scholarly journals Absence of Bim sensitizes mice to experimental Trypanosoma cruzi infection

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Marcela Hernández-Torres ◽  
Rogério Silva do Nascimento ◽  
Monica Cardozo Rebouças ◽  
Alexandra Cassado ◽  
Kely Catarine Matteucci ◽  
...  
Keyword(s):  
T Cells ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Parasite Load ◽  
Peritoneal Macrophages ◽  
T Cell Response ◽  
No Production ◽  
Similar Reduction ◽  
Ifn Γ

AbstractChagas disease is a life-threatening disorder caused by the protozoan parasite Trypanosoma cruzi. Parasite-specific antibodies, CD8+ T cells, as well as IFN-γ and nitric oxide (NO) are key elements of the adaptive and innate immunity against the extracellular and intracellular forms of the parasite. Bim is a potent pro-apoptotic member of the Bcl-2 family implicated in different aspects of the immune regulation, such as negative selection of self-reactive thymocytes and elimination of antigen-specific T cells at the end of an immune response. Interestingly, the role of Bim during infections remains largely unidentified. To explore the role of Bim in Chagas disease, we infected WT, Bim+/−, Bim−/− mice with trypomastigotes forms of the Y strain of T. cruzi. Strikingly, our data revealed that Bim−/− mice exhibit a delay in the development of parasitemia followed by a deficiency in the control of parasite load in the bloodstream and a decreased survival compared to WT and Bim+/− mice. At the peak of parasitemia, peritoneal macrophages of Bim−/− mice exhibit decreased NO production, which correlated with a decrease in the pro-inflammatory Small Peritoneal Macrophage (SPM) subset. A similar reduction in NO secretion, as well as in the pro-inflammatory cytokines IFN-γ and IL-6, was also observed in Bim−/− splenocytes. Moreover, an impaired anti-T. cruzi CD8+ T-cell response was found in Bim−/− mice at this time point. Taken together, our results suggest that these alterations may contribute to the establishment of a delayed yet enlarged parasitic load observed at day 9 after infection of Bim−/− mice and place Bim as an important protein in the control of T. cruzi infections.

scholarly journals A Parasite Biomarker Set for Evaluating Benznidazole Treatment Efficacy in Patients with Chronic Asymptomatic Trypanosoma cruzi Infection

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Adriana Egui ◽  
M. Carmen Thomas ◽  
Ana Fernández-Villegas ◽  
Elena Pérez-Antón ◽  
Inmaculada Gómez ◽  
...  
Keyword(s):  
T Cells ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Parasite Load ◽  
Drastic Reduction ◽  
Content Type ◽  
Short Period ◽  
Before And After ◽  
Cruzi Infection

ABSTRACT One of the current greatest challenges of Chagas disease is the establishment of biomarkers to assess the efficacy of drugs in a short period of time. In this context, the reactivity of sera from 66 adults with chronic indeterminate Chagas disease (IND) for a set of four Trypanosoma cruzi antigens (KMP11, PFR2, HSP70, and 3973d) was analyzed before and after benznidazole treatment. The results showed that the reactivity against these antigens decreased at 9, 24, and 48 months after treatment. Moreover, the 42.4% and 68.75% of IND patients met the established standard criteria of therapeutic efficacy (STEC) at 24 and 48 months posttreatment, respectively. Meeting the STEC implied that there was a continuous decrease in the reactivity of the patient sera against the four antigens after treatment and that there was a substantial decrease in the reactivity for at least two of the antigens. This important decrease in reactivity may be associated with a drastic reduction in the parasite load, but it is not necessarily associated with a parasitological cure. After treatment, a positive PCR result was only obtained in patients who did not meet the STEC. The percentage of granzyme B+/perforin+ CD8+ T cells was significantly higher in patients who met the STEC than in those who did not meet the STEC (35.2% versus 2.2%; P < 0.05). Furthermore, the patients who met the STEC exhibited an increased quality of the multifunctional response of the antigen-specific CD8+ T cells compared with that in the patients who did not meet the STEC.

scholarly journals Essential Role of Platelet-Activating Factor in Control of Leishmania (Leishmania)amazonensis Infection

