Abstract
During the onset of Trypanosoma cruzi infection, an effective immune response is necessary to control parasite replication and ensure host survival. Macrophages have a central role in innate immunity, acting as an important trypanocidal cell and triggering the adaptive immune response through antigen presentation and cytokine production. However, T. cruzi displays immune evasion mechanisms that allow infection and replication in macrophages, favoring its chronic persistence. One potential mechanism is the release of T. cruzi strain Y extracellular vesicle (EV Y), which participate in intracellular communication by carrying functional molecules that signal host cells and can modulate the immune response. The present work aimed to evaluate immune modulation by EV Y in C57BL/6 mice, a prototype resistant to infection by T. cruzi strain Y, and the effects of direct EV Y stimulation of macrophages in vitro. EV Y inoculation in mice prior to T. cruzi infection resulted in increased parasitemia, elevated cardiac parasitism, decreased plasma nitric oxide (NO), reduced NO production by spleen cells, and modulation of cytokine production, with a reduction in TNF-α in plasma and decreased production of TNF-α and IL-6 by spleen cells from infected animals. In vitro assays using bone marrow-derived macrophages showed that stimulation with EV Y prior to infection by T. cruzi increased the parasite internalization rate and release of infective trypomastigotes by these cells. In this same scenario, EV Y induced lipid body formation and prostaglandin E2 (PGE2) production by macrophages even in the absence of T. cruzi. In infected macrophages, EV Y decreased production of PGE2 and cytokines TNF-α and IL-6 24 h after infection. These results suggest that EV Y modulates the host response in favor of the parasite and indicates a role for lipid bodies and PGE2 in immune modulation exerted by EVs.
Highlights
The protozoan Trypanosoma cruzi, the etiologic agent of Chagas disease, was discovered by Carlos Chagas more than 100 years ago when its life cycle, vector, and pathogenesis in humans were described [1]
Cardiac parasitism was evaluated in phosphate-buffered saline (PBS) or extracellular vesicles (EVs) Y-inoculated mice at 12 dpi
In 2009, a study reported that inoculation with EVs shed by T. cruzi prior to infection in susceptible BALB/c mice increased cardiac parasitism and accelerated mortality rates, without a significant increase in blood parasitemia [26]
Summary
The protozoan Trypanosoma cruzi, the etiologic agent of Chagas disease, was discovered by Carlos Chagas more than 100 years ago when its life cycle, vector, and pathogenesis in humans were described [1]. In vector-borne transmissions, metacyclic trypomastigotes are released in the triatomine excreta when insects feed on mammalian blood These metacyclic trypomastigotes invade host cells where they transform into replicative amastigotes. A strong and persistent polarized T helper 1 response is established against intracellular parasites [11], and an anti-T. cruzi CD8 immune response is focused on parasitic immunodominant epitopes. These T-cell responses are important for controlling parasitemia, tissue parasitism, and polyclonal B-cell activation with antibody production [12]. Due to T. cruzi immune evasion mechanisms, this intense immune response fails to clear parasitic infection, leading to its persistence and development of the chronic phase of Chagas disease [13]
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