**1.1 Malaria** *(Plasmodium spp)*

Different species of *Plasmodium spp*. can infect humans causing malaria disease; the most common, *Plasmodium falciparum*, is responsible for the majority of deaths. In contrast, *Plasmodium vivax* is responsible for the majority of cases. The symptoms of malaria range from asymptomatic parasitemia to severe disease, including cerebral malaria and death. Pregnant women and children under the age of five are particularly vulnerable to the disease. A combination of infected red blood cell sequestration in the microvasculature, endothelial activation, procoagulant action, and, most importantly, pro-inflammatory responses are thought to be the cause of the pathology. This disease is a huge public health burden, with an estimated 241 million cases reported in 2020 in 85 malaria-endemic countries (including the territory of French Guiana), resulting in 405,000 deaths [1–3].

Female Anopheles mosquitoes transmit the parasites, which have a complex life cycle that alternates between sexual and asexual phases. The infection begins with the bite of the mosquito, which injects parasites into the host in the form of sporozoites, which then travel to the liver. After replicating in liver cells, they mature into merozoites and are released into the bloodstream to invade host erythrocytes. Although the high parasite burden (up to 30,000 merozoites) stresses the host cell, infected hepatocytes do not undergo stress-mediated apoptosis, implying that the parasite interferes with this process in the host cell, In the erythrocyte, the parasites develop into immature gametocytes or ring-stage trophozoites, which are followed by mature trophozoites, schizonts, and merozoites. The immune system attacks these parasites; sporozoites in the liver find hepatic macrophages known as Kupffer cells, while parasites in the blood can find circulating monocytes and neutrophils [4].

#### **1.2 Chagas disease** *(Trypanosoma cruzi)*

*Trypanosoma cruzi is the causative agent of Chagas disease, also known as American trypanosomiasis. This is a public health problem in Latin America where it affects approximately 7 million people worldwide, and 100 million people are at risk of contracting it. Furthermore, it has become increasingly common in the United States of America, Canada, and many European and Western Pacific countries in recent decades* [5, 6]*.*

The life cycle of the protozoan parasite *Trypanosoma cruzi* involves both vertebrate and invertebrate hosts. Vectorial transmission to vertebrate hosts occurs via the bite of insect triatomine vectors (from the Reduviidae subfamily known as "kissing bugs"), which shed metacyclic trypomastigotes in their feces after feeding allowing the entry of trypomastigotes through skin wounds and mucosal membranes. Other infection routes are the oral ingestion of food contaminated with triatomine feces, such as fruit juices, blood transfusion or organ transplant, laboratory accidents, and congenital transmission from the mother to child during pregnancy. The last form became the most important nowadays and explains the presence of new cases in non-endemic countries as mentioned above.

Trypomastigotes can infect a wide range of nucleated cells, including macrophages, cardiac muscle cells, and nervous system glial cells, exploiting phagocytic or non-phagocytic mechanisms depending on the class of cell involved. After a brief residence in a parasitophorous vacuole, parasites go through the cytoplasm and differentiate into amastigotes. After several divisions (binary fission), amastigotes transform back into trypomastigotes, which are released from the host cell and can infect neighboring cells or reach the bloodstream and infect different organs, particularly the heart.

*Trigonoscuta cruzi* infection in humans is characterized by a brief acute phase with nonspecific symptoms and a long chronic phase in which most individuals do not exhibit pathology. In contrast, some infected people (around 10 to 30% of cases) *Close Encounters: Pathogenic Protists-Host Cell Interactions DOI: http://dx.doi.org/10.5772/intechopen.111398*

develop specific pathology cardiomyopathy and mega syndromes of the digestive system, which cause significant morbidity and may lead to mortality [5–7]. The development of Chagas pathology is complex and multifactorial, involving parasite immune evasion strategies, genetically programmed deficiencies in host immunological homeostasis, and autoreactive events marked by the presence of autoantibodies. *T. cruzi* genetic material has been identified in tissues destroyed during chronic infection, showing that the parasite plays an active role in pathogenesis [8, 9]. In fact, despite a vigorous immune response, the host fails to clear the parasites from the tissues, allowing the infection to remain indefinitely.