2000 ◽  
Vol 68 (11) ◽  
pp. 6355-6361 ◽  
Author(s):  
Maria Valdrinez Campana Lonardoni ◽  
Momtchillo Russo ◽  
Sonia Jancar
Keyword(s):  
Lymph Nodes ◽  
Platelet Activating Factor ◽  
Parasite Load ◽  
Peritoneal Macrophages ◽  
Leishmania Infection ◽  
Prostaglandin E ◽  
No Production ◽  
Regional Lymph Nodes

ABSTRACT In the present study we investigated the role of platelet-activating factor (PAF) and prostaglandins in experimental Leishmania (Leishmania)amazonensis infection and the relationship between these mediators and nitric oxide (NO) production. Mouse peritoneal macrophages elicited with thioglicolate were infected with leishmania amastigotes, and the infection index determined 48 h later. The course of infection was monitored for 5 weeks in mice infected in the footpad with promastigotes by measuring the footpad swelling and parasite load in regional lymph nodes and spleen. The addition of PAF to C57BL/6 mouse macrophages significantly inhibited parasite growth and induced NO production. Treatment of macrophages with a selective PAF antagonist, WEB2086, increased the infection, indicating that endogenously produced PAF regulates macrophage ability to control leishmania infection. This effect of PAF was abolished by addition of the inhibitor of NO synthesis, L-NAME, to the cultures. The addition of prostaglandin E2 significantly increased the infection and NO production. Treatment with cyclo-oxygenase inhibitor, indomethacin, reduced the infection and PAF-induced release of NO. Thus, the increased NO production induced by PAF seems to be mediated by prostaglandins. The more-selective inhibitors of cyclo-oxygenase 2, nimesulide and NS-398, had no significant effect. Thus, antileishmanial activity correlates better with the presence of PAF or absence of prostaglandins than with NO production. In vivo treatment with PAF antagonists significantly increased leishmania lesions, as well as the parasite load, in regional lymph nodes and spleens. These findings indicate that PAF is essential for the control of leishmania infection.

scholarly journals Interleukin-6 and Interleukin-12 Participate in Induction of a Type 1 Protective T-Cell Response during Vaccination with a Tuberculosis Subunit Vaccine

1999 ◽  
Vol 67 (11) ◽  
pp. 5747-5754 ◽  
Author(s):  
Irene S. Leal ◽  
Birgitte Smedegård ◽  
Peter Andersen ◽  
Rui Appelberg
Keyword(s):  
T Cells ◽  
Interleukin 6 ◽  
Neutralizing Antibodies ◽  
Subunit Vaccine ◽  
T Cell Response ◽  
Interleukin 12 ◽  
Cell Mediated Immunity ◽  
Ifn Γ ◽  
Dimethyldioctadecylammonium Bromide

ABSTRACT We examined the role of cytokines in the development of gamma interferon (IFN-γ)-secreting protective T cells following immunization with a culture filtrate subunit vaccine againstMycobacterium tuberculosis containing the adjuvant dimethyldioctadecylammonium bromide (DDA). Depletion of either interleukin-6 (IL-6) or IL-12 with specific neutralizing antibodies during vaccination reduced the priming of T cells for antigen-specific proliferation and IFN-γ secretion. Such reduction was also observed in IL-6 gene-disrupted mice as compared to wild-type animals. IL-6 was found to play a role in the initial differentiation of Th1 cells but not in their expansion. The defect found after IL-6 depletion or in IL-6-knockout mice was compensated by the inclusion of recombinant mouse IL-12 in the vaccine. The induction of protective immunity against an intravenous or an aerosol challenge with live, virulentM. tuberculosis was markedly reduced by neutralizing either IL-6 or IL-12 during immunization with the vaccine. Likewise, the effects of IL-6 neutralization were partially reversed by including IL-12 in the vaccine. Our data point to an important role of IL-6 and IL-12 in the generation of cell-mediated immunity to tuberculosis.

scholarly journals Immunization of Mice with a TolA-Like Surface Protein of Trypanosoma cruzi Generates CD4+T-Cell-Dependent Parasiticidal Activity

1999 ◽  
Vol 67 (9) ◽  
pp. 4603-4612 ◽  
Author(s):  
Natalie M. Quanquin ◽  
Charles Galaviz ◽  
David L. Fouts ◽  
Ruth A. Wrightsman ◽  
Jerry E. Manning
Keyword(s):  
T Cells ◽  
T Cell ◽  
Trypanosoma Cruzi ◽  
Gene Family ◽  
Expression System ◽  
Interleukin 2 ◽  
No Production ◽  
Sequence Identity ◽  
Flagellar Proteins ◽  
Ifn Γ

