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New Insights into Kinetoplastid Parasites: Molecular and Cellular Aspects

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

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 21473

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Dr. Rubem F. S. Menna-Barreto

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Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro 21040-360, CEP, Brazil
Interests: trypanosomatids; electron microscopy; mitochondria; oxidative stress; chemotherapy

Special Issue Information

Dear Colleagues,

Trypanosomatids are a group of protozoa that include Trypanosoma cruzi, Trypanosoma brucei and Leishmania spp., which are the etiological agents of Chagas disease, sleeping sickness and leishmaniasis, respectively. These diseases are classified as neglected tropical diseases associated with poverty, and affect millions of people worldwide. Other non-pathogenic trypanosomatids such as Angomonas deanei and Strigomonas culicis colonize a great variety of insects, and are also very interesting models, especially due to the presence of an endosymbiotic bacterium in the cytosol, providing an essential biosynthetic pathway for the protozoa. The current treatments of these diseases are unsatisfactory, showing limited efficacy and high toxicity in many cases. Trypanosomatids and their invertebrate or vertebrate hosts present a complex relationship and the balance is based on immune response and the protozoans’ virulence. It is clear that the success of the infection depends on cellular, biochemical and molecular mechanisms which are not completely known. The better comprehension of these checkpoints could contribute to the development of alternative anti-parasitic strategies in the future. In this scenario, oxidative stress plays a paradoxical role during protozoa infection, sometimes participating in the cell signaling and regulation, or presenting cytotoxicity, culminating in the parasite death. The description of antioxidant enzymes as virulence factors reinforces the importance of these molecular processes as well as the adaptative approaches of the trypanosomatids to survive in oxidative environments in the host and the implications for the success of the infection. On the other hand, autophagy is a physiological mechanism in eukaryotic cells to regulate homeostasis by the self-digestion of nonfunctional cellular structures, reducing the presence of redundant and damaged organelles and macromolecules. The contribution of autophagic process for the trypanosomatids has been described, especially in chemotherapy, subverting drugs’ effects. The scope of this Special Issue includes the cellular, molecular and biochemical features in trypanosomatids (including redox mechanisms and autophagy) that influence protozoa–host interactions. We will accept reviews or original contributions.

Dr. Rubem F. S. Menna-Barreto
Guest Editor

Manuscript Submission Information

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Keywords

trypanosomatids
Trypanosoma spp.
Leishmania spp.
monoxenic trypanosomatids
chemotherapy
molecular biology
cell biology
biochemistry
autophagy
oxidative stress

Published Papers (10 papers)

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Research

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12 pages, 2092 KiB

Open AccessArticle

Trypanosoma cruzi STIB980: A TcI Strain for Drug Discovery and Reverse Genetics

by Anna Fesser, Sabina Beilstein, Marcel Kaiser, Remo S. Schmidt and Pascal Mäser

Pathogens 2023, 12(10), 1217; https://doi.org/10.3390/pathogens12101217 - 4 Oct 2023

Cited by 1 | Viewed by 1193

Abstract

Since the first published genome sequence of Trypanosoma cruzi in 2005, there have been tremendous technological advances in genomics, reverse genetics, and assay development for this elusive pathogen. However, there is still an unmet need for new and better drugs to treat Chagas disease. Here, we introduce a T. cruzi assay strain that is useful for drug research and basic studies of host–pathogen interactions. T. cruzi STIB980 is a strain of discrete typing unit TcI that grows well in culture as axenic epimastigotes or intracellular amastigotes. We evaluated the optimal parameters for genetic transfection and constructed derivatives of T. cruzi STIB980 that express reporter genes for fluorescence- or bioluminescence-based drug efficacy testing, as well as a Cas9-expressing line for CRISPR/Cas9-mediated gene editing. The genome of T. cruzi STIB980 was sequenced by combining short-read Illumina with long-read Oxford Nanopore technologies. The latter served as the primary assembly and the former to correct mistakes. This resulted in a high-quality nuclear haplotype assembly of 28 Mb in 400 contigs, containing 10,043 open-reading frames with a median length of 1077 bp. We believe that T. cruzi STIB980 is a useful addition to the antichagasic toolbox and propose that it can serve as a DTU TcI reference strain for drug efficacy testing. Full article

(This article belongs to the Special Issue New Insights into Kinetoplastid Parasites: Molecular and Cellular Aspects)

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18 pages, 4860 KiB

Open AccessArticle

An X-Domain Phosphoinositide Phospholipase C (PI-PLC-like) of Trypanosoma brucei Has a Surface Localization and Is Essential for Proliferation

by Núria W. Negrão, Logan P. Crowe, Brian S. Mantilla, Rodrigo P. Baptista, Sharon King-Keller, Guozhong Huang and Roberto Docampo