#### **1.3 Leishmaniasis** *(Leishmania spp)*

To cause leishmaniasis, *Leishmania* parasites infect and develop into phagocytic cells [10]. Clinical symptoms of the disease range from skin or mucocutaneous disorders to visceral infections, which are caused by different parasite strains and the delicate balance of parasite proliferation, the patient's immune response, and the consequent degenerative alterations. Consequently, *L. major*, *L. tropica*, and *L. mexicana* produce mainly the cutaneous forms, *L. braziliensis* causes the mucocutaneous illness, and *L. donovani* causes the most severe visceral disease (called kala-azar which means black fever in Hindi language). Infections caused by *Leishmania spp.* are a major public health concern across the world. This illness is seen in 88 different nations. More than 350 million individuals worldwide are at risk of leishmaniasis [11, 12], with 12 million already infected.

The life cycle of *Leishmania* is rather straightforward, with two basic stages: motile flagellate promastigotes residing in the stomach of the sandfly vector and immotile amastigotes within the phagolysosomal vesicles of vertebrate host macrophages.

A variety of sandfly species from two primary genera, *Phlebotomus* and *Lutzomyia*, transmit the illness to the host. Female infected sandflies spread the illness by injecting the promastigote form into the skin during a blood meal. After being inoculated into the upper dermis, metacyclic promastigotes are phagocytosed by skin-resident macrophages and dendritic cells and largely localized to phagolysosomes [10]. The internal development of Leishmania metacyclic promastigotes into amastigotes devoid of exterior flagella takes 12 to 24 hours. Amastigotes reproduce and survive intracellularly inside the phagolysosomal compartment, acting as a reservoir for transmission [13]. Moreover, polymorphonuclear neutrophils are attracted to the site of infection to clear promastigotes [14]. Explaining the significant inflammatory response produced after roughly 3 weeks [15]. As a sandfly feeds on the blood of an infected vertebrate host, it consumes amastigotes-containing monocytes and macrophages. Amastigotes are discharged into the sandfly's midgut, where they evolve into flagellated promastigotes through a process known as metacyclogenesis. Metacyclic promastigotes enter the throat and oral cavity, where they will be transmitted during the next blood meal.

#### **1.4 Toxoplasmosis** *(Toxoplasma gondii)*

*Toxoplasma gondii* is an obligate intracellular parasite of the order *Coccidia* with felines as the unique definitive hosts. It is a zoonotic illness that regularly affects a range of wild and domestic animals, with humans serving as unwitting hosts.

The protozoan parasite *T. gondii* infects 25 to 30% of the world's human population, with significant prevalences in South America and tropical African countries. As of 2020, the World Health Organization reported around 240 million illnesses and 600,000 deaths [16] (World malaria report 2021). Infected fetuses (congenital toxoplasmosis) and immunocompromised people are the most vulnerable to this illness. More than 80% of cases of primary acquired infection in immunocompetent people in Europe or North America are asymptomatic. In other instances, patients may develop fever or cervical lymphadenopathy, which may be accompanied by myalgia, asthenia, or other nonspecific clinical symptoms. Toxoplasmosis is extremely dangerous in immunocompromised patients, and toxoplasmic encephalitis, the most common manifestation of the disease in these patients can cause a variety of symptoms ranging from headache, lethargy, lack of coordination, or ataxia to hemiparesis, loss of memory, dementia, or focal major motor seizures, usually associated with fever. The lungs, eyes, and heart are also often damaged, leading to myocarditis, while *Toxoplasma* has been isolated from other organs such as the liver, pancreas, bone marrow, bladder, lymph nodes, kidney, spleen, and skin. Toxoplasmic retinochoroiditis is a less prevalent complication.

