TLR-Mediated Host Immune Response to Parasitic Infectious Diseases

*M. Magdalena Aguirre-García, Araceli Rojas-Bernabé, A. Pamela Gómez-García and Alma R. Escalona-Montaño*

#### **Abstract**

Toll-like receptors (TLRs) are important for the host immune response to a variety of pathogens, including bacteria, viruses, fungi, and parasites. These receptors become activated upon recognizing pathogen-associated molecular patterns (PAMPs) and thus initiate the innate immune response to the corresponding pathogen. A key aspect of TLRs is their activation of signaling that leads to cytokine production and an inflammatory response. Additionally, TLRs act as the bridge between innate and acquired immunity, enhancing phagocytosis and the process of killing parasites. We herein focus on how parasites (protozoans and helminths) and their derived products have the capability of stimulating or evading the host response by triggering or inhibiting TLR activation. Parasites often develop successful survival strategies that imply interference with the host immune response. Accordingly, many of these organisms have molecules that modulate inflammation and other aspects of host immunity. Taking advantage of such mechanisms, there are some anti-inflammatory therapies based on human infection with helminths. Helminths and protozoans influence the activity of various TLRs, especially TLR2, TLR4, and TLR9. A better understanding of the role of TLRs and their parasite-derived ligands should certainly provide new therapeutic tools for combatting various parasitic and inflammatory diseases.

**Keywords:** TLRs, protozoans, helminths, immune response, disease

#### **1. Introduction**

Toll-like receptors (TLRs) have the important function of recognizing a variety of pathogens, including bacteria, viruses, fungi, and parasites. They recognize pathogen-associated molecular patterns (PAMPs) and consequently initiate the innate immune response. The well-known TLRs that are responsible for binding to PAMPs act as a bridge between innate and acquired immunity. Accordingly, they are not only involved in the production of cytokines and chemokines but also enhance phagocytosis and the process of killing parasites.

Parasites are organisms that live on or inside an organism and benefit by deriving nutrients at the expense of the host. We herein review how protozoan and helminth parasites trigger differential activation of TLRs in order to regulate host immune cells. In some cases, the activation of these TLR receptors by PAMPs contributes to an effective control of the infection, while in other cases there is a negative

regulation resulting in the exacerbation of the infection, as shown in distinct in vivo animal models. In patients with diverse clinical manifestations of parasitic infections, TLRs and cytokines play a key role in the host response to the disease. A better understanding of the role of TLRs and their ligands should certainly provide new therapeutic tools and perhaps allow for the development of vaccines to control parasitic infections.

#### **2. Protozoan parasites**

Among the many protozoan parasites, those presently examined are *Leishmania* spp., *Trypanosoma* spp., *Naegleria fowleri, Plasmodium* spp., *Toxoplasma gondii*, *Giardia lamblia*, *Entamoeba histolytica*, *Trichomonas vaginalis*, *Blastocystis* spp., and *Acanthamoeba* spp.

#### **2.1** *Leishmania* **spp.**

Leishmaniasis, an infectious disease endemic in 88 countries representing 5 continents, is caused by parasitic protozoa in the genus *Leishmania* [1]. This parasite gives rise to a variety of disorders, ranging from cutaneous lesions to visceral disease [2]. The latter can be generated by *Leishmania donovani*, *L. infantum*, and *L. chagasi* [3].

