An Animal Model of Acute and Chronic Chagas Disease With the Reticulotropic Y Strain of Trypanosoma cruzi That Depicts the Multifunctionality and Dysfunctionality of T Cells.

Jose Mateus,Paola Lasso,Concepción J Puerta,Claudia Cuervo,John Mario González,Adriana Cuéllar,Paula Guerrero

doi:10.3389/fimmu.2019.00918

Jose Mateus, Paola Lasso + Show 5 more

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https://doi.org/10.3389/fimmu.2019.00918

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Abstract

Chagas disease (ChD), a complex and persistent parasitosis caused by Trypanosoma cruzi, represents a natural model of chronic infection, in which some people exhibit cardiac or digestive complications that can result in death 20–40 years after the initial infection. Nonetheless, due to unknown mechanisms, some T. cruzi-infected individuals remain asymptomatic throughout their lives. Actually, no vaccine is available to prevent ChD, and treatments for chronic ChD patients are controversial. Chronically T. cruzi-infected individuals exhibit a deterioration of T cell function, an exhaustion state characterized by poor cytokine production and increased inhibitory receptor co-expression, suggesting that these changes are potentially related to ChD progression. Moreover, an effective anti-parasitic treatment appears to reverse this state and improve the T cell response. Taking into account these findings, the functionality state of T cells might provide a potential correlate of protection to detect individuals who will or will not develop the severe forms of ChD. Consequently, we investigated the T cell response, analyzed by flow cytometry with two multicolor immunofluorescence panels, to assess cytokines/cytotoxic molecules and the expression of inhibitory receptors, in a murine model of acute (10 and 30 days) and chronic (100 and 260 days) ChD, characterized by parasite persistence for up to 260 days post-infection and moderate inflammation of the colon and liver of T. cruzi-infected mice. Acute ChD induced a high antigen-specific multifunctional T cell response by producing IFN-γ, TNF-α, IL-2, granzyme B, and perforin; and a high frequency of T cells co-expressed 2B4, CD160, CTLA-4, and PD-1. In contrast, chronically infected mice with moderate inflammatory infiltrate in liver tissue exhibited monofunctional antigen-specific cells, high cytotoxic activity (granzyme B and perforin), and elevated levels of inhibitory receptors (predominantly CTLA-4 and PD-1) co-expressed on T cells. Taken together, these data support our previous results showing that similar to humans, the T. cruzi persistence in mice promotes the dysfunctionality of T cells, and these changes might correlate with ChD progression. Thus, these results constitute a model that will facilitate an in-depth search for immune markers and correlates of protection, as well as long-term studies of new immunotherapy strategies for ChD.

Highlights

During the last decades, animal models have facilitated the study of complex diseases to analyze the components that potentially explain human pathologies
The parasite load was below the limit of quantification (LOQ) in the majority of chronically infected mice, when comparing the parasite loads according to the dpi, higher parasite loads in the colon, heart, liver, and skeletal muscle tissues were detected in mice at 10 or 30 dpi compared with those at 100 or 260 dpi (Supplementary Figure 4B)
In Chagas disease (ChD), chronically infected individuals have dysfunctional CD8+ T cells exhibiting impaired cytokine production and increased inhibitory receptor co-expression, similar to the findings described above [25, 26]

Summary

Introduction

Animal models have facilitated the study of complex diseases to analyze the components that potentially explain human pathologies. Protozoa are complex eukaryotic unicellular organisms because of their structure and metabolic activities [3] These parasites are a challenge to human health and a global threat because they persist for long periods of time, causing severe pathologies. Some species, such as Leishmania spp., Plasmodium spp., and Trypanosoma cruzi, are human pathogens, causing leishmaniasis, malaria, and Chagas disease (ChD), respectively. These illnesses were described many years ago, no vaccines are currently available and their effective etiological treatments are limited [4, 5]. A striking example of this success is the measurement of the quality (or multifunctional capacity) of the CD4+ T cell cytokine response as a crucial determinant for monitoring vaccine-mediated protection against L. major and Plasmodium berghei infection in mice [6, 7]

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