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Current Insights and Challenges in Trypanosoma cruzi Genetics, Pathology, and...
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Current Insights and Challenges in Trypanosoma cruzi Genetics, Pathology, and Therapeutic Strategies

A special issue of Microorganisms (ISSN 2076-2607). This special issue belongs to the section "Parasitology".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 11217

Special Issue Editors

Dr. Maria-Jesus Pinazo

E-Mail Website
Guest Editor
Instituto de Salud Global de Barcelona (ISGlobal), Hospital Clínic, Universidad de Barcelona, 08036 Barcelona, Spain
Interests: Trypanosoma cruzi; Chagas disease; neglected tropical diseases; biomarkers; public health; drug discovery; responsible research and innovation
Dr. Alejandro Gabriel Schijman

E-Mail Website
Guest Editor
Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (INGEBI), CONICET, C1428 ADN, Buenos Aires, Argentina
Interests: Trypanosoma cruzi; Chagas disease; neglected tropical diseases; molecular parasitology; epidemiology and diagnosis

Special Issue Information

Dear Colleagues, 

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is endemic in 21 Latin American countries and an emerging disease in other countries all around the world. With it considered as one of the neglected tropical diseases, the control of T. cruzi infection has been traditionally limited by several factors in terms of people at risk and comprehensive management strategies.  

Even if current evidence indicates that parasite persistence is fundamental for triggering and sustaining pathogenic processes, there is still an incomplete understanding in host–pathogen interactions. This major limitation has hampered successful diagnosis and prognosis evaluations as well as new approaches to treatment strategies covering the diverse eco-epidemiological and clinical settings of T. cruzi infection. 

The genetic diversity of T. cruzi implies differences in the clinical manifestations of Chagas disease, as well as the degree of infectivity, virulence, pathogenicity, antigenic capacity, and susceptibility or resistance to trypanocidal drugs. Host- derived factors (genetics, immunological state, comorbidities, etc.) also have relevant implications on disease progression and prognosis. 

In this Special Issue, we aim to contribute to Chagas disease updated knowledge in genetics, pathology, and therapeutic strategies. We encourage researchers investigating T. cruzi host–parasite interactions and new insights into therapeutic approaches to contribute with original research articles, letters, or reviews. Contributions on progression and/or therapeutic response biomarkers will be highly appreciated.

Dr. Maria-Jesus Pinazo
Dr. Alejandro Gabriel Schijman
Guest Editors

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Keywords

  • Chagas disease
  • Trypanosoma cruzi
  • genetics
  • host–pathogen interactions
  • prognosis
  • biomarkers
  • drugs discovery
  • vaccine

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Published Papers (4 papers)