Regarding cutaneous lesions, the most pathogenic agents of American cutaneous leishmaniasis in Brazil are *L. (Viannia) braziliensis* and *L.* (L.) *amazonensis*, capable of inducing localized cutaneous leishmaniasis, borderline disseminated cutaneous leishmaniasis, anergic diffuse cutaneous leishmaniasis, and mucosal leishmaniasis [4]. In Mexico, *L. mexicana* evokes a wide spectrum of cutaneous diseases. For instance, localized cutaneous leishmaniasis is characterized by ulcers at the site of parasite inoculation, while parasites in diffuse cutaneous leishmaniasis spread throughout the skin and form disfiguring nodules [5]. In Iran, cutaneous leishmaniasis is endemic in 18 of 31 provinces, and approximately one-fifth of the cases belong to anthroponotic cutaneous leishmaniasis, stemming from *L. tropica* [6]. *L. panamensis*, a member of the *Viannia* subgenus of *Leishmania*, is known to provoke mucosal leishmaniasis. It produces destructive lesions of the nasal, oral, and hypopharyngeal mucosa [1].

#### **2.2** *Trypanosoma* **spp.**

The causal agent of Chagas disease, *Trypanosoma cruzi*, was first described by the Brazilian physician Carlos Chagas in 1909 [7]. This pathology is endemic in Central and South America, and evidence exists of some cases in the United States, Europe, and Japan due to travel and migration. The parasite is an intracellular protozoan of the Trypanosomatidae family, transmitted to humans by blood-feeding reduviid bugs.

There are two phases of Chagas disease. The acute phase is generally asymptomatic, although some patients present symptoms such as fever, nausea, vomiting, anorexia, and diarrhea [8]. In the chronic phase, infected individuals can remain asymptomatic for decades, although around 30% eventually develop cardiac or gastrointestinal complications characteristic of the disease.

#### **2.3 Other protozoans**

*Naegleria fowleri* is a protozoan that invades the central nervous system and provokes primary amoebic meningoencephalitis. During the process of infection, it induces an important inflammatory response [9].

**39**

*TLR-Mediated Host Immune Response to Parasitic Infectious Diseases*

prevalent sexually transmitted diseases in the world [14].

dysentery, with liver abscesses forming in rare cases [15].

*Acanthamoeba* spp. are free-living amoebae found in lakes, rivers, swimming pools, thermal baths, and tap water [10]. They infect humans and animals as opportunistic pathogens in immunocompromised hosts [11]. These parasites are able to generate severe diseases, including amebic *Acanthamoeba keratitis*, a painful sight-threatening infection of the cornea, and granulomatous amebic encephalitis, a

*Giardia lamblia*, the causal agent of giardiasis, colonizes the lumen of the upper small intestine. The parasite adheres to the surface of enterocytes without traversing

*P. falciparum*, the protozoan parasite responsible for malaria, is transmitted by the bite of mosquitoes. It results in a wide spectrum of clinical manifestations during the vector-parasite-host interaction. The first asexual reproduction process

*Trichomonas vaginalis* is a flagellated protozoan parasite that infects the human genitourinary tract. It is the causative organism of trichomoniasis, one of the most

*Entamoeba histolytica*, the etiologic agent of amebiasis, is a pathogenic enteric protozoan. The manifestations of the disease range from mild diarrhea to severe

*Blastocystis*, an enteric parasite, colonizes the colonic epithelia of human and animal hosts [16]. Infection with this parasite gives rise to diarrhea, abdominal pain,

The word helminth is derived from the Greek "helmins," which means parasite worm. Helminth is an umbrella term that includes many species of worms from different genera, having parasitism in common. They are quite frequently found in the population. The immune response depends largely on the type of parasite and

These large extracellular organisms have a complicated life cycle. They frequently migrate through blood vessels and tissues until reaching the definitive organ, such as the intestine, lungs, liver, or lymphatic organs. Some invade and

Because helminths have developed strategies of evasion of the host immune response, they are often able to survive. Hence, they can weaken the immune response and survive for years in the infected host, establishing chronic infection [18]. When the host immune response is adequately activated, on the other hand,

