11b− and CD8α<sup>−</sup> CD11b+ ) DCs [73, 74], are associated to the protective effect of CD8+ T-cells, which produce INF-γ and induce parasite death, reducing the parasite burden in hepatocytes [75–78]. On the other hand, during the acute phase of infection CD8α-CD11b<sup>+</sup> DC activates CD4<sup>+</sup> T-cells, inducing the production of IL-12, IL-6, IFN-γ and TNF-α [79–83].
