Trypanosoma cruzi Infection Is a Potent Risk Factor for Non-alcoholic Steatohepatitis Enhancing Local and Systemic Inflammation Associated with Strong Oxidative Stress and Metabolic Disorders (original) (raw)
Related papers
Integrated Cytokine and Metabolic Analysis of Pathological Responses to Parasite Exposure in Rodents
Journal of Proteome Research, 2010
Parasitic infections cause a myriad of responses in their mammalian hosts, on immune as well as on metabolic level. A multiplex panel of cytokines and metabolites derived from four parasite-rodent models, namely, Plasmodium berghei-mouse, Trypanosoma brucei brucei-mouse, Schistosoma mansoni-mouse, and Fasciola hepatica-rat were statistically coanalyzed. 1 H NMR spectroscopy and multivariate statistical analysis were used to characterize the urine and plasma metabolite profiles in infected and noninfected animals. Each parasite generated a unique metabolic signature in the host. Plasma cytokine concentrations were obtained using the 'Meso Scale Discovery' multi cytokine assay platform. Multivariate data integration methods were subsequently used to elucidate the component of the metabolic signature which is associated with inflammation and to determine specific metabolic correlates with parasite-induced changes in plasma cytokine levels. For example, the relative levels of acetyl glycoproteins extracted from the plasma metabolite profile in the P. berghei-infected mice were statistically correlated with IFN-γ, whereas the same cytokine was anticorrelated with glucose levels. Both the metabolic and the cytokine data showed a similar spatial distribution in principal component analysis scores plots constructed for the combined murine data, with samples from all infected animals clustering according to the parasite species and whereby the protozoan infections (P. berghei and T. b. brucei) grouped separately from the helminth infection (S. mansoni). For S. mansoni, the main infection-responsive cytokines were IL-4 and IL-5, which covaried with lactate, choline, and D-3-hydroxybutyrate. This study demonstrates that the inherently differential immune response to singleand multicellular parasites not only manifests in the cytokine expression, but also consequently imprints on the metabolic signature, and calls for in-depth analysis to further explore direct links between immune features and biochemical pathways.
International immunopharmacology, 2018
The high fat diet (HFD) can trigger metabolic and cardiovascular diseases. Trypanosoma cruzi infection induces progressive inflammatory manifestations capable to affect the structure and the function of important organs such as the heart and liver. Here we aimed to investigate the effects of a HFD on the immune response and matrix metalloproteinase (MMP) activities during acute infection with the T. cruzi strain VL-10. The VL-10 strain has cardiac tropism and causes myocarditis in mice. Male C57BL/6 mice were treated with either: (i) regular diet (Reg) or (ii) HFD for 8 weeks, after which mice in each group were infected with T. cruzi. Mice were euthanized on day 30 after infection, and the liver and heart were subjected to histology and zymography to determine MMP-2 activities and plasma levels of IL-10, TNF, CCL2, and CCL5. T. cruzi-infected HFD animals had higher parasitemia, LDL and total cholesterol levels. Regardless of diet, plasma levels of all inflammatory mediators and car...
Oncotarget, 2016
Chronic obesity and Chagas disease (caused by the protozoan Trypanosoma cruzi) represent serious public health concerns. The interrelation between parasite infection, adipose tissue, immune system and metabolism in an obesogenic context, has not been entirely explored. A novel diet-induced obesity model (DIO) was developed in C57BL/6 wild type mice to examine the effect of chronic infection (DIO+I) on metabolic parameters and on obesity-related disorders. Dyslipidemia, hyperleptinemia, and cardiac/hepatic steatosis were strongly developed in DIO mice. Strikingly, although these metabolic alterations were collectively improved by infection, plasmatic apoB100 levels remain significantly increased in DIO+I, suggesting the presence of pro-atherogenic small and dense LDL particles. Moreover, acute insulin resistance followed by chronic hyperglycemia with hypoinsulinemia was found, evidencing an infection-related-diabetes progression. These lipid and glucose metabolic changes seemed to be...