*Fasciola hepatica* is a trematode worm that mainly affects livestock (e.g., cows, sheep, and goats) and humans. It is transmitted through the ingestion of aquatic plants contaminated with metacercaria. *Ascaris lumbricoides*, a parasitic intestinal worm, is transmitted by ingesting water contaminated with embryonic eggs. *Trichuris trichiura* and *T. suis*, other species of intestinal worms, remain in the large intestine of mammals in the form of adult larvae. The infection occurs after the ingestion of the eggs, which hatch in the small intestine and release the infective larvae [19]. *Schistosoma mansoni* are larvae of worms that live in waters and ponds contaminated by feces. They are able to penetrate the skin of people who bath or swim in contaminated pools. In the adult stage, these parasites produce eggs that are excreted through the stool [20]. *Strongyloides stercoralis* is an infection generated by the larvae. These are acquired through the skin and later lodge themselves in the intestine. *Trichinella spiralis* is a parasitic nematode, which infects the muscle tissue

*DOI: http://dx.doi.org/10.5772/intechopen.84679*

fatal disease of the central nervous system.

the enterocyte barrier [12].

occurs in the human liver [13].

flatulence, vomiting, and bloating [17].

**3. Helminth parasites**

its interaction with the host.

colonize various cell types.

infections are eliminated quickly.

#### *TLR-Mediated Host Immune Response to Parasitic Infectious Diseases DOI: http://dx.doi.org/10.5772/intechopen.84679*

*Acanthamoeba* spp. are free-living amoebae found in lakes, rivers, swimming pools, thermal baths, and tap water [10]. They infect humans and animals as opportunistic pathogens in immunocompromised hosts [11]. These parasites are able to generate severe diseases, including amebic *Acanthamoeba keratitis*, a painful sight-threatening infection of the cornea, and granulomatous amebic encephalitis, a fatal disease of the central nervous system.

*Giardia lamblia*, the causal agent of giardiasis, colonizes the lumen of the upper small intestine. The parasite adheres to the surface of enterocytes without traversing the enterocyte barrier [12].

*P. falciparum*, the protozoan parasite responsible for malaria, is transmitted by the bite of mosquitoes. It results in a wide spectrum of clinical manifestations during the vector-parasite-host interaction. The first asexual reproduction process occurs in the human liver [13].

*Trichomonas vaginalis* is a flagellated protozoan parasite that infects the human genitourinary tract. It is the causative organism of trichomoniasis, one of the most prevalent sexually transmitted diseases in the world [14].

*Entamoeba histolytica*, the etiologic agent of amebiasis, is a pathogenic enteric protozoan. The manifestations of the disease range from mild diarrhea to severe dysentery, with liver abscesses forming in rare cases [15].

*Blastocystis*, an enteric parasite, colonizes the colonic epithelia of human and animal hosts [16]. Infection with this parasite gives rise to diarrhea, abdominal pain, flatulence, vomiting, and bloating [17].

### **3. Helminth parasites**

*Toll-like Receptors*

parasitic infections.

*Acanthamoeba* spp.

**2.1** *Leishmania* **spp.**

and hypopharyngeal mucosa [1].

**2.2** *Trypanosoma* **spp.**

**2.3 Other protozoans**

**2. Protozoan parasites**

regulation resulting in the exacerbation of the infection, as shown in distinct in vivo animal models. In patients with diverse clinical manifestations of parasitic infections, TLRs and cytokines play a key role in the host response to the disease. A better understanding of the role of TLRs and their ligands should certainly provide new therapeutic tools and perhaps allow for the development of vaccines to control

Among the many protozoan parasites, those presently examined are *Leishmania* spp., *Trypanosoma* spp., *Naegleria fowleri, Plasmodium* spp., *Toxoplasma gondii*, *Giardia lamblia*, *Entamoeba histolytica*, *Trichomonas vaginalis*, *Blastocystis* spp., and

