Specific activation of CD4–CD8– double-negative T cells by<i>Trypanosoma cruzi</i>-derived glycolipids induces a proinflammatory profile associated with cardiomyopathy in Chagas patients

Passos, Lívia Silva Araújo; Magalhães, Luísa Mourão Dias; Soares, Rodrigo Pedro; Marques, Alexandre F.; Nunes, Maria do Carmo Pereira; Gollob, Kenneth J.; Dutra, Walderez O.

doi:10.1111/cei.12992

Cited by 18 publications

(20 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For T. cruzi , these parasites possess membrane lipids that may be involved in the induction of severe disease. It was demonstrated that T. cruzi glycolipids activate a specific γδ-T cell population associated with cardiomyopathy, a severe outcome of Chagas disease ( Passos et al, 2017 ).…”

Section: Immune Evasion and Disease Severitymentioning

confidence: 99%

Lipid hijacking: A unifying theme in vector-borne diseases

O’Neal

Butler

Rolandelli

et al. 2020

eLife

View full text Add to dashboard Cite

Vector-borne illnesses comprise a significant portion of human maladies, representing 17% of global infections. Transmission of vector-borne pathogens to mammals primarily occurs by hematophagous arthropods. It is speculated that blood may provide a unique environment that aids in the replication and pathogenesis of these microbes. Lipids and their derivatives are one component enriched in blood and are essential for microbial survival. For instance, the malarial parasite Plasmodium falciparum and the Lyme disease spirochete Borrelia burgdorferi, among others, have been shown to scavenge and manipulate host lipids for structural support, metabolism, replication, immune evasion, and disease severity. In this Review, we will explore the importance of lipid hijacking for the growth and persistence of these microbes in both mammalian hosts and arthropod vectors.

show abstract

Section: Immune Evasion and Disease Severitymentioning

confidence: 99%

Lipid hijacking: A unifying theme in vector-borne diseases

O’Neal

Butler

Rolandelli

et al. 2020

eLife

View full text Add to dashboard Cite

show abstract

“…In addition, it is known that the vast majority of the peripheral TCR gamma-delta + cells are DN. Previous studies by us have shown that these cells are associated with Chagas heart disease and that they are specifically activated by glycoconjugates (GCL fraction) from T. cruzi trypomastigotes (24). Thus, the fact that PRO did not increase the expression of CD69 by DN TCR gamma-delta T cells was not surprising.…”

Section: Discussionmentioning

confidence: 99%

“…Antigenic fractions of T. cruzi were obtained using the methodology proposed by Gazos-Lopes et al (23) with adaptations (24). Frozen pellets obtained as described above were suspended in 1.6 mL of ultrapure water (W) and transferred to 13 × 100 mm polytetrafluoroethylene (PTFE)-lined screw cap Pyrex culture tubes.…”

Section: Methodsmentioning

confidence: 99%

Activation of Human CD11b+ B1 B-Cells by Trypanosoma cruzi-Derived Proteins Is Associated With Protective Immune Response in Human Chagas Disease

et al. 2019

View full text Add to dashboard Cite

B-cells mediate humoral adaptive immune response via the production of antibodies and cytokines, and by inducing T-cell activation. These functions can be attributed to distinct B-cell subpopulations. Infection with Trypanosoma cruzi, the causative agent of Chagas disease, induces a polyclonal B-cell activation and lytic antibody production, critical for controlling parasitemia. Individuals within the chronic phase of Chagas disease may remain in an asymptomatic form (indeterminate), or develop severe cardiomyopathy (cardiac form) that can lead to death. Currently, there is no effective vaccine to prevent Chagas disease, and no treatment to halt the development of the cardiomyopathy once it is installed. The pathology associated with cardiac Chagas disease is a result of an inflammatory reaction. Thus, discovering characteristics of the host's immune response that favor the maintenance of favorable heart function may unveil important immunotherapeutic targets. Given the importance of B cells in antibody production and parasite control, we investigated T. cruzi-derived antigenic fractions responsible for B-cell activation and whether frequencies and functional characteristics of B-cell subpopulations are associated with different clinical outcomes of human Chagas disease. We stimulated cells from indeterminate (I) and cardiac (C) Chagas patients, as well as non-infected individuals (NI), with T. cruzi-derived protein- (PRO), glycolipid- (GCL) and lipid (LIP)-enriched fractions and determined functional characteristics of B-cell subpopulations. Our results showed that the frequency of B-cells was similar amongst groups. PRO, but not GCL nor LIP, led to an increased frequency of B1 B-cells in I, but not C nor NI. Although stimulation with PRO induced higher TNF expression by B1 B-cells from C and I, as compared to NI, it induced expression of IL-10 in cells from I, but not C. Stimulation with PRO induced an increased frequency of the CD11b+ B1 B-cell subpopulation, which was associated with better cardiac function. Chagas patients displayed increased IgM production, and activation of gamma-delta T-cells, which have been associated with B1 B-cell function. Our data showed that PRO activates CD11b+ B1 B-cells, and that this activation is associated with a beneficial clinical status. These findings may have implications in designing new strategies focusing on B-cell activation to prevent Chagas disease cardiomyopathy.