ABSTRACT The gene family encoding a trypomastigote-specific protein restricted to the part of the flagellum in contact with the cell body of the trypomastigote form of Trypanosoma cruzi has been isolated, characterized, and expressed in a baculovirus expression system. The gene family contains three tandemly repeated members that have 97 to 100% sequence identity. The predicted protein encoded by the gene family has both significant amino acid sequence identity and other physical and biological features in common with the TolA proteins of Escherichia coli and Pseudomonas aeruginosa. Based on these similarities, we have designated this gene family tolT. Immunization of mice with recombinant TolT generates a population of CD4+ T lymphocytes that recognize T. cruzi-infected macrophages, resulting in the production of gamma interferon (IFN-γ), which leads to NO production and a 50 to 60% reduction in parasite numbers compared to that seen with infected macrophages incubated with naive T cells. This population of T cells also produces both IFN-γ and interleukin 2 (IL-2) but not IL-4 or IL-5 when incubated with spleen cells stimulated with TolT antigen, indicating that they are of the T-helper 1 type. T cells from mice chronically infected with T. cruzi also produce significant levels of IFN-γ when cocultured with macrophages and either TolT protein or paraflagellar rod protein, indicating that both of these flagellar proteins produce positive T-cell responses in mice chronically infected with T. cruzi.

scholarly journals Treatment with Soluble Interleukin-15Rα Exacerbates Intracellular Parasitic Infection by Blocking the Development of Memory CD8+ T Cell Response

2002 ◽  
Vol 195 (11) ◽  
pp. 1463-1470 ◽  
Author(s):  
Imtiaz A. Khan ◽  
Magali Moretto ◽  
Xiao-qing Wei ◽  
Martha Williams ◽  
Joseph D. Schwartzman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Parasitic Infection ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Memory Cd8 T Cells ◽  
Ifn Γ

Interferon (IFN)-γ–producing CD8+ T cells are important for the successful resolution of the obligate intracellular parasite Toxoplasma gondii by preventing the reactivation or controlling a repeat infection. Previous reports from our laboratory have shown that exogenous interleukin (IL)-15 treatment augments the CD8+ T cell response against the parasite. However, the role of endogenous IL-15 in the proliferation of activated/memory CD8+ T cells during toxoplasma or any other infection is unknown. In this study, we treated T. gondii immune mice with soluble IL-15 receptor α (sIL-15Rα) to block the host endogenous IL-15. The treatment markedly reduced the ability of the immune animals to control a lethal infection. CD8+ T cell activities in the sIL-15Rα–administered mice were severely reduced as determined by IFN-γ release and target cell lysis assays. The loss of CD8+ T cell immunity due to sIL-15Rα treatment was further demonstrated by adoptive transfer experiments. Naive recipients transferred with CD44hi activated/memory CD8+ T cells and treated with sIL-15Rα failed to resist a lethal T. gondii infection. Moreover, sIL-15Rα treatment of the recipients blocked the ability of donor CD44hi activated/memory CD8+ T cells to replicate in response to T. gondii challenge. To our knowledge, this is the first demonstration of the important role of host IL-15 in the development of antigen-specific memory CD8+ T cells against an intracellular infection.

scholarly journals T Cell Immunity Evaluation and Immunodominant Epitope T Cell Receptor Identification of Severe Acute Respiratory Syndrome Coronavirus 2 Spike Glycoprotein in COVID-19 Convalescent Patients

2021 ◽  
Vol 9 ◽  
Author(s):  
Luo Li ◽  
Qian Chen ◽  
Xiaojian Han ◽  
Meiying Shen ◽  
Chao Hu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Severe Acute Respiratory Syndrome ◽  
Vaccine Development ◽  
Cell Receptor ◽  
T Cell Response ◽  
Cell Immunity ◽  
Ifn Γ

