Blocking activation of CD4-CD8- T cells modulates their cytotoxic potential and decreases the expression of inflammatory and chemotactic receptors.

CD4-CD8- (double negative - DN) T cells represent a small fraction of circulating T lymphocytes but are a major source of pro-inflammatory cytokines in patients with infectious diseases, including chronic Chagas cardiomyopathy (CCC), one of the deadliest cardiopathies known. Chagas disease is caused by an infection with the protozoan parasite Trypanosoma cruzi and can lead to either an asymptomatic form or a high-mortality cardiac disease. While circulating DN T cells represent a major inflammatory cytokine-expressing cell population in Chagas disease, their potential to be recruited to the heart and to perform cytotoxicity has not been determined. Our previous studies showed that blocking DN T cell activation decreases the expression of IFN-gamma, a cytokine involved in the severity of CCC. Here, studying a well-characterized cohort of Chagas patients with CCC or the asymptomatic form of Chagas disease (indeterminate form, IND), we evaluated the expression of cytotoxic molecules, cytokine and chemokine receptors in γδ+ and αß+ DN T cells by multiparameter flow cytometry, and investigated whether blocking the activation of DN T cells influences the expression of these molecules. We observed that DN T cells from CCC display a higher expression of granzyme A, perforin, inflammatory molecules, and inflammatory chemokine receptors than cells from IND. Messenger RNA coding for these molecules is also upregulated in the heart of CCC patients. Importantly, blocking the activation of DN T cells from CCC modulates their cytotoxic potential and the expression of inflammatory and of chemokine receptors, suggesting that targeting DN T cell activation may be a valid strategy to reduce recruitment to the heart, inflammation, cytotoxicity and, thereby diminish CCC progression and severity.

Cytokine Networks as Targets for Preventing and Controlling Chagas Heart Disease.

Chagas disease, a neglected disease caused by the protozoan Trypanosoma cruzi, is endemic in 21 Latin American countries, affecting 6-8 million people. Increasing numbers of Chagas disease cases have also been reported in non-endemic countries due to migration, contamination via blood transfusions or organ transplantation, characterizing Chagas as an emerging disease in such regions. While most individuals in the chronic phase of Chagas disease remain in an asymptomatic clinical form named indeterminate, approximately 30% of the patients develop a cardiomyopathy that is amongst the deadliest cardiopathies known. The clinical distinctions between the indeterminate and the cardiac clinical forms are associated with different immune responses mediated by innate and adaptive cells. In this review, we present a collection of studies focusing on the human disease, discussing several aspects that demonstrate the association between chemokines, cytokines, and cytotoxic molecules with the distinct clinical outcomes of human infection with Trypanosoma cruzi. In addition, we discuss the role of gene polymorphisms in the transcriptional control of these immunoregulatory molecules. Finally, we discuss the potential application of cytokine expression and gene polymorphisms as markers of susceptibility to developing the severe form of Chagas disease, and as targets for disease control.

T-cell receptor variable region usage in Chagas disease: A systematic review of experimental and human studies.

T cells recognize their ligand, the peptide major histocompatibility complex (MHC), via the T-cell receptor (TCR), which is composed of covalently linked α and ß or γ and δ chains. This recognition is critical for T-cell ontogeny and controls the selection, activation, and function of T lymphocytes. Specific TCR αß variable regions have been associated with immunopathogenesis of Chagas disease. Here, we present a systematic review that compiles experimental in vivo and human data regarding the preferential expression of variable alpha (Vα) and variable beta (Vß) chain regions in Trypanosoma cruzi infection. The original studies indexed in PubMed/Medline, Scopus, and Web of Science databases were screened according to the PRISMA strategy. The analysis showed that expression of TCR Vα subfamilies were evaluated in one human study, and, unlike TCR Vß, TCR Vα presented a more restricted usage. Despite the great variability in the usage of TCR Vß regions in human Chagas disease, a down-regulation of TCR Vß5 expression by T cells from patients in the acute phase of the disease was shown. Opposingly, this TCR region was found overly expressed in CD4+ T cells from chronic Chagas patients. It was also demonstrated that murine Vß9+ T cells derived from nonlymphoid organs of T. cruzi-infected animals had a modulatory profile, while splenic Vß9+ T cells produced inflammatory cytokines, indicating that although they display the same TCR Vß region usage, these cells are functionally distinct. Despite the limitations of few papers and year of publication of the studies, compiling the data derived from them reveals that further investigation of TCR usage will point to their potential role in protective or pathogenic responses, as biomarkers of disease progression, and in the search for dominant peptides potentially useful for the development of vaccines or therapies.

