Extracellular Vesicles Shed By Trypanosoma cruzi Potentiate Infection and Elicit Lipid Body Formation and PGE2 Production in Murine Macrophages

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.

Role of Extracellular Vesicles in Cellular Cross Talk in Malaria

“…EVs act indirectly by inducing the production of prostaglandin E2 (PGE2) by macrophages, which, at high concentrations, inhibits the release of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-10, and IL-6) and reduced antigen presentation. Taken together, these data show that EVs from T. cruzi exerts a potent immunomodulatory effects on host immune cells during infection, promoting an environment more favorable to T. cruzi during the first steps of infection (136). In order to produce EVs, T. brucei rhodesiense build flagellar membrane nanotubes that dissociate and form vesicles leading to EV release.…”

Message in a vesicle – trans-kingdom intercommunication at the vector–host interface

“…speculated that this could be due to the inhibition of the C3 convertase, which is a key component during the complement activation (Lidani et al, 2017;Wyllie and Ramirez, 2017). Interestingly, vesicles from one strain do not confer complement resistance to trypanosomes from a different group (Wyllie and Ramirez, 2017).…”

“…This strain-dependent resistance highlights the level of specificity in the ability of the parasite to protect itself from the immune system of its host. Extracellular vesicles derived from T. cruzi also promote an immunosuppressive response through the induction of IL-4 and IL-10 in the heart tissue, and a reduction of iNOS and TNF production by macrophages (Lovo-Martins et al, 2018;Trocoli Torrecilhas et al, 2009). Accordingly, priming of macrophages with extracellular vesicles from T. cruzi results in fewer macrophages that are positive for MHC class II molecules, suggesting that vesicles can suppress macrophage stimulation and dampen T cell activation (Lovo-Martins et al, 2018).…”

“…Extracellular vesicles derived from T. cruzi also promote an immunosuppressive response through the induction of IL-4 and IL-10 in the heart tissue, and a reduction of iNOS and TNF production by macrophages (Lovo-Martins et al, 2018;Trocoli Torrecilhas et al, 2009). Accordingly, priming of macrophages with extracellular vesicles from T. cruzi results in fewer macrophages that are positive for MHC class II molecules, suggesting that vesicles can suppress macrophage stimulation and dampen T cell activation (Lovo-Martins et al, 2018). Such an immunosuppression is further indicated by the decreased expression of CD86 (B7-2), a co-stimulatory molecule involved in T cell activation (Lovo-Martins et al, 2018).…”

“…Mosquitoes, ticks and sandflies, among other arthropods, secrete salivary proteins that contribute to microbial transmission (Leitner et al, 2013;Shaw et al, 2016;Šimo et al, 2017). One immune evasion strategy used by vector-borne pathogens to promote a successful infection is through the secretion of extracellular vesicles (Atayde et al, 2015;Babatunde et al, 2018;Lovo-Martins et al, 2018;Nogueira et al, 2015;Silverman et al, 2010a,b;Sisquella et al, 2017;Trocoli Torrecilhas et al, 2009). Extracellular vesicles are involved in the exchange of molecular cargo between cells.…”