Plos Neglected Tropical Diseases, 2010
Intravenous challenge with Trypanosoma cruzi can be used to investigate the process and consequences of blood parasite clearance in experimental Chagas disease. One hour after intravenous challenge of chronically infected mice with 5610 6 trypomastigotes, the liver constituted a major site of parasite accumulation, as revealed by PCR. Intact parasites and/or parasite remnants were visualized at this time point scattered in the liver parenchyma. Moreover, at this time, many of livercleared parasites were viable, as estimated by the frequency of positive cultures, which considerably diminished after 48 h. Following clearance, the number of infiltrating cells in the hepatic tissue notably increased: initially (at 24 h) as diffuse infiltrates affecting the whole parenchyma, and at 48 h, in the form of large focal infiltrates in both the parenchyma and perivascular spaces. Phenotypic characterization of liver-infiltrating cells 24 h after challenge revealed an increase in Mac1 + , CD8 + and CD4 + cells, followed by natural killer (NK) cells. As evidence that liver-infiltrating CD4 + and CD8 + cells were activated, increased frequencies of CD69 + CD8 + , CD69 + CD4 + and CD25 + CD122 + CD4 + cells were observed at 24 and 48 h after challenge, and of CD25 2 CD122 + CD4 + cells at 48 h. The major role of CD4 + cells in liver protection was suggested by data showing a very high frequency of interferon (IFN)-c-producing CD4 + cells 24 h after challenge. In contrast, liver CD8 + cells produced little IFN-c, even though they showed an enhanced potential for secreting this cytokine, as revealed by in vitro T cell receptor (TCR) stimulation. Confirming the effectiveness of the liver immune response in blood parasite control during the chronic phase of infection, no live parasites were detected in this organ 7 days after challenge.
Fasciola hepatica infection downregulates Th1 responses in mice
Parasite Immunology, 2000
Immune responses induced with helminth parasites have been extensively studied, but there is limited information on those to Fasciola hepatica, especially on the subtype of T cell induced with this parasite. We investigated the local andsystemic Tcell responses of different strains of mice following oral infection with doses of metacercariae from F. hepatica. Spleen cells from BALB/c and 129Sv/Ev mice given a low-dose (5 metacercariae) infection exhibited a Th2 response, producing high levels of the cytokines IL-4 and IL-5, and low levels of IFN-g and IL-2. In contrast, C57BL/6 mice showed a mixed Th1/Th2 response. A more marked polarization to a Th2 response was observed in BALB/c, 129Sv/Ev exposed to a high-dose (15 metacercariae) infection and the C57BL/6 mice also exhibited a clear Th2 response. IL-4 defective (IL-4 ¹/¹ ) C57BL/6 mice infected with 5 metacercariae produced less IFN-g and more IL-5 compared to their wild-type C57BL/6 counterparts, suggesting that IL-4 is important in establishing the Th2 type response in murine fasciolosis. However, the secretion of IFN-g and IL-2 was completely suppressed in the high-dose infection and this was also observed in IL-4 ¹/¹ mice. Thus, liver flukes may secrete molecules that downregulate Th1 responses. T cell responses in the mesenteric (MLN) and hepatic lymph nodes (HLN) were also examined since newly excysted juveniles infect through the intestinal wall of their host before migrating to the hepatic tissue. Cells from both MLN and HLN secreted higher levels of IL-4 and IL-5 compared to spleen cells. We also observed a difference in cytokine profiles secreted by the MLN and HLN, which may reflect responses to antigens liberated by newly excysted juveniles and hepatic stage parasites, respectively.
