Myeloid-Derived Suppressor Cells in Trypanosoma cruzi Infection

Fresno, Manuel; Gironès, Núria

doi:10.3389/fcimb.2021.737364

Cited by 10 publications

(5 citation statements)

References 126 publications

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“…Interestingly, in both spleen and heart of T. cruzi-infected mice, infiltrating MDSCs coexpress iNOS and arginase-1 and suppress T cell proliferation . We do not discard the possibility that these cells may also be present in the aorta of T.cruzi-infected mice.…”

Section: Resultsmentioning

confidence: 87%

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Trypanosoma cruzi Infection Promotes Vascular Remodeling and Coexpression of α-Smooth Muscle Actin and Macrophage Markers in Cells of the Aorta

et al. 2022

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Chagas disease is an emerging global health problem; however, it remains neglected. Increased aortic stiffness (IAS), a predictor of cardiovascular events, has recently been reported in asymptomatic chronic Chagas patients. After vascular injury, smooth muscle cells (SMCs) can undergo alterations associated with phenotypic switch and transdifferentiation, promoting vascular remodeling and IAS. By studying different mouse aortic segments, we tested the hypothesis that Trypanosoma cruzi infection promotes vascular remodeling. Interestingly, the thoracic aorta was the most affected by the infection. Decreased expression of SMC markers and increased expression of proliferative markers were observed in the arteries of acutely infected mice. In acutely and chronically infected mice, we observed cells coexpressing SMC and macrophage (Mo) markers in the media and adventitia layers of the aorta, indicating that T. cruzi might induce cellular processes associated with SMC transdifferentiation into Mo-like cells or vice versa. In the adventitia, the Mo cell functional polarization was associated with an M2-like CD206+arginase-1+ phenotype despite the T. cruzi presence in the tissue. Only Mo-like cells in inflammatory foci were CD206+iNOS+. In addition to the disorganization of elastic fibers, we found thickening of the aortic layers during the acute and chronic phases of the disease. Our findings indicate that T. cruzi infection induces a vascular remodeling with SMC dedifferentiation and increased cell populations coexpressing α-SMA and Mo markers that could be associated with IAS promotion. These data highlight the importance of studying large vessel homeostasis in Chagas disease.

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Section: Resultsmentioning

confidence: 87%

“…In addition to inflammatory infiltrate, it has been reported that during T. cruzi infection, myeloid-derived suppressor cells (MDSCs) infiltrate the heart and mediate the myocarditis . Interestingly, in both spleen and heart of T.…”

Section: Resultsmentioning

confidence: 99%

Trypanosoma cruzi Infection Promotes Vascular Remodeling and Coexpression of α-Smooth Muscle Actin and Macrophage Markers in Cells of the Aorta

et al. 2022

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“…NOS2, the gene for inducible Nitric Oxide Synthase (iNOS), is a key signaling molecule in the induction of NO. NO has been shown to have both beneficial and detrimental effects on T. cruzi infection ( Fresno and Gironès, 2021 ). NO activates macrophage-killing mechanisms and can be protective against T. cruzi infection ( Muñoz-Fernández et al, 1992 ; Lee et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

“…In fact, mice defective in iNOS signaling are unable to control T. cruzi parasite burdens and succumb to infection ( Hölscher et al, 1998 ). However, it has also been shown that myeloid-derived suppressor CD11b+Ly6C+Ly6G lo cells (MDSC) are present in the spleens and hearts of T. cruzi -infected mice, they express iNOS and Arg1, and they induce expansion of Foxp3-expressing regulatory T cells ( Huang et al, 2006 ; Fresno and Gironès, 2021 ). Further, induction of NO by iNOS interferes with IL-2R signaling and alters the stability of IL-2 mRNA ( Bronte and Zanovello, 2005 ).…”

Section: Discussionmentioning

confidence: 99%

Immunomodulatory proteins from hookworms reduce cardiac inflammation and modulate regulatory responses in a mouse model of chronic Trypanosoma cruzi infection

Jones,

Zhan,

Ernste

et al. 2023

Front. Parasitol.

