Host-Derived Extracellular Vesicles in Blood and Tissue Human Protozoan Infections

Abstract

Blood and tissue protozoan infections are responsible for an enormous burden in tropical and subtropical regions, even though they can also affect people living in high-income countries, mainly as a consequence of migration and travel. These pathologies are responsible for heavy socio-economic issues in endemic countries, where the lack of proper therapeutic interventions and effective vaccine strategies is still hampering their control. Moreover, the pathophysiological mechanisms associated with the establishment, progression and outcome of these infectious diseases are yet to be fully described. Among all the players, extracellular vesicles (EVs) have raised significant interest during the last decades due to their capacity to modulate inter-parasite and host-parasite interactions. In the present manuscript, we will review the state of the art of circulating host-derived EVs in clinical samples or in experimental models of human blood and tissue protozoan diseases (i.e., malaria, leishmaniasis, Chagas disease, human African trypanosomiasis and toxoplasmosis) to gain novel insights into the mechanisms of pathology underlying these conditions and to identify novel potential diagnostic markers.

Keywords: Chagas’ disease; biomarkers; extracellular vesicles; host–pathogen interaction; human African trypanosomiasis; human leishmaniasis; malaria; protozoan infections; toxoplasmosis.

Figure 1

Erythrocytic life cycle of Plasmodium spp. within the human host. After a first initial liver stage, merozoites are released in the bloodstream, where they will infect red blood cells (RBC) to initiate the asexual intra-erythrocytic cycle. Within the RBC, merozoites become first immature trophozoites (ring stage), then mature trophozoites, and finally divide to become schizonts. These will eventually erupt from the RBC, releasing new merozoites in the bloodstream that will infect the new RBC. Occasionally, a portion of trophozoites will mature into gametocytes, which can be taken up by the mosquito vector. The image was created with BioRender.com.

Figure 2

Life cycle of Leishmania spp. within the human/canid host. Metacyclic promastigotes are inoculated in the host by an infected sandfly during a blood meal. The intracellular life cycle occurs within nucleated cells, preferentially macrophages, where promastigotes are phagocytised, transformed into amastigotes and start replicating. Following the rupture of the infected cell, amastigotes can invade new mononuclear cells or reach target organs such as the viscera, lymph nodes and bone marrow. The image was created with BioRender.com.

Figure 3

Trypanosoma cruzi life cycle within the human host. Metacyclic trypromastigotes are released by bedbug faeces on the host skin. Penetration occurs following scratches on the purulent insect bite wound. Within the host, metacyclic trypomastiogtes infect nucleated cells, become amastigotes, and replicate. The majority of amastigotes become trypomastigotes, inducing the lysis of the infected cells and the consequent release of parasites in the extracellular space. Both trypromastigotes, and amastigotes can reach, through the bloodstream, distant target organs such as the viscera and heart, where they infect tissue cells. T. cruzi infection may also affect the skeletal muscles and produce neurological disorders. The image was created with BioRender.com.

Figure 4

Trypanosoma brucei gambiense and T. b. rhodesiense life cycles within the human host. Metacyclic trypomastigotes are injected through the bite of a tsetse fly during the blood meal into the host bloodstream, where they replicate extracellularly. Parasites replicate by binary fission as long, slender trypomastigote forms in various body fluids, including blood, lymph and—when they reach the central nervous system—cerebrospinal fluid. The image was created with BioRender.com.

Figure 5

Toxoplasma gondii life cycle within the human host. Humans acquire T. gondii infection following ingestion of food contaminated with tissue cysts full of bradyzoites or with sporulated oocysts containing sporozoites. Tachyzoites and sporozoites are then released in the stomach and enter epithelial cells, from which they egress as tachyzoites. Tachyzoites can then invade any kind of cell (e.g., monocytes) to replicate by endodyogeny and disseminate to target organs, such as skeletal muscles, eyes, brain and heart, where they eventually form tissue cysts. During pregnancy, T. gondii can pass through the placenta and infect the foetus, causing miscarriages or developmental defects. The image was created with BioRender.com.