Leishmaniasis, an infectious disease endemic in 88 countries representing 5 continents, is caused by parasitic protozoa in the genus *Leishmania* [1]. This parasite gives rise to a variety of disorders, ranging from cutaneous lesions to visceral disease [2]. The latter can be generated by *Leishmania donovani*, *L. infantum*, and *L. chagasi* [3]. Regarding cutaneous lesions, the most pathogenic agents of American cutaneous leishmaniasis in Brazil are *L. (Viannia) braziliensis* and *L.* (L.) *amazonensis*, capable of inducing localized cutaneous leishmaniasis, borderline disseminated cutaneous leishmaniasis, anergic diffuse cutaneous leishmaniasis, and mucosal leishmaniasis [4]. In Mexico, *L. mexicana* evokes a wide spectrum of cutaneous diseases. For instance, localized cutaneous leishmaniasis is characterized by ulcers at the site of parasite inoculation, while parasites in diffuse cutaneous leishmaniasis spread throughout the skin and form disfiguring nodules [5]. In Iran, cutaneous leishmaniasis is endemic in 18 of 31 provinces, and approximately one-fifth of the cases belong to anthroponotic cutaneous leishmaniasis, stemming from *L. tropica* [6]. *L. panamensis*, a member of the *Viannia* subgenus of *Leishmania*, is known to provoke mucosal leishmaniasis. It produces destructive lesions of the nasal, oral,

The causal agent of Chagas disease, *Trypanosoma cruzi*, was first described by the Brazilian physician Carlos Chagas in 1909 [7]. This pathology is endemic in Central and South America, and evidence exists of some cases in the United States, Europe, and Japan due to travel and migration. The parasite is an intracellular protozoan of the Trypanosomatidae family, transmitted to humans by blood-feeding reduviid bugs. There are two phases of Chagas disease. The acute phase is generally asymptomatic, although some patients present symptoms such as fever, nausea, vomiting, anorexia, and diarrhea [8]. In the chronic phase, infected individuals can remain asymptomatic for decades, although around 30% eventually develop cardiac or

*Naegleria fowleri* is a protozoan that invades the central nervous system and provokes primary amoebic meningoencephalitis. During the process of infection, it

gastrointestinal complications characteristic of the disease.

induces an important inflammatory response [9].

**38**

The word helminth is derived from the Greek "helmins," which means parasite worm. Helminth is an umbrella term that includes many species of worms from different genera, having parasitism in common. They are quite frequently found in the population. The immune response depends largely on the type of parasite and its interaction with the host.

These large extracellular organisms have a complicated life cycle. They frequently migrate through blood vessels and tissues until reaching the definitive organ, such as the intestine, lungs, liver, or lymphatic organs. Some invade and colonize various cell types.

Because helminths have developed strategies of evasion of the host immune response, they are often able to survive. Hence, they can weaken the immune response and survive for years in the infected host, establishing chronic infection [18]. When the host immune response is adequately activated, on the other hand, infections are eliminated quickly.

*Fasciola hepatica* is a trematode worm that mainly affects livestock (e.g., cows, sheep, and goats) and humans. It is transmitted through the ingestion of aquatic plants contaminated with metacercaria. *Ascaris lumbricoides*, a parasitic intestinal worm, is transmitted by ingesting water contaminated with embryonic eggs. *Trichuris trichiura* and *T. suis*, other species of intestinal worms, remain in the large intestine of mammals in the form of adult larvae. The infection occurs after the ingestion of the eggs, which hatch in the small intestine and release the infective larvae [19]. *Schistosoma mansoni* are larvae of worms that live in waters and ponds contaminated by feces. They are able to penetrate the skin of people who bath or swim in contaminated pools. In the adult stage, these parasites produce eggs that are excreted through the stool [20]. *Strongyloides stercoralis* is an infection generated by the larvae. These are acquired through the skin and later lodge themselves in the intestine. *Trichinella spiralis* is a parasitic nematode, which infects the muscle tissue

of practically all mammals. *Toxocara canis*, round worms found in dogs, can infect humans if ingested in the form of the infective eggs of *Toxocara*. The larvae migrate to the intestine, liver, or lungs.
