C57BL/6 Mice Pretreated With Alpha-Tocopherol Show a Better Outcome of Trypanosoma cruzi Infection With Less Tissue Inflammation and Fibrosis (original) (raw)
Related papers
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
T cells responding to Trypanosoma cruzi detected by membrane TNF-α and CD154 in chagasic patients
Immunity, inflammation and disease, 2017
Chagas disease is a parasitic infection whose pathogenesis is related to parasite persistence and a dysfunctional cellular immune response. Variability in cytokine secretion among chronic Trypanosoma cruzi-infected patients might preclude the identification of the pool of antigen specific T cells. The goal of this study was to determine the fraction of T cells responding to T. cruzi antigen measured by the expression of membrane TNF-α and CD154. A total of 21 chagasic patients, 11 healthy and 5 non-chagasic cardiomyopathy controls were analyzed. PBMCs were short-term cultured in the presence of anti-CD28, anti-CD49d, anti-TNF-α, and TACE (TNF-α converting enzyme) inhibitor either under T. cruzi-lysate or polyclonal stimuli. Cells were stained with anti-CD3, anti-CD4, anti-CD8, and anti-CD154, and analyzed with flow cytometry. CD4+ and CD8+ T cells in chagasic patients displayed higher percentages of membrane-bound TNF-α+ and CD154+ compared with controls after T. cruzi-antigen stimu...
Infection and Immunity, 2007
Chagas disease patients 3 4 Running title: Modulation of co-stimulatory molecules and cytokines by T. cruzi 5 6 Abstract 1 2 Interactions between macrophages and lymphocytes through co-stimulatory molecules and 3 cytokines are essential for mounting an efficient immune response, and controlling its 4 pathogenic potential. Here we demonstrate the immunomodulatory capacity of T. cruzi, the 5 causative agent of Chagas disease, through its ability to induce differential expression of 6 co-stimulatory molecules and cytokines by monocytes and T-cells. Co-stimulatory 7 molecule and cytokine modulation were evaluated using cells from non-infected individuals 8 and patients with the asymptomatic indeterminate, or the severe cardiac clinical forms of 9
PLOS Neglected Tropical Diseases, 2010
A century after the discovery of Trypanosoma cruzi in a child living in Lassance, Minas Gerais, Brazil in 1909, many uncertainties remain with respect to factors determining the pathogenesis of Chagas disease (CD). Herein, we simultaneously investigate the contribution of both host and parasite factors during acute phase of infection in BALB/c mice infected with the JG and/or CL Brener T. cruzi strains. JG single infected mice presented reduced parasitemia and heart parasitism, no mortality, levels of pro-inflammatory mediators (TNF-a, CCL2, IL-6 and IFN-c) similar to those found among naïve animals and no clinical manifestations of disease. On the other hand, CL Brener single infected mice presented higher parasitemia and heart parasitism, as well as an increased systemic release of pro-inflammatory mediators and higher mortality probably due to a toxic shock-like systemic inflammatory response. Interestingly, coinfection with JG and CL Brener strains resulted in intermediate parasitemia, heart parasitism and mortality. This was accompanied by an increase in the systemic release of IL-10 with a parallel increase in the number of MAC-3 + and CD4 + T spleen cells expressing IL-10. Therefore, the endogenous production of IL-10 elicited by coinfection seems to be crucial to counterregulate the potentially lethal effects triggered by systemic release of pro-inflammatory mediators induced by CL Brener single infection. In conclusion, our results suggest that the composition of the infecting parasite population plays a role in the host response to T. cruzi in determining the severity of the disease in experimentally infected BALB/c mice. The combination of JG and CL Brener was able to trigger both protective inflammatory immunity and regulatory immune mechanisms that attenuate damage caused by inflammation and disease severity in BALB/c mice.
Acute Trypanosoma cruzi infection: IL-12, IL-18, TNF, sTNFR and NO in T. rangeli-vaccinated mice
Vaccine, 2004
We have developed an experimental model of vaccination against the infection with the protozoa Trypanosoma cruzi, the agent of Chagas disease in Latin America. Vaccination was performed with Trypanosoma rangeli, a non-pathogenic protozoa sharing many antigens with T. cruzi. It strongly protected BALB/c mice, sharply reducing parasitaemia and mortality rate of the acute T. cruzi infection. The aim of the present work was to complete our previous study on the production of IFN-␥ and IL-10 in this vaccination model by investigating the production of IL-12p35 and p40, IL-18, TNF, TNF soluble receptors (sTNFR), and nitric oxide (NO), factors known to play a key role in the outcome of T. cruzi infection. We show that the protection obtained against the acute T. cruzi infection was surprisingly associated with reduced circulating levels of IL-18 and NO, whereas the release of IL-12p40 was enhanced in comparison to non-vaccinated infected animals. IL-12p35 remained undetectable in infected animals, vaccinated or not. The balance between sTNFR and TNF suggested a decrease of TNF bioactivity in vaccinated mice. These results show that the protection induced by the vaccination with T. rangeli against a challenging infection with T. cruzi is not associated with the strong type 1 immune response usually involved in the control of intracellular pathogens, particularly questioning the protective role of NO during the acute phase of T. cruzi infection.