show abstract

“…On the other hand, the prevalence of IFN‐γ‐producing γδ DN T cells over the regulatory response is linked to severe cardiac clinical form of Chagas´ disease. Corroborating, stimulation with T. cruzi ‐derived glycolipids induces TNF‐α and IL‐10 expression by peripheral γδ T cells from indeterminate individuals, while promotes IFN‐γ expression by γδ T cells from cardiac patients 35 . Similar profile was observed in patients with cutaneous leishmaniasis, who present reduced levels of circulating IL‐10‐expressing γδ DN T cells with regulatory properties, while the frequency of αβ DN T cells with proinflammatory properties is increased, when compared to healthy individuals 36 …”

Section: Discussionmentioning

confidence: 99%

IL-18R signaling is required for γδ T cell response and confers resistance to Trypanosoma cruzi infection

Mota

Echevarria-Lima

Kyle-Cezar

et al. 2020

Journal of Leukocyte Biology

View full text Add to dashboard Cite

IFN-producing T cells have been suggested to play an important role in protection against infection with Trypanosoma cruzi. However, little is known about the mechanisms leading to functional differentiation of this T cell subset in this model. In the current work, we investigated the possibility that the IL-18/MyD88 pathway is central for the generation of effector T cells, playing a role for resistance against infection. We found that splenic + CD3 + cells were rapidly expanded (10-14 days post infection), which was accompanied by an early T cell infiltration into the heart. In the following days, intracardiac parasitism was reduced, the protective immunity being accompanied by decreased T cells tissue infiltration. As predicted, there was a drastic reduction of T cells in Myd88-and Il18r1-deficient mice, both transgenic strains displaying a susceptible phenotype with increased intracardiac parasitism. In vivo and in vitro assays confirmed that IL-18R deficiency hampered T cell proliferation. Further characterization revealed that T. cruzi infection up-regulates IL-18R expression in WT + T cell population whereas Il18r1 −/− mice showed impaired generation of cytotoxic GzB + and IFN-producing T cells. Consistently, in vitro cytotoxicity assay confirmed that cytolytic function was impaired in Il18r1-deficient T cells. As a proof of concept, adoptive transfer of WT T cells rescues Il18r1-deficient mice from susceptibility, reducing parasitemia and abrogating the mortality. Collectively, our findings implicate the IL-18R-MyD88 signaling in the mechanisms underlying generation of immunoprotective T cells response in experimental Trypanosoma cruzi infection.

show abstract

Specific activation of CD4–CD8– double-negative T cells byTrypanosoma cruzi-derived glycolipids induces a proinflammatory profile associated with cardiomyopathy in Chagas patients

Cited by 18 publications

References 55 publications

Lipid hijacking: A unifying theme in vector-borne diseases

Lipid hijacking: A unifying theme in vector-borne diseases

Activation of Human CD11b+ B1 B-Cells by Trypanosoma cruzi-Derived Proteins Is Associated With Protective Immune Response in Human Chagas Disease

IL-18R signaling is required for γδ T cell response and confers resistance to Trypanosoma cruzi infection

Contact Info

Product

Resources

About