CD8+ T Cell Response Quality Is Related to Parasite Control in an Animal Model of Single and Mixed Chronic Trypanosoma cruzi Infections

Abstract

Chagas disease (ChD) is a chronic infection caused by Trypanosoma cruzi. This highly diverse intracellular parasite is classified into seven genotypes or discrete typing units (DTUs) and they overlap in geographic ranges, vectors, and clinical characteristics. Although studies have suggested that ChD progression is due to a decline in the immune response quality, a direct relationship between T cell responses and disease outcome is still unclear. To investigate the relationship between parasite control and immune T cell responses, we used two distinct infection approaches in an animal model to explore the histological and parasitological outcomes and dissect the T cell responses in T. cruzi-infected mice. First, we performed single infection experiments with DA (TcI) or Y (TcII) T. cruzi strains to compare the infection outcomes and evaluate its relationship with the T cell response. Second, because infections with diverse T. cruzi genotypes can occur in naturally infected individuals, mice were infected with the Y or DA strain and subsequently reinfected with the Y strain. We found different infection outcomes in the two infection approaches used. The single chronic infection showed differences in the inflammatory infiltrate level, while mixed chronic infection by different T. cruzi DTUs showed dissimilarities in the parasite loads. Chronically infected mice with a low inflammatory infiltrate (DA-infected mice) or low parasitemia and parasitism (Y/Y-infected mice) showed increases in early-differentiated CD8+ T cells, a multifunctional T cell response and lower expression of inhibitory receptors on CD8+ T cells. In contrast, infected mice with a high inflammatory infiltrate (Y-infected mice) or high parasitemia and parasitism (DA/Y-infected mice) showed a CD8+ T cell response distinguished by an increase in late-differentiated cells, a monofunctional response, and enhanced expression of inhibitory receptors. Overall, our results demonstrated that the infection outcomes caused by single or mixed T. cruzi infection with different genotypes induce a differential immune CD8+ T cell response quality. These findings suggest that the CD8+ T cell response might dictate differences in the infection outcomes at the chronic T. cruzi stage. This study shows that the T cell response quality is related to parasite control during chronic T. cruzi infection.

Trypanosoma cruzi-specific CD8+ T cells and other immunological hallmarks in chronic Chagas cardiomyopathy: Two decades of research

“…In contrast, infected mice with a high inflammatory infiltrate (Y-infected mice) or high parasitaemia and parasitism (DA/Y-infected mice) showed a CD8 + T cell response distinguished by an increase in late-differentiated cells, a monofunctional response, and enhanced expression of inhibitory receptors. Overall, our results demonstrated that the infection caused by single or mixed T. cruzi infection with different parasite genotypes induce a differential immune CD8 + T cell response quality, which suggest that the quality of CD8 + T cell response might dictate differences in the parasite control and infection outcomes at the chronic T. cruzi stage ( Mateus et al., 2017 ; Mateus et al., 2021 ).…”

“…Although all parasite DTU’s are known to be circulating in Colombia ( Guhl and Ramirez, 2013 ), parasites belonging to DTU TcI and, to a lesser extent, DTU TcII, have been the ones mainly recovered from patients ( Ramirez et al., 2010 ). In this context, our results from mice chronic infections with DTU TcI (DA), and DTU TcII (Y) strains showed that both parasite strain and type of infection (single or double) influenced parasitemia, parasitism and inflammatory response ( Mateus et al., 2021 ). Therefore, it is possible that parasite DTUs could affect disease outcomes.…”

“…Second, because infections with diverse T. cruzi genotypes can occur in naturally infected individuals, mice were infected with the Y or DA strain and subsequently reinfected with the Y strain. We found differences in the infection outcomes in the two infection strategies used ( Mateus et al., 2021 ). The single chronic infection displayed differences in the inflammatory infiltrate level, while mixed chronic infection by different T. cruzi DTUs showed dissimilarities in the parasite loads.…”

Modulation of STAT-1, STAT-3, and STAT-6 activities in THP-1 derived macrophages infected with two Trypanosoma cruzi strains

“…This pronounced genetic variability allows reinfections by different strains, also known as co-infections, polyparasitism, or mixed infections. Previous studies have described polyparasitism in insect vectors (11,12), human patients (13)(14)(15)(16), experimental infection and treatment effects in animal models (17)(18)(19)(20). At endemic areas, the occurrence of co-infections is estimated between 9 and 57% (14)(15)(16)21).…”