A better understanding of the role of T cells in the immune response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is helpful not only for vaccine development but also for the treatment of COVID-19 patients. In this study, we determined the existence of SARS-CoV-2-specific T cells in the blood of COVID-19 convalescents. Meanwhile, the specific T cell response in the non-RBD region was stronger than in the RBD region. We also found that SARS-CoV-2 S-specific reactive CD4+ T cells exhibited higher frequency than CD8+ T cells in recovered COVID-19 patients, with greater number of corresponding epitopes presented. Importantly, we isolated the SARS-CoV-2-specific CD4+ T cell receptors (TCRs) and inserted the TCRs into allogenic CD4+ T cells. These TCR-T cells can be activated by SARS-CoV-2 spike peptide and produce IFN-γ in vitro. These results might provide valuable information for the development of vaccines and new therapies against COVID-19.

scholarly journals Role of cytokines and nitric oxide in the induction of tuberculostatic macrophage functions

2000 ◽  
Vol 9 (6) ◽  
pp. 261-269 ◽  
Author(s):  
Vera L. Petricevich ◽  
Rosely C. B. Alves
Keyword(s):  
Nitric Oxide ◽  
Culture Media ◽  
Peritoneal Macrophages ◽  
Interferon Γ ◽  
Enzyme Linked Immunosorbent Assay ◽  
No Production ◽  
Phenotypic Differences ◽  
Ifn Γ ◽  
Necrosis Factor

The aim of this study was to determine phenotypic differences when BCG invades macrophages. Bacilli prepared from the same BCG primary seed, but produced in different culture media, were analysed with respect to the ability to stimulate macrophages and the susceptibility to treatment with cytokines and nitric oxide (NO). Tumour necrosis factor (TNF) activity was assayed by measuring its cytotoxic activity on L-929 cells, interleukin-6 (IL-6) and interferon γ (IFN-γ) were assayed by enzyme-linked immunosorbent assay (ELISA), whereas NO levels were detected by Griess colorimetric reactions in the culture supernatant of macrophages incubated with IFN-γ , TNF or NO and subsequently exposed to either BCG-I or BCG-S. We found that BCG-I and BCGS bacilli showed different ability to simulate peritoneal macrophages. Similar levels of IL-6 were detected in stimulated macrophages with lysate from two BCG samples. The highest levels of TNF and IFN-γ were observed in macrophages treated with BCG-S and BCG-I, respectively. The highest levels of NO were observed in cultures stimulated for 48h with BCG-S. We also found a different susceptibility of the bacilli to ex ogenous treatm ent w ith IFN-γ and TNF which were capable of killing 60 and 70% of both bacilli, whereas NO was capable of killing about 98 and 47% of BCG-I and BCG-S, respectively. The amount of bacilli proportionally decreased with IFN-γ and TNF, suggesting a cytokine-related cytotox ic effect. Moreover, NO also decreased the viable number of bacilli. Interestingly, NO levels of peritoneal macrophages were significantly increased after cytokine treatment. This indicates that the treatment of macrophages with cytokines markedly reduced bacilli number and presented effects on NO production. The results obtained here emphasize the importance of adequate stimulation for guaranteeing efficient killing of bacilli. In this particular case, the IFN-γ and TNF were involved in the activation of macrophage bactericidal activity.

scholarly journals CD4+ T Cells in the Pathogenesis of Murine Ocular Toxoplasmosis

2004 ◽  
Vol 72 (9) ◽  
pp. 4966-4972 ◽  
Author(s):  
Fangli Lu ◽  
Shiguang Huang ◽  
Lloyd H. Kasper
Keyword(s):  
T Cells ◽  
B Cells ◽  
Parasite Burden ◽  
Parasite Load ◽  
T Cell Response ◽  
Ocular Toxoplasmosis ◽  
Ocular Infection ◽  
Necrosis Factor Alpha ◽  
Factor Alpha