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Research

10 pages, 2145 KiB  
Communication
Loop-Mediated Isothermal Amplification of Trypanosoma cruzi DNA for Point-of-Care Follow-Up of Anti-Parasitic Treatment of Chagas Disease
by Arturo A. Muñoz-Calderón, Susana A. Besuschio, Season Wong, Marisa Fernández, Lady J. García Cáceres, Patricia Giorgio, Laura A. Barcan, Cole Markham, Yanwen E. Liu, Belkisyole Alarcón de Noya, Silvia A. Longhi and Alejandro G. Schijman
Microorganisms 2022, 10(5), 909; https://doi.org/10.3390/microorganisms10050909 - 26 Apr 2022
Cited by 12 | Viewed by 2201
Abstract
A loop-mediated isothermal amplification assay was evaluated as a surrogate marker of treatment failure in Chagas disease (CD). A convenience series of 18 acute or reactivated CD patients who received anti-parasitic treatment with benznidazole was selected—namely, nine orally infected patients: three people living [...] Read more.
A loop-mediated isothermal amplification assay was evaluated as a surrogate marker of treatment failure in Chagas disease (CD). A convenience series of 18 acute or reactivated CD patients who received anti-parasitic treatment with benznidazole was selected—namely, nine orally infected patients: three people living with HIV and CD reactivation, five chronic CD recipients with reactivation after organ transplantation and one seronegative recipient of a kidney and liver transplant from a CD donor. Fifty-four archival samples (venous blood treated with EDTA or guanidinium hydrochloride-EDTA buffer and cerebrospinal fluid) were extracted using a Spin-column manual kit and tested by T. cruzi Loopamp kit (Tc-LAMP, index test) and standardized real-time PCR (qPCR, comparator test). Of them, 23 samples were also extracted using a novel repurposed 3D printer designed for point-of-care DNA extraction (PrintrLab). The agreement between methods was estimated by Cohen’s kappa index and Bland–Altman plot analysis. The T. cruzi Loopamp kit was as sensitive as qPCR for detecting parasite DNA in samples with parasite loads higher than 0.5 parasite equivalents/mL and infected with different discrete typing units. The agreement between qPCR and Tc-LAMP (Spin-column) or Tc-LAMP (PrintrLab) was excellent, with a mean difference of 0.02 [CI = −0.58–0.62] and −0.04 [CI = −0.45–0.37] and a Cohen’s kappa coefficient of 0.78 [CI = 0.60–0.96] and 0.90 [CI = 0.71 to 1.00], respectively. These findings encourage prospective field studies to validate the use of LAMP as a surrogate marker of treatment failure in CD. Full article
(This article belongs to the Special Issue Current Insights and Challenges in Trypanosoma cruzi Genetics, Pathology, and Therapeutic Strategies)
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16 pages, 1858 KiB  
Article
Genetic Diversity of Trypanosoma cruzi in Panama Inferred by Multi-locus Sequence Typing of Mitochondrial Genes
by Jose E. Calzada, Franklyn Samudio, Corina de Juncá, Vanessa Pineda, Barbara A. Burleigh and Azael Saldaña
Microorganisms 2022, 10(2), 287; https://doi.org/10.3390/microorganisms10020287 - 26 Jan 2022
Cited by 5 | Viewed by 2754
Abstract
The objective of this study was to provide information on Trypanosoma cruzi genetic diversity among isolates obtained from different biological sources circulating in endemic areas of Panama. Initial discrete typing units (DTUs) assignment was performed evaluating three single locus molecular markers (mini-exon, heat [...] Read more.
The objective of this study was to provide information on Trypanosoma cruzi genetic diversity among isolates obtained from different biological sources circulating in endemic areas of Panama. Initial discrete typing units (DTUs) assignment was performed evaluating three single locus molecular markers (mini-exon, heat shock protein 60 and glucose-6-phosphate isomerase genes). Further diversity within TcI lineages was explored using a multi-locus sequence typing approach with six maxicircle genes. Haplotype network analysis and evolutionary divergency estimations were conducted to investigate the genetic relatedness between Panamanian TcI isolates and isolates from different endemic regions in the Americas. Our molecular approach validated that TcI is the predominant DTU circulating in Panama across different hosts and vector species, but also confirmed the presence of TcIII and TcVI circulating in the country. The phylogenetic tree topography for most Panamanian TcI isolates displayed a high level of genetic homogeneity between them. The haplotype network analysis inferred a higher genetic diversity within Panamanian TcI isolates, displaying eight different haplotypes circulating in endemic regions of the country, and revealed geographical structuring among TcI from different endemic regions in the Americas. This study adds novelty on the genetic diversity of T. cruzi circulating in Panama and complements regional phylogeographic studies regarding intra-TcI variations. Full article
(This article belongs to the Special Issue Current Insights and Challenges in Trypanosoma cruzi Genetics, Pathology, and Therapeutic Strategies)
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19 pages, 3745 KiB  
Article
Nicastrin-Like, a Novel Transmembrane Protein from Trypanosoma cruzi Associated to the Flagellar Pocket
by Guilherme Curty Lechuga, Paloma Napoleão-Pêgo, Larissa Rodrigues Gomes, Andressa da Matta Durans, David William Provance, Jr. and Salvatore Giovanni De-Simone
Microorganisms 2021, 9(8), 1750; https://doi.org/10.3390/microorganisms9081750 - 17 Aug 2021
Cited by 4 | Viewed by 2802
Abstract
Nicastrin (NICT) is a transmembrane protein physically associated with the polytypical aspartyl protease presenilin that plays a vital role in the correct localization and stabilization of presenilin to the membrane-bound γ-secretase complex. This complex is involved in the regulation of a wide range [...] Read more.
Nicastrin (NICT) is a transmembrane protein physically associated with the polytypical aspartyl protease presenilin that plays a vital role in the correct localization and stabilization of presenilin to the membrane-bound γ-secretase complex. This complex is involved in the regulation of a wide range of cellular events, including cell signaling and the regulation of endocytosed membrane proteins for their trafficking and protein processing. Methods: In Trypanosoma cruzi, the causal agent of the Chagas disease, a NICT-like protein (Tc/NICT) was identified with a short C-terminus orthologous to the human protein, a large ectodomain (ECD) with numerous glycosylation sites and a single-core transmembrane domain containing a putative TM-domain (457GSVGA461) important for the γ-secretase complex activity. Results: Using the Spot-synthesis strategy with Chagasic patient sera, five extracellular epitopes were identified and synthetic forms were used to generate rabbit anti-Tc/NICT polyclonal serum that recognized a ~72-kDa molecule in immunoblots of T. cruzi epimastigote extracts. Confocal microscopy suggests that Tc/NICT is localized in the flagellar pocket, which is consistent with data from our previous studies with a T. cruzi presenilin-like protein. Phylogenetically, Tc/NICT was localized within a subgroup with the T. rangeli protein that is clearly detached from the other Trypanosomatidae, such as T. brucei. These results, together with a comparative analysis of the selected peptide sequence regions between the T. cruzi and mammalian proteins, suggest a divergence from the human NICT that might be relevant to Chagas disease pathology. As a whole, our data show that a NICT-like protein is expressed in the infective and replicative stages of T. cruzi and may be considered further evidence for a γ-secretase complex in trypanosomatids. Full article
(This article belongs to the Special Issue Current Insights and Challenges in Trypanosoma cruzi Genetics, Pathology, and Therapeutic Strategies)
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Graphical abstract