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IntroductionHookworms are parasitic helminths that secrete a variety of proteins that induce anti-inflammatory immune responses, stimulating increased CD4+Foxp3+ regulatory T cells and IL-10 production. Hookworm-derived recombinant proteins AIP-1 and AIP-2 have been shown to reduce inflammation in mouse models of inflammatory bowel disease and inflammatory airway disease by inducing CD4+Foxp3+ cells and IL-10 production. In contrast, chronic infection with the protozoal parasite Trypanosoma cruzi, the causative agent of Chagas disease, leads to chronic inflammation in tissues. Persistence of the parasites in tissues drives chronic low-grade inflammation, with increased infiltration of inflammatory cells into the heart, accompanied by increased production of inflammatory cytokines. There are no current antiparasitic drugs that effectively reduce or prevent chronic myocarditis caused by the onset of Chagas disease, thus new therapies are urgently needed. Therefore, the impact of AIP-1 and AIP-2 on myocarditis was investigated in a mouse model of chronic T. cruzi infection. MethodsFemale BALB/c mice infected with bioluminescent T. cruzi H1 strain trypomastigotes for 70 days were treated once daily for 7 days with 1mg/kg AIP-1 or AIP-2 protein by intraperitoneal injection. Control mice were left untreated or treated once daily for 14 days with 25mg/kg aspirin in drinking water. At 84 days of infection, splenocytes, cardiac tissue and serum were collected for evaluation. ResultsTreatment with both AIP-1 and AIP-2 proteins significantly reduced cardiac cellular infiltration, and reduced cardiac levels of IFNγ, IL-6 and IL-2. AIP-2 treatment reduced cardiac expression of COX-2. Further, while incubation with AIP-1 and AIP-2 proteins did not induce a significant upregulation of an immunoregulatory phenotype in dendritic cells (DC), there was a modest upregulation of CD11c+CD11b+MHCII+SIRPα+ expression, suggesting a regulatory phenotype. Ex-vivo stimulation of splenocytes from the treatment groups with AIP-1 loaded DC induced reduced levels of cytotoxic and pro-inflammatory T cells, stimulation with AIP-2 loaded DC specifically induced enhanced levels of CD4+CD25+Foxp3+ regulatory T cells among treatment groups. DiscussionAll in vivo and in vitro results demonstrate that hookworm-derived AIP-1 and AIP-2 proteins reduce T. cruzi induced cardiac inflammation, possibly through multiple anti-inflammatory mechanisms.

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“…These suppressor cells derived from the myeloid line (MDSC) are characterized by a group of heterogeneous cells that have the ability to inhibit the activity of cells through mechanisms associated with the production of reactive oxygen species (ROS), expression of arginase 1 (ARG1) and inducible nitric oxide synthase (iNOS), and the presence of immunosuppressive cytokines ( Medina and Hartl, 2018 ). Studies in mice have shown the importance of MDSCs in the infection control as well as and their future application in the development of immunotherapeutic measures against T. cruzi ( Fresno and Gironès, 2021 ). Therefore, we are analysing MDSCs in patients with different stages of the disease to determine their role in human Chagas disease.…”

Section: Perspectivesmentioning

confidence: 99%

Trypanosoma cruzi-specific CD8+ T cells and other immunological hallmarks in chronic Chagas cardiomyopathy: Two decades of research

Puerta

Cuéllar

Lasso

et al. 2023

Front. Cell. Infect. Microbiol.

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Trypanosoma cruzi, the causal agent of Chagas disease, has coexisted with humans for thousands of years. Therefore, the parasite has developed several mechanisms of antigenic variability that has allowed it to live inside the cells and evade the host immune response. Since T. cruzi displays an intracellular cycle-stage, our research team focused on providing insights into the CD8+ T cells immune response in chronic Chagas cardiomyopathy. We began our work in the 2000s studying parasite antigens that induce natural immune responses such as the KMP11 protein and TcTLE, its N-terminal derived peptide. Different approaches allowed us to reveal TcTLE peptide as a promiscuous CD8+ T cell epitope, able of inducing multifunctional cellular immune responses and eliciting a humoral response capable of decreasing parasite movement and infective capacity. Next, we demonstrated that as the disease progresses, total CD8+ T cells display a dysfunctional state characterized by a prolonged hyper-activation state along with an increase of inhibitory receptors (2B4, CD160, PD-1, TIM-3, CTLA-4) expression, an increase of specific terminal effector T cells (TTE), a decrease of proliferative capacity, a decrease of stem cell memory (TSCM) frequency, and a decrease of CD28 and CD3ζ expression. Thus, parasite-specific CD8+ T cells undergo clonal exhaustion, distinguished by an increase in late-differentiated cells, a mono-functional response, and enhanced expression of inhibitory receptors. Finally, it was found that anti-parasitic treatment induces an improved CD8+ T cell response in asymptomatic individuals, and a mouse animal model led us to establish a correlation between the quality of the CD8+ T cell responses and the outcome of chronic infection. In the future, using OMICs strategies, the identification of the specific cellular signals involved in disease progression will provide an invaluable resource for discovering new biomarkers of progression or new vaccine and immunotherapy strategies. Also, the inclusion of the TcTLE peptide in the rational design of epitope-based vaccines, the development of immunotherapy strategies using TSCM or the blocking of inhibitory receptors, and the use of the CD8+ T cell response quality to follow treatments, immunotherapies or vaccines, all are alternatives than could be explored in the fight against Chagas disease.

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Myeloid-Derived Suppressor Cells in Trypanosoma cruzi Infection

Cited by 10 publications

References 126 publications

Trypanosoma cruzi Infection Promotes Vascular Remodeling and Coexpression of α-Smooth Muscle Actin and Macrophage Markers in Cells of the Aorta

Trypanosoma cruzi Infection Promotes Vascular Remodeling and Coexpression of α-Smooth Muscle Actin and Macrophage Markers in Cells of the Aorta

Immunomodulatory proteins from hookworms reduce cardiac inflammation and modulate regulatory responses in a mouse model of chronic Trypanosoma cruzi infection

Trypanosoma cruzi-specific CD8+ T cells and other immunological hallmarks in chronic Chagas cardiomyopathy: Two decades of research

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