Impact of microplastics on the intestinal microbiota: A systematic review of preclinical evidence.

AIMS: We systematically review the in vivo preclinical evidence on the impact of microplastics (MPs) on the intestinal microbiota and morphofunctional changes involving the intestinal mucosa. METHODS: By using a comprehensive and structured search in electronic databases 28 original studies were recovered and analyzed. KEY FINDINGS: Zebrafish and mice were the main animal models, while the dose and shape of MPs used were quite heterogeneous. Studies show that MPs are potential triggers of intestinal dysbiosis, which has been characterized by enrichment of Firmicutes, Proteobacteria and Chlamydia. Conversely, there was a reduction in Bacteroidetes phylum abundance. By trapping and stimulating intestinal inflammatory infiltrate, exposure to MPs increased intestinal permeability and the expression of immune signatures associated with inflammation, such as IL-1α, IL-1ß, TNF-α, IFN-γ and IL-6. SIGNIFICANCE: Thus, current evidence supports potential inflammatory and dysbiotic properties of MPs. In addition, the data indicate that MPs can display structural changes secondary to exposure to MPs. Analysis of methodological quality indicated that current preclinical evidence is at high risk of bias. We hope that controlling that bias sources described in this systematic review will be useful to improve the quality of reports.

Yacon-based product improves intestinal hypertrophy and modulates the production of glucagon-like peptide-1 in postmenopausal experimental model.

AIMS: The progressive decline in estrogen level puts postmenopausal women at a higher risk of developing cardiometabolic diseases. Thus, we evaluated the potential beneficial effects of yacon-based product (YBP) on glycemic profile and intestinal health of postmenopausal rats. METHODS: Eighty Wistar rats were randomized into 4 ovariectomized (OVX) groups or 4 celiotomized groups treated with a standard diet (SD) or diet supplemented with YBP at 6% of fructooligosaccharide (FOS)/inulin. KEY FINDINGS: The continued consumption of YBP at 6% of FOS/inulin did not generate liver damage and gastrointestinal disorders. Rats fed with YBP displayed higher food consumption, but this did not increase the body weight gain, abdominal circumference and body fat percentual of OVX rats. Furthermore, we also found that the FOS/inulin fermentation present in the YBP resulted in cecum, ileum and colon crypts hypertrophy and increased the lactic acid levels in the cecal content. We observed an increase of glucagon-like peptide-1 (GLP-1) immunoreactive cells and there was no change in the glucose and insulin plasma levels of YBP-fed OVX rats. SIGNIFICANCE: Our findings indicated that YBP when consumed previously and after the menopausal period has important effects on the morphology and function of intestinal mucous of rats and has potential to modulate indirectly the glycemic and insulinemic profiles, weight gain and body fat percentual in the hypoestrogenic period through metabolites produced in the fermentation process.

Doxycycline hyclate: A schistosomicidal agent in vitro with immunomodulatory potential on granulomatous inflammation in vivo.

We investigated the effect in vitro and in vivo of doxycycline hyclate (Dx), a broad-spectrum antibiotic inhibitor of matrix metaloproteinases (MMPs), on adult Schistosoma mansoni worms and granulomatous liver inflammation in infected mice. Adult S. mansoni worms in culture treated with different concentrations of Dx (50-180 µg/mL) were studied for eight days to assess its morphology, eggs production, and mortality. Uninfected mice and those infected with S. mansoni, untreated and treated with praziquantel (Pz; 200 mg/kg) or Dx (50 mg/kg), were evaluated for 60 days. Our results indicated that Dx induced dose-dependent integumentary lesions (bubbles, tubercle collapse, spicule disappearance, peeling, and erosion), reduced mating rate and eggs-laying in adult S. mansoni worms. The effective lethal dose required to kill 50% of worms was 112.0 µg/mL Dx (DL50). In mice, S. mansoni infection induced hepatomegaly, intense IL-4, IL-10, TNF-α and TGF-ß production, granulomatous inflammation and hepatic glycogen depletion. The number and size of the granulomas was similar in untreated and Dx-treated animals. Untreated animals showed a predominance of productive granulomas, and intense MMP-2 and MMP-9 activities. Dx-treated mice exhibited a significant increase in IL-4 levels, tissue inflammation, proportion of involutive granulomas, and hepatic collagenogenesis, as well as attenuated MMP-2 and MMP-9 activities. Our findings indicated that Dx is toxic to adult S. mansoni worms in vitro. However, in vitro beneficial effects were not reproduced in vivo, since Dx treatment increased liver granulomatous inflammation and collagenogenesis in S. mansoni-infected mice by a process potentially associated with Dx-mediated hepatic MMP-2 and MMP-9 inhibition.