**9. Conclusion**

*Toll-like Receptors*

infectious diseases [109].

to 55% efficacy [115].

of TLRs or agonists of their negative regulators have been investigated as vaccine adjuvants to enhance an effective immune response against tumors, allergies, and

gistic therapeutic effect on inflammatory disease [111].

response in experimental visceral leishmaniasis [112].

for the suppression of inflammation [53, 116].

The vaccine adjuvant properties of TLR7 and/or TLR8 agonists imiquimod and R848 were tested in the model of infection by *L. major*, determining the immune response before and after infection. Protective immunity was generated following subcutaneous but not intramuscular vaccination [110]. In another study, the effect of *L. major* polyclonal anti-murine TLR2 and TLR4 antibodies was assessed on cutaneous leishmaniasis and inflammatory arthritis. Both antibodies suppressed the development of clinical parameters, accompanied by reduced pro-inflammatory cytokine production. Hence, anti-TLR2 and TLR4 antibodies possibly have a syner-

In visceral leishmaniasis, evaluation was made of anti-*Leishmania* immune responses. The protective efficacy of the glycosphingophospholipid (GSPL) antigen of *L. donovani* parasites when acting as a ligand for β-(1-4)-galactose terminal NKT cells suggests an important role of TLR4. This receptor may function as an upstream sensor by GSPL and induce the intracellular inflammatory signaling necessary for killing parasites. Treatment with GSPL was able to cause a highly effective T-cell response that contributed to good control of infection. Therefore, the synergism of TLR4 and NKT cells prompted GSPL to evoke a host-protective immunological

The collateral effects of a malaria infection during pregnancy correlate with immune activation in placental tissue. Since TLR4 plays a key role in this process, its blockage could be a potential strategy for therapeutic intervention to reduce the incidence of malaria-induced pathology both in the mother and the fetus [113]. Skin scarification with the *P. falciparum* peptide vaccine in combination with a TLR agonist produces systemic neutralizing antibodies with the potential of blocking parasite egress from the skin (and thus avoiding the invasion of liver cells) [114]. A good adjuvant formulation is crucial in the development of a successful vaccine. In the amebiasis model, the nanoliposome adjuvant containing synergistic TLR4 and TLR7/8 agonists successfully elicited balanced systemic humoral and cellular immune responses. The immunization protected against infection with up

Since helminths use various molecules to regulate the host immune response, some of these may have potential therapeutic action against allergies and other inflammatory diseases. This anti-inflammatory strategy has been successful in treating diseases in animal models. Helminth-derived molecules are potent immunomodulators that could possibly be used for the design of new anti-inflammatory drugs. For example, the nematodes *T. suis* and *T. spiralis* induce a significant suppression of symptoms in autoimmune encephalomyelitis, an animal model validated for multiple sclerosis. Therefore, infection with live nematodes is not a prerequisite

Crohn's disease and ulcerative colitis are closely related to inflammatory processes. Some therapies, such as the ingestion of eggs of *T. suis*, promote a TLR2- and TLR4-regulated decline in inflammatory activity as well as a reduction in adverse effects of inflammation. This is based on the ability of helminths to polarize the response of helper T cells to a Th2 type, which inhibits inflammation. *F. hepatica*, on the other hand, exerts influence on dendritic cells activated by CpG, thus fostering the development of Tregs and a decrease in the severity and incidence of the disease

*A. suum* diminishes ocular allergic disease and *T. spiralis*, by evoking a Th2 response, and inhibits the production of IFN-γ to relieve colitis. These results are interesting because they demonstrate the interference of a helminth infection with the

[117]. *S. mansoni* alleviates allergies and reduces inflammation in airways.

**48**

TLRs, one of the best characterized families of receptors, have a critical role in the host defense against infection. Additionally, they play a key role in the capacity of different protozoans and helminths to be able to generate a continuous activation of the host immune system by modulating the elements of the innate and/or adaptive response. Such intervention by these parasites in the immune response is aimed at promoting their survival inside the host. Single-nucleotide polymorphisms in TLRs participate importantly in increasing parasitemia in the host. However, agonists of TLRs can have a dual role. Whereas they may serve as adjuvants or vaccines to promote the maturation of dendritic cells and thus induce an adaptive immune response, they are also capable of triggering inflammatory cytokine production that has a pathogenic role in many diseases. Consequently, antibodies to TLRs and inhibitors of TLR signaling pathways have considerable potential as therapeutic agents. It is still necessary to clarify their mechanisms for modulating the response of these receptors to be able to design and develop innovative therapeutic targets.