International Journal for Parasitology, 2007
Innate and adaptive immunity collaborate in the protection of intracellular pathogens including Trypanosoma cruzi infection. However, the parasite molecules that regulate the host immune response have not been fully identified. We previously demonstrated that the immunisation of C57BL/6 mice with cruzipain, an immunogenic T. cruzi glycoprotein, induced a strong specific T-cell response. In this study, we demonstrated that active immunisation with cruzipain was able to stimulate nitric oxide (NO) production by splenocytes. Immune cells also showed increased inducible nitric oxide synthase protein and mRNA expression. Spleen adherent cells secreted high levels of IFN-c and IL-12. Microbicidal activity in vitro was mainly mediated by reactive nitrogen intermediaries and IFN-c, as demonstrated by the inhibitory effects of NO synthase inhibitor or by IFN-c neutralisation. Specific T-cells were essential for NO, IFN-c and TNF-a production. Furthermore, we reported that cruzipain enhanced CD80 and major histocompatibility complex-II molecule surface expression on F4/80+ spleen cells. Interestingly, we also showed that cruzipain up-regulated toll like receptor-2 expression, not only in F4/80+ but also in total spleen cells which may be involved in the effector immune response. Our findings suggest that a single parasite antigen such as cruzipain, through adaptive immune cells and cytokines, can modulate the macrophage response not only as antigen presenting cells, but also as effector cells displaying enhanced microbicidal activity with reactive nitrogen intermediary participation. This may represent a mechanism that contributes to the immunoregulatory process during Chagas disease. Ó
Molecular Immunology, 2008
Toll-like receptor (TLR) family is crucial for microbial elimination and homeostasis, and has an important immunoregulatory role. In this study, we comparatively analyze innate immune response and tissular injury elicited in BALB/c and C57BL/6 (B6) mice during acute Trypanosoma cruzi infection. The liver was the most affected tissue with numerous cellular infiltrates, apoptotic cells and necrotic areas. The apoptotic rate, evaluated by Hoescht stain, was highest in liver of B6. Infection increased transaminase activities in both mouse strains, although they were highest in B6. BALB/c showed sixfold higher parasitemias than B6 but the latter presented higher mortality (80%) than BALB/c (40%). To gain insight into the molecular basis, we investigated the TLRs commitment in liver. We found that, TLR2 and TLR4 were up-regulated in BALB/c while they were down-regulated in B6. However, TLR9 showed a diminution in BALB/c and an increase in B6 at the end of infection. Moreover, an intensified pro-inflammatory cytokine profile was observed in B6 and F4/80+ and Gr1+ leukocytes were the predominant cells in liver from both mouse strains. Thus, altered TLR2, TLR4 and TLR9 signalling and exacerbate inflammatory cytokine profile could be responsible of the fatal hepatic damage observed in infected B6.
OnLine Journal of Biological Sciences, 2015
The study of biotherapies as an intervention in experimental models of infection is a possible means to understand the effects of these highly diluted medications. The present study evaluated the immunological and parasitological effects of biotherapies that were prepared from mouse serum that was uninfected (sarcode: BSNI 13cH group) and chronically infected with the Y strain of T. cruzi (nosode: BSI 13cH group), dynamization 13cH, in male Swiss mice at 28 days of age. On days 0 and 12 after infection (a.i.), the BSNI 13cH group exhibited a pronounced Th1 response that was attributable to a reduction of interleukin-4 (IL-4) concentrations, with no significant differences in interferon-γ (IFN-γ) concentrations and a decrease in IL-17A concentrations on day 0 a.i. compared with the control and BSI 13cH groups. However, this cytokine balance was not sufficient to alter blood parasitemia in treated animals, likely because of a decrease in IFN-γ concentrations on day 8 a.i., thus hindering a more effective Th1 response. In contrast, the BSI 13cH group presented a pronounced Th2 response that was attributable to an increase in IL-4 concentrations (on days 0 and 8 a.i.) and a decrease in IFN-γ concentration (on day 12 a.i.) compared with the control and BSNI 13cH groups. This cytokine balance suppressed the immune response to T. cruzi in murine infection, resulting in a significant increase in blood parasitemia, decrease in the patent period and subsequently a decrease in survival time. The results indicate that these highly diluted medications differentially modulate the immune system and represent a substantial contribution to the field of homeopathic medicine, providing evidence of the action of these medications.