Current Research on Trypanosoma cruzi Infection

A special issue of Pathogens (ISSN 2076-0817). This special issue belongs to the section "Parasitic Pathogens".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 18098

Special Issue Editors

Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio Janeiro 21941-902, Brazil
Interests: Trypanosoma cruzi; Tritrichomonas foetus; Toxoplasma gondii; Leishmania; Giardia
School of Medicine, The City University of New York, New York, NY 10031, USA
Interests: Chagas disease; host-pathogen interactions; immunity; drug and vaccine discovery
Special Issues, Collections and Topics in MDPI journals
1. Institut Pasteur de Montevideo, Montevideo 11400, Uruguay
2. Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay
Interests: Trypanosoma cruzi; Leishmania; genomics; molecular parasitology; Chagas disease; Neospora caninum
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Trypanosoma cruzi is a parasitic protozoan that causes Chagas disease, an important life-long infection in humans with high prevalence in Latin American countries. This protozoan presents a complex life cycle involving both vertebrate and invertebrate hosts. One key step of the life cycle is the process of infection of mammalian cells by some developmental stages of the protozoan. In this process, infective forms (trypomastigotes, transitional forms, and amastigotes) attach to the host cell surface and trigger a process of invasion involving the assembly of an endocytic vacuole, known as parasitophorous vacuole. The parasite is able to disrupt the membrane lining the vacuole and enter into the cytoplasm of the host cell where it multiplies several times in the form of amastigotes. Subsequently, these transform into trypomastigotes and cell rupture takes place, releasing many trypomastigotes into the intercellular space. When infection takes place in a mammalian host, the parasite induces several host responses, involving the participation of different cell types with the stimulation of production of several molecules that modulate the immune and inflammatory response, leading to lesions observed in several tissues and organs, causing Chagas disease.

The purpose of this thematic Special Issue is to present a series of reviews and original articles dealing with all aspects related to T. cruzi–host interaction in vitro and in vivo in a broad perspective.

Prof. Dr. Wanderley De Souza
Prof. Dr. Fernando Villalta
Prof. Dr. Carlos Robello
Guest Editors

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Published Papers (9 papers)

