STING Signaling Drives Production of Innate Cytokines, Generation of CD8+ T Cells and Enhanced Protection Against Trypanosoma cruzi Infection

A variety of signaling pathways are involved in the induction of innate cytokines and CD8+ T cells, which are major players in protection against acute Trypanosoma cruzi infection. Previous data have demonstrated that a TBK-1/IRF3-dependent signaling pathway promotes IFN-β production in response to Trypanosoma cruzi, but the role for STING, a main interactor of these proteins, remained to be addressed. Here, we demonstrated that STING signaling is required for production of IFN-β, IL-6, and IL-12 in response to Trypanosoma cruzi infection and that STING absence negatively impacts activation of IRF-dependent pathways in response to the parasite. We reported no significant activation of IRF-dependent pathways and cytokine expression in RAW264.7 macrophages in response to heat-killed trypomastigotes. In addition, we showed that STING is essential for T. cruzi DNA-mediated induction of IFN-β, IL-6, and IL-12 gene expression in RAW264.7 macrophages. We demonstrated that STING-knockout mice have significantly higher parasitemia from days 5 to 8 of infection and higher heart parasitism at day 13 after infection. Although we observed similar heart inflammatory infiltrates at day 13 after infection, IFN-β, IL-12, CXCL9, IFN-γ, and perforin gene expression were lower in the absence of STING. We also showed an inverse correlation between parasite DNA and the expression of CXCL9, IFN-γ, and perforin genes in the hearts of infected animals at day 13 after infection. Finally, we reported that STING signaling is required for splenic IFN-β and IL-6 expression early after infection and that STING deficiency results in lower numbers of splenic parasite-specific IFN-γ and IFN-γ/perforin-producing CD8+ T cells, indicating a pivotal role for STING signaling in immunity to Trypanosoma cruzi.

Chagas Disease in Pregnant Women from Endemic Regions Attending the Hospital General de Mexico, Mexico City

Trypanosoma cruzi infection leads to Chagas disease (CD), a neglected tropical infection of significant public health importance in South and Central America and other, non-endemic, countries. Pregnant women and their children are of particular importance to screen as T. cruzi can be transmitted vertically. The objective of this study was to screen for T. cruzi infection among pregnant women from endemic areas seen at the Hospital General de Mexico for prenatal care, so that they and their children may be quickly connected to CD treatment. Pregnant women were recruited through the hospital prenatal clinic and screened for T. cruzi infection using a series of serological and molecular tests. Of 150 screened patients, mean age 26.8 (SD 6.4), 30 (20.0%) were positive by at least one diagnostic test. Of these, only nine (6%) were positive as determined by PCR. Diagnosis of chronic CD is difficult in endemic places like Mexico due to the limitations of current commercially available diagnostic tests. Further evaluation of diagnostic performance of various assays could improve current CD diagnostic algorithms and proper care management in these regions. Genetic variability in the parasite may also play a role in the differing assay performances seen in this study, and this may be a valuable avenue of further research.

Galectins in Chagas Disease: A Missing Link Between Trypanosoma cruzi Infection, Inflammation, and Tissue Damage

Trypanosoma cruzi, the protozoan parasite causative agent of Chagas disease, affects about seven million people worldwide, representing a major global public health concern with relevant socioeconomic consequences, particularly in developing countries. In this review, we discuss the multiple roles of galectins, a family of β-galactoside-binding proteins, in modulating both T. cruzi infection and immunoregulation. Specifically, we focus on galectin-driven circuits that link parasite invasion and inflammation and reprogram innate and adaptive immune responses. Understanding the dynamics of galectins and their β-galactoside-specific ligands during the pathogenesis of T. cruzi infection and elucidating their roles in immunoregulation, inflammation, and tissue damage offer new rational opportunities for treating this devastating neglected disease.

Biotherapy of mice’s serum 13cH modifies parasitological and immunological parameters of Trypanosoma cruzi infection.

Background: T. cruzi biotherapies’ alter the infection course by this protozoan [1,2], fact that encourages the evaluation of other highly diluted medicines which modulates host’s immune system. Aim: Evaluate effect of biotherapy produced from mices’s serum in experimental infection by T. cruzi. Methodology: A blind, randomized and controlled study was performed. Animals: 60 male Swiss mice, four weeks old were inoculated intraperitoneally with 1400 trypomastigotes-Y strain and divided: MNI: mice non-infected by T. cruzi; IC: treated with hydroalcoholic solution 7%; BSI13cH: treated with mice’s serum infected by T. cruzi 13cH. Biotherapies: produced from mice’s serum infected by T. cruzi in 13cH dynamization [3]. Treatment: mice were treated 48 hours before and after infection. Subsequently animals were treated 56/56 hours until 9th day of infection (d.i). The medicine was diluted in water (1/100mL) and offered ad libitum, for 16 hours. Parasitological parameters: were evaluated pre-patent and patent period, parasitemia peak, total parasitemia and mortality [4]. Cytokine dosage: IL-4, IL-17, TNF-α and IFN-γ were measured in serum on 0, 8th and 12th d.i., by enzyme immunoassay. Ethics: study was approved by Ethics Committee for Experiments in Animals/UEM. Statistic: data were compared with Mann Whitney or Student t test, significance 5%. Results: BSI13cH showed tendency to increase total parasitemia (p=0.06) and parasitemia peak (p=0.05), with lower patent period (p=0.03) and higher mortality (p=0.03) compared to IC. In dosage of cytokines BSI13cH group showed on 0 d.i. a decrease in IL-17 (p = 0.02) and increased IL-4 (p = 0.01) compared to MNI (baseline value), probably caused by modulation of medication administration 48 hours before infection. IL-17 concentration didn’t vary throughout the infection to BSI13cH, different IC that tended to decrease concentration of cytokine on 8th d.i. IL-4 increased significantly on 0 d.i. to BSI13cH, with subsequent return to baseline values. IC group didn’t change significantly IL-4 value along the infection. IFN-γ concentration on 12th d.i. to BSI13cH was lower (p = 0.00) than IC, which increased this cytokine on 8th and 12th di. TNF-α concentration of BSI13cH followed the same evolution as IC, with an increase on 8th and 12th d.i. (Figure 1). The medicine seems initially promote Th2 response (IL-4), hindering the development of effective Th1 response (INF-γ), causing an increase of parasitemia and animals' death. Conclusions: BSI13cH demonstrated effect in experimental infection by T. cruzi with increased parasitemia, animals’ premature death and modulated immune response differently of IC.