Congenital infection is typically the outcome of a primary infection acquired by the mother during pregnancy. The incidence of vertical transmission and the severity of fetal harm is determined by the stage of pregnancy at which the mother becomes infected. It is more dangerous when the infection develops in the early trimester of pregnancy, resulting in significant abnormalities or termination. The parasite's replication causes necrosis and severe inflammation, resulting in serious abnormalities in the brain and eye organs. Mental retardation, convulsions, microcephaly, hydrocephalus, hearing, and psychomotor impairment are all serious consequences. Microphthalmia, cataracts, increased intraocular pressure, strabismus, optic neuritis, and retinal necrosis can also be detected, as can uveitis and retinochoroiditis, which can lead to blindness. Retinochoroiditis is a typical characteristic that can be present regardless of the period of maternal infection [17].

Intermediate hosts become infected by the consumption of sporulated oocytes present in contaminated meat. In the intestinal epithelial cells, *T. gondii* develops in rapidly growing tachyzoites which travel throughout the body. In the infected cells, parasites proliferate in parasitophorous vacuoles. In response to immunological pressure, the parasites encyst as bradyzoites, a slow-growing form. Tissue cysts are most commonly found in long-lived cells like muscular, endothelium, or neural cells.

When members of the cat family consume bradyzoites, they undergo sexual development within intestinal epithelial cells, ending in the discharge of oocysts that undergo meiosis in the environment to generate eight haploid sporozoites. The consumption of oocysts by a wide range of hosts results in acute infection. Humans become infected by consuming oocysts that can contaminate food or drink, or by eating undercooked meat with tissue cysts [7].

To survive in the host cell, *T. gondii* typically resides in a vacuole, which inhibits lysosomal degradation and promotes parasite reproduction.

### **2. Phagocytosis**

The first person to describe the absorption of particles by cells was Élie Metchnikoff (1845–1916), who also highlighted the significance of this process for the host's reaction to damage and infection. Phagocytosis is a sophisticated mechanism for ingesting and eliminating infections that also plays a crucial role in the elimination of apoptotic cells, which is essential for maintaining tissue homeostasis. Target particle identification, signaling to start the internalization machinery, phagosome formation, and phagolysosome maturation are the four key stages of phagocytosis [18].

The key aspects of the early events of phagocytosis of protist parasites under study will be discussed in the following section.

#### **2.1 Recognition and phagocytosis of** *Plasmodium spp*

Microorganisms express molecules known as pathogen-associated molecular patterns (PAMPs), which are only expressed by pathogens and not by host cells. Glycosylphosphatidylinositol (GPI) anchors, nucleic acids, and Hemozoin are all Plasmodium PAMPs [2]. Pattern recognition receptors (PRRs) such as CD36, toll-like receptors (TLRs), and complement receptor 3 identify these PAMPs and trigger the parasite uptake.

Phagocytes, particularly monocytes, and macrophages, may also perform opsonic phagocytosis of *Plasmodium spp*. Certain opsonins, notably antibodies, have been found in functional investigations to increase successful phagocytosis. Protective immunity in malaria has been linked to the IgG1 and IgG3 subclasses. MSP (the merozoite surface proteins) 2 and 3, MSP-Duffy binding-like proteins 1 and 2, and glutamate-rich proteins have been discovered as targets of these opsonizing antibodies in merozoites [19].

Immune system cells have immunoglobulin (Ig) binding receptors, FcgR I receptors, FcgRII and FcgRIIII, and complement receptors CR1 and CR3. These factors, when combined, can aid in the phagocytic absorption of antigens opsonized with components such as IgG or C3b [1].

The complement receptor CR1 recognizes and phagocytoses ring-parasitized red blood cells opsonized by IgG and complement. Parasites cause changes in the membrane proteins of hosts' erythrocytes, exposing antigenic regions identified by autoantibodies. For example, band 3 protein is clustered and oxidized, and it is also underglycosylated [20]. Protein 1 (PfEMP1), which is expressed on the membrane of *Plasmodium falciparum*-infected erythrocytes, is also a significant target of opsonizing antibodies, with antibodies recognizing distinct domains of this protein [20].

When activated, neutrophils can produce reactive oxygen species (ROS), which are highly poisonous chemicals that can kill parasites by inflicting oxidative damage.