17 pages, 2674 KiB  
Article
Identification of Trypanosoma cruzi Growth Inhibitors with Activity In Vivo within a Collection of Licensed Drugs
by Nieves Martinez-Peinado, Nuria Cortes-Serra, Julian Sherman, Ana Rodriguez, Juan M. Bustamante, Joaquim Gascon, Maria-Jesus Pinazo and Julio Alonso-Padilla
Microorganisms 2021, 9(2), 406; https://doi.org/10.3390/microorganisms9020406 - 16 Feb 2021
Cited by 4 | Viewed by 2761
Abstract
Chagas disease, caused by the parasite Trypanosoma cruzi (T. cruzi), affects more than six million people worldwide, with its greatest burden in Latin America. Available treatments present frequent toxicity and variable efficacy at the chronic phase of the infection, when the disease [...] Read more.
Chagas disease, caused by the parasite Trypanosoma cruzi (T. cruzi), affects more than six million people worldwide, with its greatest burden in Latin America. Available treatments present frequent toxicity and variable efficacy at the chronic phase of the infection, when the disease is usually diagnosed. Hence, development of new therapeutic strategies is urgent. Repositioning of licensed drugs stands as an attractive fast-track low-cost approach for the identification of safer and more effective chemotherapies. With this purpose we screened 32 licensed drugs for different indications against T. cruzi. We used a primary in vitro assay of Vero cells infection by T. cruzi. Five drugs showed potent activity rates against it (IC50 < 4 µmol L−1), which were also specific (selectivity index >15) with respect to host cells. T. cruzi inhibitory activity of four of them was confirmed by a secondary anti-parasitic assay based on NIH-3T3 cells. Then, we assessed toxicity to human HepG2 cells and anti-amastigote specific activity of those drugs progressed. Ultimately, atovaquone-proguanil, miltefosine, and verapamil were tested in a mouse model of acute T. cruzi infection. Miltefosine performance in vitro and in vivo encourages further investigating its use against T. cruzi. Full article
(This article belongs to the Special Issue Current Insights and Challenges in Trypanosoma cruzi Genetics, Pathology, and Therapeutic Strategies)
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