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Updated: Aug 21, 2025
Quantitative 3D Imaging of Trypanosoma cruzi-Infected Cells, Dormant Amastigotes, and T Cells in Intact Clarified Organs
Published on: June 23, 2022
Modulation of STAT-1, STAT-3, and STAT-6 activities in THP-1 derived macrophages infected with two Trypanosoma cruzi
Melissa Martins Oliveira1, Camila Ramalho Bonturi2, Bruno Ramos Salu2
1¹Microbiology, Immunology and Parasitology Department, Escola Paulista de Medicina, Federal University of São Paulo - UNIFESP, São Paulo, Brazil.
Insights
This study reveals how Trypanosoma cruzi strains G and CL interact differently with human macrophages, impacting immune responses and parasite survival. Co-infection alters the inflammatory environment, promoting parasite persistence.
Area of Science:
- Immunology
- Parasitology
- Cell Biology
Background:
- Chagas' disease, caused by Trypanosoma cruzi, is a neglected tropical disease with complex host-parasite interactions.
- Trypanosoma cruzi exhibits genetic variability, leading to co-infections with unclear immune modulation.
- Understanding parasite evasion mechanisms is crucial for disease progression and chronic symptom management.
Purpose of the Study:
- To investigate the co-infection dynamics of Trypanosoma cruzi strains G and CL in human macrophages.
- To compare the effects of monoinfection versus co-infection on macrophage activation and cytokine profiles.
- To elucidate the impact of different parasite strains and infective forms on host immune evasion and parasite persistence.
Main Methods:
- Human macrophages derived from THP-1 cells were activated via classical or alternative pathways.
- Flow cytometry was used to assess macrophage infectivity by trypomastigotes and extracellular amastigotes (EAs).
- Analysis included reactive oxygen species (ROS) production, cytokine profiles (IFN-γ, TNF-α, IL-1β, IL-4, IL-10, TGF-β), and STAT factor activation.
Main Results:
- Trypomastigotes were more infective than EAs; strain G infected more macrophages than strain CL.
- Classically activated macrophages showed lower infection rates; IL-4 stimulation increased CL infection.
- Co-infection was rare, but altered cytokine profiles towards inflammation and increased STAT activation, promoting parasite survival.
Conclusions:
- Trypanosoma cruzi strains differentially modulate macrophage responses, influencing parasite persistence.
- Co-infection leads to a distinct inflammatory milieu compared to monoinfection, favoring parasite survival.
- Parasite infective form and host immune activation state significantly impact infection outcomes and immune evasion strategies.
Abstract:
Trypanosoma cruzi is the causative protozoan of Chagas' Disease, a neglected tropical disease that affects 6-7 million people worldwide. Interaction of the parasite with the host immune system is a key factor in disease progression and chronic symptoms. Although the human immune system is capable of controlling the disease, the parasite has numerous evasion mechanisms that aim to maintain intracellular persistence and survival. Due to the pronounced genetic variability of T. cruzi, co-infections or mixed infections with more than one parasite strain have been reported in the literature. The intermodulation in such cases is unclear. This study aimed to evaluate the co-infection of T. cruzi strains G and CL compared to their individual infections in human macrophages derived from THP-1 cells activated by classical or alternative pathways. Flow cytometry analysis demonstrated that trypomastigotes were more infective than extracellular amastigotes (EAs) and that strain G could infect more macrophages than strain CL. Classically activated macrophages showed lower number of infected cells and IL-4-stimulated cells displayed increased CL-infected macrophages. However, co-infection was a rare event. CL EAs decreased the production of reactive oxygen species (ROS), whereas G trypomastigotes displayed increased ROS detection in classically activated cells. Co-infection did not affect ROS production. Monoinfection by strain G or CL mainly induced an anti-inflammatory cytokine profile by decreasing inflammatory cytokines (IFN-γ, TNF-α, IL-1β) and/or increasing IL-4, IL-10, and TGF-β. Co-infection led to a predominant inflammatory milieu, with reduced IL-10 and TGF-β, and/or promotion of IFN-γ and IL-1β release. Infection by strain G reduced activation of intracellular signal transducer and activator of transcription (STAT) factors. In EAs, monoinfections impaired STAT-1 activity and promoted phosphorylation of STAT-3, both changes may prolong cell survival. Coinfected macrophages displayed pronounced activation of all STATs examined. These activations likely promoted parasite persistence and survival of infected cells. The collective results demonstrate that although macrophages respond to both strains, T. cruzi can modulate the intracellular environment, inducing different responses depending on the strain, parasite infective form, and co-infection or monoinfection. The modulation influences parasite persistence and survival of infected cells.
