Immune exhaustion in chronic Chagas disease: Pro-inflammatory and immunomodulatory action of IL-27 in vitro

Natale, María A.; Minning, Todd; Albareda, María Cecilia; Eiro, Melisa D. Castro; Alvarez, M; Lococo, Bruno; Cesar, Gonzalo; Bertocchi, Graciela; Elias, María Josefina; Caputo, María Belén; Tarleton, Rick L.; Laucella, Susana A.

doi:10.1371/journal.pntd.0009473

Cited by 5 publications

(2 citation statements)

References 69 publications

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“…Memory CD8 + T cells are crucial in infection control, especially in the infected tissues (38,39). However, it was also described that memory T cells might acquire a non-functional phenotype in peripheral tissues either in tumor environments or during T cruzi infection, the so-called exhausted or dysfunctional phenotype (40,41). Therefore, the simple presence of increased numbers of effector memory T cells does not guarantee a better immune response.…”

Section: Discussionmentioning

confidence: 99%

C57BL/6 Mice Pretreated With Alpha-Tocopherol Show a Better Outcome of Trypanosoma cruzi Infection With Less Tissue Inflammation and Fibrosis

et al. 2022

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Chagas disease is accompanied by a multisystem inflammatory disorder that follows Trypanosoma cruzi infection. Alpha-tocopherol has been described as an antioxidant and a potential adjuvant to enhance immune responses to vaccines. Therefore, we have evaluated the immune response to T. cruzi infection upon alpha-tocopherol pre-administration. The results show that administration of alpha-tocopherol before the infection results in lower parasitemia and lower mortality of C57BL/6 mice infected with the Tulahuen T. cruzi strain. Alpha-tocopherol administration in normal C57BL/6 mice resulted in higher levels of IFN-γ production by T and NK cells before and after the infection with T. cruzi. More importantly, previous administration of alpha-tocopherol increased the production of IL-10 by T and myeloid suppressor cells and the formation of effector memory T cells while decreasing the expression of PD-1 on T cells. These results suggest that alpha-tocopherol may limit the appearance of dysfunctional T cells during the acute and early chronic phases of T. cruzi infection, contributing to control infection. In addition, alpha-tocopherol could diminish tissue inflammation and fibrosis in late acute disease. These results strongly suggest that alpha-tocopherol may be a helpful agent to be considered in Chagas disease.

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Section: Discussionmentioning

confidence: 99%

C57BL/6 Mice Pretreated With Alpha-Tocopherol Show a Better Outcome of Trypanosoma cruzi Infection With Less Tissue Inflammation and Fibrosis

et al. 2022

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“…A major issue is that disease progression is still poorly understood, and patients at an increased risk of developing severe disease cannot be distinguished from those who may remain in the asymptomatic chronic stage, making any prognosis uncertain. Pathogenesis has been associated with immune exhaustion, allowing parasite persistence in host tissues ( 3 , 4 ), providing the rationale to target the parasite through drugs or therapeutic vaccines ( 2 ). However, the efficacy of benznidazole treatment is variable, and while it can consistently decrease parasite burden, it can also delay the appearance of new electrocardiographic (ECG) abnormalities and the progression to more severe Kuschnir group of cardiac disease in patients treated early ( 5 , 6 ), but it fails to stop or delay the progression of fibrotic heart disease in symptomatic patients ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

Intra-host Trypanosoma cruzi strain dynamics shape disease progression: the missing link in Chagas disease pathogenesis

Dumonteil,

Desale,

et al. 2023

Microbiol Spectr

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Chronic Chagasic cardiomyopathy develops years after infection in 20–40% of patients, but disease progression is poorly understood. Here, we assessed Trypanosoma cruzi parasite dynamics and pathogenesis over a 2.5-year period in naturally infected rhesus macaques. Individuals with better control of parasitemia were infected with a greater diversity of parasite strains compared to those with increasing parasitemia over time. Also, the in vivo parasite multiplication rate decreased with increasing parasite diversity, suggesting competition among strains or a stronger immune response in multiple infections. Significant differences in electrocardiographic (ECG) profiles were observed in Chagasic macaques compared to uninfected controls, suggesting early conduction defects, and changes in ECG patterns over time were observed only in macaques with increasing parasitemia and lower parasite diversity. Disease progression was also associated with plasma fibronectin degradation, which may serve as a biomarker. These data provide a novel framework for the understanding of Chagas disease pathogenesis, with parasite diversity shaping disease progression. IMPORTANCE Chagas disease progression remains poorly understood, and patients at increased risk of developing severe cardiac disease cannot be distinguished from those who may remain asymptomatic. Monitoring of Trypanosoma cruzi strain dynamics and pathogenesis over 2–3 years in naturally infected macaques shows that increasing parasite diversity in hosts is detrimental to parasite multiplication and Chagasic cardiomyopathy disease progression. This provides a novel framework for the understanding of Chagas disease pathogenesis.

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Transcriptomic Evidence of Immune Modulation in Subjects With Chronic Trypanosoma cruzi Infection

Ros-Lucas,

Gabaldón-Figueira,

Martínez-Peinado

et al. 2024

The Journal of Infectious Diseases

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Chagas disease is a neglected tropical infection that affects millions of people. This study explores transcriptomic changes in T. cruzi-infected subjects before and after treatment. Using total RNA sequencing, gene transcription was analyzed in peripheral blood mononuclear cells from asymptomatic (n=19) and symptomatic (n=8) T. cruzi-infected individuals, and non-infected controls (n=15). Differential expression was compared across groups, and before/after treatment in infected subgroups. Untreated infection showed 12 upregulated and 206 downregulated genes in all T. cruzi-infected subjects, and 47 upregulated and 215 downregulated genes in the symptomatic group. Few differentially expressed genes were found after treatment and between the different infected groups. Gene set enrichment analysis highlighted immune-related pathways activated during infection, with therapy normalizing immune function. Changes in the kynurenine/tryptophan ratio, increased pre-treatment, suggested chronic immune fatigue, which was restored post-treatment. These differentially expressed genes offer insights for potential biomarkers and pathways associated with disease progression and treatment response.

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Immune exhaustion in chronic Chagas disease: Pro-inflammatory and immunomodulatory action of IL-27 in vitro

Cited by 5 publications

References 69 publications

C57BL/6 Mice Pretreated With Alpha-Tocopherol Show a Better Outcome of Trypanosoma cruzi Infection With Less Tissue Inflammation and Fibrosis

C57BL/6 Mice Pretreated With Alpha-Tocopherol Show a Better Outcome of Trypanosoma cruzi Infection With Less Tissue Inflammation and Fibrosis

Intra-host Trypanosoma cruzi strain dynamics shape disease progression: the missing link in Chagas disease pathogenesis

Transcriptomic Evidence of Immune Modulation in Subjects With Chronic Trypanosoma cruzi Infection

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