Strain‐Dependent Immune Signaling by Small Extracellular Vesicles Derived From Trypanosoma cruzi ‐Infected Macrophages

Abstract

Among extracellular vesicles (EVs), exosomes, comprised within small EVs are bilayered nanovesicles carrying specific cargo that are released into the interstitial space in a highly regulated manner. In this study, we investigated the message transmitted through macrophage-derived small EVs in response to the interaction with Trypanosoma cruzi, the protozoan responsible for Chagas disease. We utilized two distinct parasite strains, the virulent CL Brener and the attenuated TCC. When taken up by naϊve macrophages (Mφs) in vitro, small EVs derived from TCC-infected cells favor an adverse environment for parasite spread, with M1-like cytokine pattern. In contrast, EVs from CL Brener-infected cells fostered a more permissive environment with reduced TNF-α/IL-10 ratio, higher phagocytic activity and reduced migration capacity, which may hinder a timely immune response. Further, while naïve Mφs´ EVs induced iNOS and nitric oxide (NO) secretion, EVs from T. cruzi-infected Mφs failed to robustly activate iNOS, suggesting the parasite may modulate EV-mediated communication to avoid NO toxicity. In vivo assays showed distinct parasitemia courses with higher parasite burden when mice were treated with small EVs from CL Brener-infected Mφs. Overall, small EVs released by infected Mφs serve as messengers in T. cruzi infection, inducing different immune responses based on parasite virulence.