Pathogens 2023, 12(3), 386; https://doi.org/10.3390/pathogens12030386 - 28 Feb 2023

Viewed by 1587

Abstract

Trypanosoma brucei is the causative agent of African trypanosomiasis, a deadly disease that affects humans and cattle. There are very few drugs to treat it, and there is evidence of mounting resistance, raising the need for new drug development. Here, we report the presence of a phosphoinositide phospholipase C (TbPI-PLC-like), containing an X and a PDZ domain, that is similar to the previously characterized TbPI-PLC1. TbPI-PLC-like only possesses the X catalytic domain and does not have the EF-hand, Y, and C2 domains, having instead a PDZ domain. Recombinant TbPI-PLC-like does not hydrolyze phosphatidylinositol 4,5-bisphosphate (PIP₂) and does not modulate TbPI-PLC1 activity in vitro. TbPI-PLC-like shows a plasma membrane and intracellular localization in permeabilized cells and a surface localization in non-permeabilized cells. Surprisingly, knockdown of TbPI-PLC-like expression by RNAi significantly affected proliferation of both procyclic and bloodstream trypomastigotes. This is in contrast with the lack of effect of downregulation of expression of TbPI-PLC1. Full article

(This article belongs to the Special Issue New Insights into Kinetoplastid Parasites: Molecular and Cellular Aspects)

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16 pages, 2794 KiB

Open AccessArticle

Screening the Pathogen Box to Discover and Characterize New Cruzain and TbrCatL Inhibitors

by Thales do Valle Moreira, Luan Carvalho Martins, Lucas Abreu Diniz, Talita Cristina Diniz Bernardes, Renata Barbosa de Oliveira and Rafaela Salgado Ferreira

Pathogens 2023, 12(2), 251; https://doi.org/10.3390/pathogens12020251 - 4 Feb 2023

Cited by 4 | Viewed by 2156

Abstract

Chagas disease and Human African Trypanosomiasis, caused by Trypanosoma cruzi and T. brucei, respectively, pose relevant health challenges throughout the world, placing 65 to 70 million people at risk each. Given the limited efficacy and severe side effects associated with current chemotherapy, new drugs are urgently needed for both diseases. Here, we report the screening of the Pathogen Box collection against cruzain and TbrCatL, validated targets for Chagas disease and Human African Trypanosomiasis, respectively. Enzymatic assays were applied to screen 400 compounds, validate hits, determine IC₅₀ values and, when possible, mechanisms of inhibition. In this case, 12 initial hits were obtained and ten were prioritized for follow-up. IC₅₀ values were obtained for six of them (hit rate = 1.5%) and ranged from 0.46 ± 0.03 to 27 ± 3 µM. MMV687246 was found to be a mixed inhibitor of cruzain (K_i = 57 ± 6 µM) while MMV688179 was found to be a competitive inhibitor of cruzain with a nanomolar potency (K_i = 165 ± 63 nM). A putative binding mode for MMV688179 was obtained by docking. The six hits discovered against cruzain and TbrCatL are of great interest for further optimization by the medicinal chemistry community. Full article

(This article belongs to the Special Issue New Insights into Kinetoplastid Parasites: Molecular and Cellular Aspects)

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20 pages, 3288 KiB

Open AccessArticle

The Anti-Leishmania amazonensis and Anti-Leishmania chagasi Action of Copper(II) and Silver(I) 1,10-Phenanthroline-5,6-dione Coordination Compounds

by Simone S. C. Oliveira, Vanessa S. Santos, Michael Devereux, Malachy McCann, André L. S. Santos and Marta H. Branquinha

Pathogens 2023, 12(1), 70; https://doi.org/10.3390/pathogens12010070 - 1 Jan 2023