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Research

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15 pages, 3275 KiB  
Article
New Insights into the Role of the Trypanosoma cruzi Aldo-Keto Reductase TcAKR
Pathogens 2023, 12(1), 85; https://doi.org/10.3390/pathogens12010085 - 05 Jan 2023
Viewed by 1372
Abstract
Chagas disease is a zoonotic infectious disease caused by the protozoan parasite Trypanosoma cruzi. It is distributed worldwide, affecting around 7 million people; there is no effective treatment, and it constitutes a leading cause of disability and premature death in the Americas. [...] Read more.
Chagas disease is a zoonotic infectious disease caused by the protozoan parasite Trypanosoma cruzi. It is distributed worldwide, affecting around 7 million people; there is no effective treatment, and it constitutes a leading cause of disability and premature death in the Americas. Only two drugs are currently approved for the treatment, Benznidazole and Nifurtimox, and both have to be activated by reducing the nitro-group. The T. cruzi aldo-keto reductase (TcAKR) has been related to the metabolism of benznidazole. TcAKR has been extensively studied, being most efforts focused on characterizing its implication in trypanocidal drug metabolism; however, little is known regarding its biological role. Here, we found that TcAKR is confined, throughout the entire life cycle, into the parasite mitochondria providing new insights into its biological function. In particular, in epimastigotes, TcAKR is associated with the kinetoplast, which suggests additional roles of the protein. The upregulation of TcAKR, which does not affect TcOYE expression, was correlated with an increase in PGF2α, suggesting that this enzyme is related to PGF2α synthesis in T. cruzi. Structural analysis showed that TcAKR contains a catalytic tetrad conserved in the AKR superfamily. Finally, we found that TcAKR is also involved in Nfx metabolization. Full article
(This article belongs to the Special Issue Current Research on Trypanosoma cruzi Infection)
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15 pages, 2095 KiB  
Article
High Parasitic Loads Quantified in Sylvatic Triatoma melanica, a Chagas Disease Vector
Pathogens 2022, 11(12), 1498; https://doi.org/10.3390/pathogens11121498 - 08 Dec 2022
Viewed by 1900
Abstract
Triatoma melanica is a sylvatic vector species in Brazil. In We aimed to characterize the Trypanosoma cruzi discrete typing units (DTUs), the parasitic loads, and the blood meal sources of insects collected in rocky outcrops in rural areas in the state of Minas [...] Read more.
Triatoma melanica is a sylvatic vector species in Brazil. In We aimed to characterize the Trypanosoma cruzi discrete typing units (DTUs), the parasitic loads, and the blood meal sources of insects collected in rocky outcrops in rural areas in the state of Minas Gerais. An optical microscope (OM) and kDNA-PCR were used to examine natural infection by T. cruzi, and positive samples were genotyped by conventional multilocus PCR. Quantification of the T. cruzi load was performed using qPCR, and the blood meal sources were identified by Sanger sequencing the 12S rRNA gene. A total of 141 T. melanica were captured. Of these, ~55% (61/111) and ~91% (63/69) were positive by OM and KDNA-PCR, respectively. We genotyped ~89% (56/63) of the T. cruzi-positive triatomines, with TcI (~55%, 31/56) being the most prevalent DTU, followed by TcIII (~20%, 11/56) and TcII (~7%, 4/56). Only TcI+TcIII mixed infections were detected in 10 (~18%) specimens. A wide range of variation in the parasitic loads of T. melanica was observed, with an overall median value of 104 parasites/intestine, with females having higher T. cruzi loads than N2, N4, and N5. TcII showed lower parasitic loads compared to TcI and TcIII. The OM positive diagnosis odds ratio between T. cruzi infection when the parasite load is 107 compared to 103 was approximately 29.1. The most frequent blood meal source was Kerodon rupestris (~58%), followed by Thrichomys apereoides (~18%), Wiedomys cerradensis (~8%), Galactis cuja (~8%) and Gallus gallus (~8%). Our findings characterize biological and epidemiological aspects of the sylvatic population of T. melanica in the study area, highlighting the need to extend surveillance and control to this vector. Full article
(This article belongs to the Special Issue Current Research on Trypanosoma cruzi Infection)
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15 pages, 7052 KiB  
Article
The Characterization of Cardiac Explants Reveals Unique Fibrosis Patterns and a Predominance of CD8+ T Cell Subpopulations in Patients with Chronic Chagas Cardiomyopathy
Pathogens 2022, 11(12), 1402; https://doi.org/10.3390/pathogens11121402 - 23 Nov 2022
Cited by 2 | Viewed by 1458
Abstract
Aim: The present study aimed to characterize the histopathological findings and the phenotype of inflammatory cells in the myocardial tissue of patients with end-stage heart failure (ESHF) secondary to CCC in comparison with ESHF secondary to non-Chagas cardiomyopathies (NCC). Methods: A total of [...] Read more.
Aim: The present study aimed to characterize the histopathological findings and the phenotype of inflammatory cells in the myocardial tissue of patients with end-stage heart failure (ESHF) secondary to CCC in comparison with ESHF secondary to non-Chagas cardiomyopathies (NCC). Methods: A total of 32 explanted hearts were collected from transplanted patients between 2014 and 2017. Of these, 21 were classified as CCC and 11 as other NCC. A macroscopic analysis followed by a microscopic analysis were performed. Finally, the phenotypes of the inflammatory infiltrates were characterized using flow cytometry. Results: Microscopic analysis revealed more extensive fibrotic involvement in patients with CCC, with more frequent foci of fibrosis, collagen deposits, and degeneration of myocardial fibers, in addition to identifying foci of inflammatory infiltrate of greater magnitude. Finally, cell phenotyping identified more memory T cells, mainly CD8+CD45RO+ T cells, and fewer transitioning T cells (CD45RA+/CD45RO+) in patients with CCC compared with the NCC group. Conclusions: CCC represents a unique form of myocardial involvement characterized by abundant inflammatory infiltrates, severe interstitial fibrosis, extensive collagen deposits, and marked cardiomyocyte degeneration. The structural myocardial changes observed in late-stage Chagas cardiomyopathy appear to be closely related to the presence of cardiac fibrosis and the colocalization of collagen fibers and inflammatory cells, a finding that serves as a basis for the generation of new hypotheses aimed at better understanding the role of inflammation and fibrogenesis in the progression of CCC. Finally, the predominance of memory T cells in CCC compared with NCC hearts highlights the critical role of the parasite-specific lymphocytic response in the course of the infection. Full article