ABSTRACT The role of CD4+ T cells in the pathogenesis of ocular toxoplasmosis was investigated in murine models utilizing inbred C57BL/6 mice deficient either in CD4+, CD8+, or B cells (μMT). Severe necrosis and inflammation with replicating parasites were observed in the eyes of control mice after primary ocular infection, and near-normal histology with few tachyzoites was observed in the eyes of mice immunized intraperitoneally with the avirulent ts-4 strain followed by intraocular challenge with the RH strain of Toxoplasma gondii. In contrast, mild inflammation without evidence of necrosis associated with increased parasite burdens were observed in the eyes of CD4 knockout (KO) mice after both primary ocular infection and challenge with RH tachyzoites. CD8 KO mice, as well as μMT mice, demonstrated increased ocular necrosis in response to either primary ocular infection or challenge. The parasite burden was increased in the eyes of both CD8 KO and μMT mice in which the parasite load was even higher. As expected, there were no increases in the levels of immunoglobulin G in serum or aqueous humor in μMT mice, and there was no increase in the levels of gamma interferon and tumor necrosis factor alpha in the sera of CD4 KO mice after both infection and challenge. These results suggest that the ocular inflammatory response to the parasite is mediated primarily by the CD4+-T-cell response. CD8+ T cells and B cells may play an important role in limiting tachyzoite proliferation in the eyes. Mice deficient in CD8+ CD4+ T cells or B cells exhibit diminished vaccine-induced resistance and increased ocular parasite burden after challenge.

scholarly journals MicroRNA-155 Deficiency Exacerbates Trypanosoma cruzi Infection

2020 ◽  
Vol 88 (7) ◽  
Author(s):  
Bijay K. Jha ◽  
Sanjay Varikuti ◽  
Gabriella R. Seidler ◽  
Greta Volpedo ◽  
Abhay R. Satoskar ◽  
...  
Keyword(s):  
T Cells ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Public Health Problem ◽  
Protozoan Parasite ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Inflammatory Monocytes ◽  
Nk T Cells

ABSTRACT Chagas disease, caused by the intracellular protozoan parasite Trypanosoma cruzi, is a public health problem affecting 6 to 8 million people, mainly in Latin America. The role of microRNAs in the pathogenesis of Chagas disease has not been well described. Here, we investigate the role of microRNA-155 (miR-155), a proinflammatory host innate immune regulator responsible for T helper type 1 and type 17 (Th1 and Th17) development and macrophage responses during T. cruzi infection. For this, we compared the survival and parasite growth and distribution in miR-155−/− and wild-type (WT) C57BL/6 mice. The lack of miR-155 caused robust parasite infection and diminished survival of infected mice, while WT mice were resistant to infection. Immunological analysis of infected mice indicated that, in the absence of miR-155, there was decreased interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) production. In addition, we found that there was a significant reduction of CD8-positive (CD8+) T cells, natural killer (NK) cells, and NK-T cells and increased accumulation of neutrophils and inflammatory monocytes in miR-155−/− mice. Collectively, these data indicate that miR-155 is an important immune regulatory molecule critical for the control of T. cruzi infection.

scholarly journals Trypanosoma cruzi Infection Is Enhanced by Vector Saliva through Immunosuppressant Mechanisms Mediated by Lysophosphatidylcholine

2008 ◽  
Vol 76 (12) ◽  
pp. 5543-5552 ◽  
Author(s):  
Rafael D. Mesquita ◽  
Alan Brito Carneiro ◽  
André Bafica ◽  
Felipe Gazos-Lopes ◽  
Christina M. Takiya ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Biological Effects ◽  
Mouse Skin ◽  
Inflammatory Cells ◽  
Peritoneal Macrophages ◽  
Massive Number ◽  
Cruzi Infection ◽  
Cell Chemotaxis

ABSTRACT Trypanosoma cruzi, the etiological agent of Chagas disease, is transmitted by bug feces deposited on human skin during a blood meal. However, parasite infection occurs through the wound produced by insect mouthparts. Saliva of the Triatominae bug Rhodnius prolixus is a source of lysophosphatidylcholine (LPC). Here, we tested the role of both triatomine saliva and LPC on parasite transmission. We show that vector saliva is a powerful inducer of cell chemotaxis. A massive number of inflammatory cells were found at the sites where LPC or saliva was inoculated into the skin of mice. LPC is a known chemoattractant for monocytes, but neutrophil recruitment induced by saliva is LPC independent. The preincubation of peritoneal macrophages with saliva or LPC increased fivefold the association of T. cruzi with these cells. Moreover, saliva and LPC block nitric oxide production by T. cruzi-exposed macrophages. The injection of saliva or LPC into mouse skin in the presence of the parasite induces an up-to-sixfold increase in blood parasitemia. Together, our data suggest that saliva of the Triatominae enhances T. cruzi transmission and that some of its biological effects are attributed to LPC. This is a demonstration that a vector-derived lysophospholipid may act as an enhancing factor of Chagas disease.

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