Frontiers in Immunology, 2019
Chagas disease (ChD), a complex and persistent parasitosis caused by Trypanosoma cruzi, represents a natural model of chronic infection, in which some people exhibit cardiac or digestive complications that can result in death 20-40 years after the initial infection. Nonetheless, due to unknown mechanisms, some T. cruzi-infected individuals remain asymptomatic throughout their lives. Actually, no vaccine is available to prevent ChD, and treatments for chronic ChD patients are controversial. Chronically T. cruzi-infected individuals exhibit a deterioration of T cell function, an exhaustion state characterized by poor cytokine production and increased inhibitory receptor co-expression, suggesting that these changes are potentially related to ChD progression. Moreover, an effective anti-parasitic treatment appears to reverse this state and improve the T cell response. Taking into account these findings, the functionality state of T cells might provide a potential correlate of protection to detect individuals who will or will not develop the severe forms of ChD. Consequently, we investigated the T cell response, analyzed by flow cytometry with two multicolor immunofluorescence panels, to assess cytokines/cytotoxic molecules and the expression of inhibitory receptors, in a murine model of acute (10 and 30 days) and chronic (100 and 260 days) ChD, characterized by parasite persistence for up to 260 days post-infection and moderate inflammation of the colon and liver of T. cruzi-infected mice. Acute ChD induced a high antigenspecific multifunctional T cell response by producing IFN-γ, TNF-α, IL-2, granzyme B, and perforin; and a high frequency of T cells co-expressed 2B4, CD160, CTLA-4, and PD-1. In contrast, chronically infected mice with moderate inflammatory infiltrate in liver tissue exhibited monofunctional antigen-specific cells, high cytotoxic activity (granzyme B and perforin), and elevated levels of inhibitory receptors (predominantly CTLA-4 and PD-1) co-expressed on T cells. Taken together, these data support our previous results showing that similar to humans, the T. cruzi persistence in mice promotes
Infection and Immunity, 2007
Interactions between macrophages and lymphocytes through costimulatory molecules and cytokines are essential for mounting an efficient immune response and controlling its pathogenic potential. Here we demonstrate the immunomodulatory capacity of Trypanosoma cruzi, the causative agent of Chagas' disease, through its ability to induce differential expression of costimulatory molecules and cytokines by monocytes and T cells. Costimulatory molecule and cytokine modulation was evaluated using cells from noninfected individuals and from patients with the asymptomatic indeterminate form and those with the severe cardiac clinical form of Chagas' disease. Our results show that while exposure of monocytes to live T. cruzi leads to an increase in the frequency of CD80 ؉ monocytes in all groups, it decreases both the frequency and intensity of CD86 expression by monocytes from patients with the cardiac form but not from those with the indeterminate form. Conversely, exposure of lymphocytes to monocytes infected with T. cruzi increased the surface expression of cytotoxic-Tlymphocyte-associated antigen 4 (CTLA-4) by T cells from indeterminate but not from cardiac patients, compared to that from control patients. These data suggest that T. cruzi induces a potentially down-regulatory environment in indeterminate subjects, which is associated with higher CD80 and CTLA-4 expression. To test the functional importance of this modulation, we evaluated the expression of cytokines after in vitro infection. Although exposure of lymphocytes to parasite-infected monocytes induced high expression of inflammatory and anti-inflammatory cytokines by T cells in all groups, indeterminate patients displayed a higher ratio of monocytes expressing interleukin 10 than tumor necrosis factor alpha following infection than did controls. These data show the ability of T. cruzi to actively change the expression of costimulatory molecules and cytokines, suggesting molecular mechanisms for the differential clinical evolution of human Chagas' disease.
A Review on the Immunological Response against Trypanosoma cruzi
Pathogens
Chagas disease is a chronic systemic infection transmitted by Trypanosoma cruzi. Its life cycle consists of different stages in vector insects and host mammals. Trypanosoma cruzi strains cause different clinical manifestations of Chagas disease alongside geographic differences in morbidity and mortality. Natural killer cells provide the cytokine interferon-gamma in the initial phases of T. cruzi infection. Phagocytes secrete cytokines that promote inflammation and activation of other cells involved in defence. Dendritic cells, monocytes and macrophages modulate the adaptive immune response, and B lymphocytes activate an effective humoral immune response to T. cruzi. This review focuses on the main immune mechanisms acting during T. cruzi infection, on the strategies activated by the pathogen against the host cells, on the processes involved in inflammasome and virulence factors and on the new strategies for preventing, controlling and treating this disease.
Clinical and Vaccine Immunology, 2007
Trypanosoma cruzi infection causes Chagas' disease, a chronic inflammatory disease. The specific inflammatory responses that cause Chagas' disease remain unclear, but data argue that parasites that persist in the host stimulate chronic self-damaging immune responses. Because T. cruzi appears to stimulate self-damaging responses, the enthusiasm to develop vaccines that boost antiparasite responses that might increase self-damaging responses has been limited. We previously demonstrated that immunization with a T. cruzi trans-sialidase protein or adoptive transfer of trans-sialidase-specific T-cell clones decreased parasitemia, morbidity, and mortality. Here we report that immunization or adoptive transfer with the protein or clones, before or during T. cruzi infection, boosts the anti-T. cruzi immune response without exacerbating acute or chronic tissue inflammation. These results argue that prophylactic and therapeutic immunotherapy for Chagas' disease can be developed sa...