(This article belongs to the Special Issue Current Research on Trypanosoma cruzi Infection)
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13 pages, 4299 KiB  
Article
Depletion of Na+/H+ Exchanger Isoform 1 Increases the Host Cell Resistance to Trypanosoma cruzi Invasion
Pathogens 2022, 11(11), 1294; https://doi.org/10.3390/pathogens11111294 - 04 Nov 2022
Viewed by 1227
Abstract
Na+/H+ exchanger isoform 1 (NHE1), a member of a large family of integral membrane proteins, plays a role in regulating the cortical actin cytoskeleton. Trypanosoma cruzi, the agent of Chagas disease, depends on F-actin rearrangement and lysosome mobilization to [...] Read more.
Na+/H+ exchanger isoform 1 (NHE1), a member of a large family of integral membrane proteins, plays a role in regulating the cortical actin cytoskeleton. Trypanosoma cruzi, the agent of Chagas disease, depends on F-actin rearrangement and lysosome mobilization to invade host cells. To determine the involvement of NHE1 in T. cruzi metacyclic trypomastigote (MT) internalization, the effect of treatment in cells with NHE1 inhibitor amiloride or of NHE1 depletion was examined in human epithelial cells. MT invasion decreased in amiloride-treated and NHE1-depleted cells. The phosphorylation profile of diverse protein kinases, whose activation is associated with remodeling of actin fibers, was analyzed in amiloride-treated and NHE1-depleted cells. In amiloride-treated cells, the phosphorylation levels of protein kinase C (PKC), focal adhesion kinase (FAK) and Akt were similar to those of untreated cells, whereas those of extracellular signal-regulated protein kinases (ERK1/2) increased. In NHE1-deficient cells, with marked alteration in the actin cytoskeleton architecture and in lysosome distribution, the levels of phospho-PKC and phospho-FAK decreased, whereas those of phospho-Akt and phospho-ERK1/2 increased. These data indicate that NHE1 plays a role in MT invasion, by maintaining the activation status of diverse protein kinases in check and preventing the inappropriate F-actin arrangement that affects lysosome distribution. Full article
(This article belongs to the Special Issue Current Research on Trypanosoma cruzi Infection)
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16 pages, 5820 KiB  
Article
Parasitemia and Differential Tissue Tropism in Mice Infected with Trypanosoma cruzi Isolates Obtained from Meccus phyllosoma in the State of Oaxaca, Mexico
Pathogens 2022, 11(10), 1141; https://doi.org/10.3390/pathogens11101141 - 02 Oct 2022
Viewed by 1317
Abstract
Trypanosoma cruzi is a parasite transmitted by the feces of triatomines. Many triatomine species are found in Mexico, and various T. cruzi variants have been isolated from these species, each showing very different virulence and cell tropism. The isolates were obtained from Meccus [...] Read more.
Trypanosoma cruzi is a parasite transmitted by the feces of triatomines. Many triatomine species are found in Mexico, and various T. cruzi variants have been isolated from these species, each showing very different virulence and cell tropism. The isolates were obtained from Meccus phyllosoma specimens in three localities in the state of Oaxaca, Mexico: Tehuantitla, Vixhana, and Guichivere. The virulence of each isolate was assessed by quantifying parasitemia, survival, and histopathologic findings. The lineage of each isolate was identified using the mini-exon gene. The expression of the tssa gene during infection was detected in the heart, esophagus, gastrocnemius, and brain. Our results show that the maximum post-infection parasitemia was higher for the Tehuantitla isolate. On genotyping, all isolates were identified as T. cruzi I. The amastigotes in the heart and gastrocnemius were verified for all isolates, but in the brain only for Tehuantitla and Vixhana. The tssa expression allowed us to detect T. cruzi isolates, for Tehuantitla, predominantly in the heart. For Vixhana, a higher tssa expression was detected in gastrocnemius, and for Guichivere, it was higher in the esophagus. Results show that virulence, tropism, and tssa expression can vary, even when the isolates are derived from the same vector species, in the same region, and at similar altitudes. Full article
(This article belongs to the Special Issue Current Research on Trypanosoma cruzi Infection)
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29 pages, 5479 KiB  
Article
Sheltered in Stromal Tissue Cells, Trypanosoma cruzi Orchestrates Inflammatory Neovascularization via Activation of the Mast Cell Chymase Pathway
Pathogens 2022, 11(2), 187; https://doi.org/10.3390/pathogens11020187 - 29 Jan 2022
Cited by 2 | Viewed by 2724
Abstract
Microangiopathy may worsen the clinical outcome of Chagas disease. Given the obstacles to investigating the dynamics of inflammation and angiogenesis in heart tissues parasitized by Trypanosoma cruzi, here we used intravital microscopy (IVM) to investigate microcirculatory alterations in the hamster cheek pouch [...] Read more.
Microangiopathy may worsen the clinical outcome of Chagas disease. Given the obstacles to investigating the dynamics of inflammation and angiogenesis in heart tissues parasitized by Trypanosoma cruzi, here we used intravital microscopy (IVM) to investigate microcirculatory alterations in the hamster cheek pouch (HCP) infected by green fluorescent protein-expressing T. cruzi (GFP-T. cruzi). IVM performed 3 days post-infection (3 dpi) consistently showed increased baseline levels of plasma extravasation. Illustrating the reciprocal benefits that microvascular leakage brings to the host-parasite relationship, these findings suggest that intracellular amastigotes, acting from inside out, stimulate angiogenesis while enhancing the delivery of plasma-borne nutrients and prosurvival factors to the infection foci. Using a computer-based analysis of images (3 dpi), we found that proangiogenic indexes were positively correlated with transcriptional levels of proinflammatory cytokines (pro-IL1β and IFN-γ). Intracellular GFP-parasites were targeted by delaying for 24 h the oral administration of the trypanocidal drug benznidazole. A classification algorithm showed that benznidazole (>24 h) blunted angiogenesis (7 dpi) in the HCP. Unbiased proteomics (3 dpi) combined to pharmacological targeting of chymase with two inhibitors (chymostatin and TY-51469) linked T. cruzi-induced neovascularization (7 dpi) to the proangiogenic activity of chymase, a serine protease stored in secretory granules from mast cells. Full article
(This article belongs to the Special Issue Current Research on Trypanosoma cruzi Infection)
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Review