Cited by 6 | Viewed by 2598

Abstract

Leishmaniasis is a neglected disease caused by protozoa belonging to the Leishmania genus. Notably, the search for new, promising and potent anti-Leishmania compounds remains a major goal due to the inefficacy of the available drugs used nowadays. In the present work, we evaluated the effects of 1,10-phenanthroline-5,6-dione (phendione) coordinated to silver(I), [Ag(phendione)₂]ClO₄ (Ag-phendione), and copper(II), [Cu(phendione)₃](ClO₄)₂·4H₂O (Cu-phendione), as potential drugs to be used in the chemotherapy against Leishmania amazonensis and Leishmania chagasi. The results showed that promastigotes treated with Ag-phendione and Cu-phendione presented a significant reduction in the proliferation rate. The IC₅₀ values calculated to Ag-phendione and Cu-phendione, respectively, were 7.8 nM and 7.5 nM for L. amazonensis and 24.5 nM and 20.0 nM for L. chagasi. Microscopical analyses revealed several relevant morphological changes in promastigotes, such as a rounding of the cell body and a shortening/loss of the single flagellum. Moreover, the treatment promoted alterations in the unique mitochondrion of these parasites, inducing significant reductions on both metabolic activity and membrane potential parameters. All these cellular perturbations induced the triggering of apoptosis-like death in these parasites, as judged by the (i) increased percentage of annexin-positive/propidium iodide negative cells, (ii) augmentation in the proportion of parasites in the sub-G₀/G₁ phase and (iii) DNA fragmentation. Finally, the test compounds showed potent effects against intracellular amastigotes; contrarily, these molecules were well tolerated by THP-1 macrophages, which resulted in excellent selective index values. Overall, the results highlight new selective and effective drugs against Leishmania species, which are important etiological agents of both cutaneous (L. amazonensis) and visceral (L. chagasi) leishmaniasis in a global perspective. Full article

(This article belongs to the Special Issue New Insights into Kinetoplastid Parasites: Molecular and Cellular Aspects)

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15 pages, 1704 KiB

Open AccessArticle

Hypoxia Effects on Trypanosoma cruzi Epimastigotes Proliferation, Differentiation, and Energy Metabolism

by Francis M. S. Saraiva, Daniela Cosentino-Gomes, Job D. F. Inacio, Elmo E. Almeida-Amaral, Orlando Louzada-Neto, Ana Rossini, Natália P. Nogueira, José R. Meyer-Fernandes and Marcia C. Paes

Pathogens 2022, 11(8), 897; https://doi.org/10.3390/pathogens11080897 - 9 Aug 2022

Cited by 4 | Viewed by 2068

Abstract

Trypanosoma cruzi, the causative agent of Chagas disease, faces changes in redox status and nutritional availability during its life cycle. However, the influence of oxygen fluctuation upon the biology of T. cruzi is unclear. The present work investigated the response of T. cruzi epimastigotes to hypoxia. The parasites showed an adaptation to the hypoxic condition, presenting an increase in proliferation and a reduction in metacyclogenesis. Additionally, parasites cultured in hypoxia produced more reactive oxygen species (ROS) compared to parasites cultured in normoxia. The analyses of the mitochondrial physiology demonstrated that hypoxic condition induced a decrease in both oxidative phosphorylation and mitochondrial membrane potential (ΔΨm) in epimastigotes. In spite of that, ATP levels of parasites cultivated in hypoxia increased. The hypoxic condition also increased the expression of the hexokinase and NADH fumarate reductase genes and reduced NAD(P)H, suggesting that this increase in ATP levels of hypoxia-challenged parasites was a consequence of increased glycolysis and fermentation pathways. Taken together, our results suggest that decreased oxygen levels trigger a shift in the bioenergetic metabolism of T. cruzi epimastigotes, favoring ROS production and fermentation to sustain ATP production, allowing the parasite to survive and proliferate in the insect vector. Full article

(This article belongs to the Special Issue New Insights into Kinetoplastid Parasites: Molecular and Cellular Aspects)

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15 pages, 1658 KiB

Open AccessArticle

Stable Episomal Transfectant Leishmania infantum Promastigotes Over-Expressing the DEVH1 RNA Helicase Gene Down-Regulate Parasite Survival Genes

by Ana Alonso, Jaime Larraga, Francisco Javier Loayza, Enrique Martínez, Basilio Valladares, Vicente Larraga and Pedro José Alcolea

Pathogens 2022, 11(7), 761; https://doi.org/10.3390/pathogens11070761 - 4 Jul 2022

Cited by 1 | Viewed by 1484

Abstract

The compartmentalization of untranslated mRNA molecules in granules occurring in many eukaryotic organisms including trypanosomatids involves the formation of complexes between mRNA molecules and RNA-binding proteins (RBPs). The putative ATP-dependent DEAD/H RNA helicase (DEVH1) from Leishmania infantum (Kinetoplastida: Trypanosomatidae) is one such proteins. The objective of this research is finding differentially expressed genes in a stable episomal transfectant L. infantum promastigote line over-expressing DEVH1 in the stationary phase of growth in axenic culture to get insight into the biological roles of this RNA helicase in the parasite. Interestingly, genes related to parasite survival and virulence factors, such as the hydrophilic surface protein/small hydrophilic endoplasmic reticulum protein (HASP/SHERP) gene cluster, an amastin, and genes related to reactive oxygen species detoxification are down-regulated in DEVH1 transfectant promastigotes. Full article

