Potential of extracellular vesicles in the pathogenesis, diagnosis and therapy for parasitic diseases

Abstract

Parasitic diseases have a significant impact on human and animal health, representing a major hazard to the public and causing economic and health damage worldwide. Extracellular vesicles (EVs) have long been recognized as diagnostic and therapeutic tools but are now also known to be implicated in the natural history of parasitic diseases and host immune response modulation. Studies have shown that EVs play a role in parasitic disease development by interacting with parasites and communicating with other types of cells. This review highlights the most recent research on EVs and their role in several aspects of parasite-host interactions in five key parasitic diseases: Chagas disease, malaria, toxoplasmosis, leishmaniasis and helminthiases. We also discuss the potential use of EVs as diagnostic tools or treatment options for these infectious diseases.

Keywords: Chagas Disease; extracellular vesicles; helminthiasis; leishmaniasis; malaria; toxoplasmosis.

FIGURE 1

An overview of the contribution of EVs to the pathogenesis of parasitic diseases. (a) Trypanosoma cruzi: parasite‐derived EVs modulate the host immune system to promote invasion via TLR‐2. In macrophages, EVs derived from the most virulent strain (YuYu) increase parasite intracellular proliferation and the host proinflammatory response, followed by the release of greater amounts of TNFα, IL‐6 and NO, which is not observed with less virulent strains (Y and Colombian). Instead, EVs isolated from Y and Colombian strains induce a proinflammatory response in splenocytes during the chronic phase of T. cruzi infection. (b) Toxoplasma gondii: Host cells infected with T. gondii produce EVs that change both host and neighbouring cells’ proliferation mechanisms. T. gondii tachyzoite‐derived EVs contain proteins used for invasion and proliferation in the host cell, suggesting a role in facilitating infection. Tachyzoite‐derived EVs induce macrophage activation and a proinflammatory response, increasing levels of IL‐12, TNFα and INFγ while reducing IL‐10. Moreover, EVs from T. gondii‐infected macrophages carry pathogen‐associated molecular patterns (PAMPs), thus driving activation and a proinflammatory phenotype in other macrophages in the vicinity. (c) Plasmodium sp.: During infection, plasma levels of EVs are elevated and correlate directly with severe disease. EVs derived from infected erythrocytes (iRBC‐EVs) influence parasite invasion and survival. These EVs also induce gametocyte differentiation, supporting parasite survival and lifecycle progression. It is also recognized that iRBC‐EVs promote endothelial cell activation, increasing parasite sequestration and induce a proinflammatory response by activating monocytes, lymphocytes and neutrophils. EVs can also be secreted by host cells, including endothelial cells, erythrocytes and platelets, thus contributing to disease aggravation. (d) Leishmania sp.: Parasite‐derived EVs subvert the host immune response, promoting parasite survival by a mechanism that induces reduction of the microbicidal agents NO and TNFα. Moreover, L. donovani‐derived EVs downmodulate the expression of CD86 and CD40 in antigen‐presenting cells (DCs). Parasite EVs promote gene transfer and are associated with drug resistance. In L. brasiliensis infection, parasite‐derived EVs increase the proinflammatory response by priming macrophages to increase the production of IL‐1β, IL‐6 and TNF‐α upon infection. Macrophages infected with L. amazonensis generate EVs that can intensify the immune response, aggravating disease. (e) Helminths: EVs derived from different helminth species directly induce endothelial cell activation and modulate the host immune response to promote survival and persistence of infection. Created with BioRender.com.