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15 pages, 866 KiB  
Review
A Review on the Immunological Response against Trypanosoma cruzi
Pathogens 2023, 12(2), 282; https://doi.org/10.3390/pathogens12020282 - 08 Feb 2023
Cited by 11 | Viewed by 2477
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Current Research on Trypanosoma cruzi Infection)
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14 pages, 359 KiB  
Review
Modulation of Virulence Factors during Trypanosoma cruzi Differentiation
Pathogens 2023, 12(1), 32; https://doi.org/10.3390/pathogens12010032 - 25 Dec 2022
Cited by 1 | Viewed by 1454
Abstract
Chagas disease is a neglected tropical disease caused by Trypanosoma cruzi. This protozoan developed several mechanisms to infect, propagate, and survive in different hosts. The specific expression of proteins is responsible for morphological and metabolic changes in different parasite stages along the [...] Read more.
Chagas disease is a neglected tropical disease caused by Trypanosoma cruzi. This protozoan developed several mechanisms to infect, propagate, and survive in different hosts. The specific expression of proteins is responsible for morphological and metabolic changes in different parasite stages along the parasite life cycle. The virulence strategies at the cellular and molecular levels consist of molecules responsible for mediating resistance mechanisms to oxidative damage, cellular invasion, and immune evasion, performed mainly by surface proteins. Since parasite surface coat remodeling is crucial to invasion and infectivity, surface proteins are essential virulence elements. Understanding the factors involved in these processes improves the knowledge of parasite pathogenesis. Genome sequencing has opened the door to high-throughput technologies, allowing us to obtain a deeper understanding of gene reprogramming along the parasite life cycle and identify critical molecules for survival. This review therefore focuses on proteins regulated during differentiation into infective forms considered virulence factors and addresses the current known mechanisms acting in the modulation of gene expression, emphasizing mRNA signals, regulatory factors, and protein complexes. Full article
(This article belongs to the Special Issue Current Research on Trypanosoma cruzi Infection)
17 pages, 12540 KiB  
Review
Animal Models of Trypanosoma cruzi Congenital Transmission
Pathogens 2022, 11(10), 1172; https://doi.org/10.3390/pathogens11101172 - 11 Oct 2022
Cited by 5 | Viewed by 3291
Abstract
Chagas disease, initiated by the etiological agent Trypanosoma cruzi, is an endemic infection in the American continent. Although vectorial transmission of T. cruzi is recognized as the main mode of infection, other routes such as congenital and blood transfusion are also documented [...] Read more.
Chagas disease, initiated by the etiological agent Trypanosoma cruzi, is an endemic infection in the American continent. Although vectorial transmission of T. cruzi is recognized as the main mode of infection, other routes such as congenital and blood transfusion are also documented as important methods of transmission. T. cruzi maternal–fetal transmission has been recorded in humans and examined by some investigators in naturally and experimentally infected mammals. Dogs are recognized as the major reservoir host in maintaining the domestic transmission of T. cruzi; however, the importance of congenital transmission in preserving the infection cycle in dogs has not been studied in detail. In this article, we reviewed the current knowledge of congenital transmission of T. cruzi in humans and compared the placental architecture of humans and different animals with particular attention to rodents, dogs, and non-human primates that have been used as experimental models of T. cruzi infection, congenital transmission, and Chagas disease pathogenesis. The placentas of humans and animals have some similar and dissimilar characteristics that should inform the study design and interpretation of results when evaluating the efficacy of new anti-parasite drugs and therapies against congenital infection. Full article
(This article belongs to the Special Issue Current Research on Trypanosoma cruzi Infection)
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