A multi-parametric analysis of Trypanosoma cruzi infection: common pathophysiologic patterns beyond extreme heterogeneity of host responses

Santi-Rocca, Julien; Fernández-Cortés, Fernando; Chillón-Marinas, Carlos; González-Rubio, María-Luisas; Mathieu, David; Gironès, Núria; Fresno, Manuel

doi:10.1038/s41598-017-08086-8

Cited by 43 publications

(54 citation statements)

References 37 publications

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“…Although our study was done with a unique strain of the parasite, it is highly virulent and with cardiac tropism, characteristics that give further strength to our results. In addition, we very recently described the existence of common pathophysiologic patterns linked to clinical outcome of Chagas disease, conserved among the genetically diverse infecting strains, which suggests that our approach could be valid [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

L-arginine supplementation reduces mortality and improves disease outcome in mice infected with Trypanosoma cruzi

et al. 2018

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Chagas disease caused by Trypanosoma cruzi is a neglected disease that affects about 7 million people in Latin America, recently emerging on other continents due to migration. As infection in mice is characterized by depletion of plasma L-arginine, the effect on infection outcome was tested in mice with or without L-arginine supplementation and treatment with 1400W, a specific inhibitor of inducible nitric oxide synthase (iNOS). We found that levels of L-arginine and citrulline were reduced in the heart and plasma of infected mice, whereas levels of asymmetric dimethylarginine, an endogenous iNOS inhibitor, were higher. Moreover, L-arginine supplementation decreased parasitemia and heart parasite burden, improving clinical score and survival. Nitric oxide production in heart tissue and plasma was increased by L-arginine supplementation, while pharmacological inhibition of iNOS yielded an increase in parasitemia and worse clinical score. Interestingly, electrocardiograms improved in mice supplemented with L-arginine, suggesting that it modulates infection and heart function and is thus a potential biomarker of pathology. More importantly, L-arginine may be useful for treating T. cruzi infection, either alone or in combination with other antiparasitic drugs. Author summaryTrypanosoma cruzi is the causative agent of the neglected Chagas disease in humans. During infection in mice, depletion of plasma L-arginine is correlated with mortality. L-arginine is a semi-essential amino acid needed for cell proliferation, and is the substrate of arginase 1 (Arg-1) and inducible nitric oxide synthase (iNOS), which is involved in the immune response against infections. Observed L-arginine depletion is likely caused by increased Arg-1 activity, but the effect on immune response are still unknown. Our PLOS Neglected Tropical Diseases | https://doi

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Section: Discussionmentioning

confidence: 99%

L-arginine supplementation reduces mortality and improves disease outcome in mice infected with Trypanosoma cruzi

et al. 2018

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“…Based on epidemiological findings as well as on animal models, it has been proposed that this heterogeneous clinical response is linked to host genetic background and the extremely high genetic diversity of T. cruzi ( 3 , 4 ). Parasite strains exhibit different organ tropism during acute and chronic infection ( 5 ). In this study, we used T. cruzi -Tulahuen strain that mainly infects liver and spleen and induces liver pathology and splenomegaly during acute phase ( 6 ).…”

Section: Introductionmentioning

confidence: 99%

NLRP3 Inflammasome and Caspase-1/11 Pathway Orchestrate Different Outcomes in the Host Protection Against Trypanosoma cruzi Acute Infection

et al. 2018

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Infection with protozoan parasite Trypanosoma cruzi results in activation of nucleotide-binding domain and leucine-rich repeat containing receptors (NLRs). NLR activation leads to inflammasome formation, the activation of caspase-1, and the subsequent cleavage of IL-1β and IL-18. Considering that inflammasome activation and IL-1β induction by macrophages are key players for an appropriate T cell response, we investigated the relevance of NLR pyrin domain-containing 3 (NLRP3) and caspase-1/11 to elucidate their roles in the induction of different T cell phenotypes and the relationship with parasite load and hepatic inflammation during T. cruzi-Tulahuen strain acute infection. We demonstrated that infected nlrp3−/− and C57BL/6 wild type (WT) mice exhibited similar parasitemia and survival, although the parasite load was higher in the livers of nlrp3−/− mice than in those of WT mice. Increased levels of transaminases and pro-inflammatory cytokines were found in the plasma of WT and nlrp3−/− mice indicating that NLRP3 is dispensable to control the parasitemia but it is required for a better clearance of parasites in the liver. Importantly, we have found that NLRP3 and caspase-1/11-deficient mice differentially modulate T helper (Th1, Th2, and Th17) and cytotoxic T lymphocyte phenotypes. Strikingly, caspase-1/11−/− mice showed the most dramatic reduction in the number of IFN-γ- and IL-17-producing CD4+ and CD8+ T cells associated with higher parasitemia and lower survival. Additionally, caspase-1/11−/− mice demonstrated significantly reduced liver inflammation with the lowest alanine aminotransferase (ALT) levels but the highest hepatic parasitic load. These results unequivocally demonstrate that caspase-1/11 pathway plays an important role in the induction of liver adaptive immunity against this parasite infection as well as in hepatic inflammation.

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“…Then, the patients can remain in an asymptomatic phase for life or, after many years without any sign of disease, develop a symptomatic chronic phase with cardiomyopathy, megavisceras, or both [ 3 ]. Moreover, these variations in the disease outcomes are related to the high genetic variability of the parasite [ 4 , 5 , 6 , 7 ].…”

Section: General Aspects Of T Cruzi Biologymentioning

confidence: 99%

Trypanosoma Cruzi Genome: Organization, Multi-Gene Families, Transcription, and Biological Implications

Herreros-Cabello

Callejas-Hernández

Gironès

et al. 2020

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Chagas disease caused by the parasite Trypanosoma cruzi affects millions of people. Although its first genome dates from 2005, its complexity hindered a complete assembly and annotation. However, the new sequencing methods have improved genome annotation of some strains elucidating the broad genetic diversity and complexity of this parasite. Here, we reviewed the genomic structure and regulation, the genetic diversity, and the analysis of the principal multi-gene families of the recent genomes for several strains. The telomeric and sub-telomeric regions are sites with high recombination events, the genome displays two different compartments, the core and the disruptive, and the genome plasticity seems to play a key role in the survival and the infection process. Trypanosoma cruzi (T. cruzi) genome is composed mainly of multi-gene families as the trans-sialidases, mucins, and mucin-associated surface proteins. Trans-sialidases are the most abundant genes in the genome and show an important role in the effectiveness of the infection and the parasite survival. Mucins and MASPs are also important glycosylated proteins of the surface of the parasite that play a major biological role in both insect and mammal-dwelling stages. Altogether, these studies confirm the complexity of T. cruzi genome revealing relevant concepts to better understand Chagas disease.

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A multi-parametric analysis of Trypanosoma cruzi infection: common pathophysiologic patterns beyond extreme heterogeneity of host responses

Cited by 43 publications

References 37 publications

L-arginine supplementation reduces mortality and improves disease outcome in mice infected with Trypanosoma cruzi

L-arginine supplementation reduces mortality and improves disease outcome in mice infected with Trypanosoma cruzi

NLRP3 Inflammasome and Caspase-1/11 Pathway Orchestrate Different Outcomes in the Host Protection Against Trypanosoma cruzi Acute Infection

Trypanosoma Cruzi Genome: Organization, Multi-Gene Families, Transcription, and Biological Implications

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