The role of extracellular vesicles in Plasmodium and other protozoan parasites

Abstract

Protozoan parasites and other microorganisms use various pathways to communicate within their own populations and to manipulate their outside environments, with the ultimate goal of balancing the rate of growth and transmission. In higher eukaryotes, including humans, circulating extracellular vesicles are increasingly recognized as key mediators of physiological and pathological processes. Recent evidence suggests that protozoan parasites, including those responsible for major human diseases such as malaria and Chagas disease, use similar machinery. Indeed, intracellular and extracellular protozoan parasites secrete extracellular vesicles to promote growth and induce transmission, to evade the host immune system, and to manipulate the microenvironment. In this review we will discuss the general pathways of extracellular vesicle biogenesis and their functions in protozoan infections.

Figure 1. Overview of EV biogenesis and functions

A. Exosome and MV biogenesis. Exosomes are derived from multivesicular bodies (MVBs). Exosome generation is initiated through inward budding of early endosomes leading to MVB formation (1). Exosomes are released when MVBs fuse with the outer cell membrane to release their cargo. ESCRT proteins, in conjunction with additional factors such as syntenin and syndecans, mediate the biogenesis of MVBs and the sorting of specific cargo to MVBs. Rab proteins regulate maturation and fusion of MVBs with the plasma membrane (2). Microvesicles (MVs) bud directly from the plasma membrane and are shed into the environment (3). Their formation also requires specific factors such as ARF-6, VPS4 and the plasma membrane protein ARRDC1. B. EV function. EVs are composed of a lipid bilayer, and they express specific receptors on their surface reflecting their cellular origin (i.e., tetraspanins, integrins). Exosomes can be identified by presence of specific ESCRT components such as TSG101 and Alix. EVs contain various bioactive molecules including protein, lipid, DNA and RNA (including miRNA bound to Argonaute-2 [Ago2]).

Figure 2. EVs in parasites

A. Plasmodium sp. P. falciparum-infected RBCs release EVs that contain multiple Maurer's cleft (MC) components. One MC component, PTP2, is essential for EV release and uptake by recipient cells. The EVs are phagocytosed and induce secretion of cytokines by macrophages. EVs can also be internalized by infected RBCs and trigger differentiation of the parasite in the recipient cell into gametocytes. B. Leishmania sp. During human infection, free-living promastigote forms and intracellular amastigotes secrete EVs that contain the parasite antigen GP63. GP63 induces host SHP-1 that down-regulates the immune response. EVs can also transferred to hepatocytes where GP63 cleaves DICER1, inhibiting the maturation of the lipid regulator miR-122, promoting growth of the parasite. C. Trichomonas vaginalis. The parasite secretes EVs that can fuse with host cells and induce secretion of IL-6 and IL-8, activating receptor expression on the surface of epithelial cells and therefore inducing parasite attachment. D. Trypanosoma cruzi. Free-living trypomastigote forms secrete vesicles containing T. cruzi antigens. When fibroblasts and cardiomyocytes adsorbe EVs they become targeted by a humoral immune response that is responsible for tissue damage. Trypomastigote forms also trigger the release of EVs from monocytes, and these monocytic EVs bind to the trypomastigotes and protect them from complement lysis by binding and neutralizing the C3 convertase.