AUTHOR=Lovo-Martins Maria Isabel , Malvezi Aparecida Donizette , Zanluqui Nágela Ghabdan , Lucchetti Bruno Fernando Cruz , Tatakihara Vera Lúcia Hideko , Mörking Patricia Alves , Oliveira Admilton Gonçalves de , Goldenberg Samuel , Wowk Pryscilla Fanini , Pinge-Filho Phileno 

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

JOURNAL=Frontiers in Immunology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.00896

DOI=10.3389/fimmu.2018.00896

ISSN=1664-3224

ABSTRACT=<p>During the onset of <italic>Trypanosoma cruzi</italic> 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, <italic>T. cruzi</italic> displays immune evasion mechanisms that allow infection and replication in macrophages, favoring its chronic persistence. One potential mechanism is the release of <italic>T. cruzi</italic> 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 <italic>T. cruzi</italic> strain Y, and the effects of direct EV Y stimulation of macrophages <italic>in vitro</italic>. EV Y inoculation in mice prior to <italic>T. cruzi</italic> 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. <italic>In vitro</italic> assays using bone marrow-derived macrophages showed that stimulation with EV Y prior to infection by <italic>T. cruzi</italic> 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 E<sub>2</sub> (PGE<sub>2</sub>) production by macrophages even in the absence of <italic>T. cruzi</italic>. In infected macrophages, EV Y decreased production of PGE<sub>2</sub> 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 PGE<sub>2</sub> in immune modulation exerted by EVs.</p>