(This article belongs to the Special Issue New Insights into Kinetoplastid Parasites: Molecular and Cellular Aspects)

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Review

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32 pages, 2772 KiB

Open AccessReview

Advances in the Immunology of the Host–Parasite Interactions in African Trypanosomosis, including Single-Cell Transcriptomics

by Boyoon Choi, Hien Thi Vu, Hai Thi Vu, Magdalena Radwanska and Stefan Magez

Pathogens 2024, 13(3), 188; https://doi.org/10.3390/pathogens13030188 - 20 Feb 2024

Viewed by 1998

Abstract

Trypanosomes are single-celled extracellular parasites that infect mammals, including humans and livestock, causing global public health concerns and economic losses. These parasites cycle between insect vectors, such as tsetse flies and vertebrate hosts, undergoing morphological, cellular, and biochemical changes. They have remarkable immune evasion mechanisms to escape the host’s innate and adaptive immune responses, such as surface coat antigenic variation and the induction of the loss of specificity and memory of antibody responses, enabling the prolongation of infection. Since trypanosomes circulate through the host body in blood and lymph fluid and invade various organs, understanding the interaction between trypanosomes and tissue niches is essential. Here, we present an up-to-date overview of host–parasite interactions and survival strategies for trypanosomes by introducing and discussing the latest studies investigating the transcriptomics of parasites according to life cycle stages, as well as host cells in various tissues and organs, using single-cell and spatial sequencing applications. In recent years, this information has improved our understanding of trypanosomosis by deciphering the diverse populations of parasites in the developmental process, as well as the highly heterogeneous immune and tissue-resident cells involved in anti-trypanosome responses. Ultimately, the goal of these approaches is to gain an in-depth understanding of parasite biology and host immunity, potentially leading to new vaccination and therapeutic strategies against trypanosomosis. Full article

(This article belongs to the Special Issue New Insights into Kinetoplastid Parasites: Molecular and Cellular Aspects)

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36 pages, 17599 KiB

Open AccessReview

Recent Advances in Chemotherapeutics for Leishmaniasis: Importance of the Cellular Biochemistry of the Parasite and Its Molecular Interaction with the Host

by Ranjeet Singh, Mohammad Kashif, Prateek Srivastava and Partha Pratim Manna

Pathogens 2023, 12(5), 706; https://doi.org/10.3390/pathogens12050706 - 12 May 2023

Cited by 8 | Viewed by 3400

Abstract

Leishmaniasis, a category 1 neglected protozoan disease caused by a kinetoplastid pathogen called Leishmania, is transmitted through dipteran insect vectors (phlebotomine, sand flies) in three main clinical forms: fatal visceral leishmaniasis, self-healing cutaneous leishmaniasis, and mucocutaneous leishmaniasis. Generic pentavalent antimonials have long been the drug of choice against leishmaniasis; however, their success is plagued with limitations such as drug resistance and severe side effects, which makes them redundant as frontline therapy for endemic visceral leishmaniasis. Alternative therapeutic regimens based on amphotericin B, miltefosine, and paromomycin have also been approved. Due to the unavailability of human vaccines, first-line chemotherapies such as pentavalent antimonials, pentamidine, and amphotericin B are the only options to treat infected individuals. The higher toxicity, adverse effects, and perceived cost of these pharmaceutics, coupled with the emergence of parasite resistance and disease relapse, makes it urgent to identify new, rationalized drug targets for the improvement in disease management and palliative care for patients. This has become an emergent need and more relevant due to the lack of information on validated molecular resistance markers for the monitoring and surveillance of changes in drug sensitivity and resistance. The present study reviewed the recent advances in chemotherapeutic regimens by targeting novel drugs using several strategies including bioinformatics to gain new insight into leishmaniasis. Leishmania has unique enzymes and biochemical pathways that are distinct from those of its mammalian hosts. In light of the limited number of available antileishmanial drugs, the identification of novel drug targets and studying the molecular and cellular aspects of these drugs in the parasite and its host is critical to design specific inhibitors targeting and controlling the parasite. The biochemical characterization of unique Leishmania-specific enzymes can be used as tools to read through possible drug targets. In this review, we discuss relevant metabolic pathways and novel drugs that are unique, essential, and linked to the survival of the parasite based on bioinformatics and cellular and biochemical analyses. Full article

(This article belongs to the Special Issue New Insights into Kinetoplastid Parasites: Molecular and Cellular Aspects)

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14 pages, 4042 KiB

Open AccessReview

Behind Base J: The Roles of JBP1 and JBP2 on Trypanosomatids

by Luiz Henrique de Castro Assis, Stephany Cacete de Paiva and Maria Isabel Nogueira Cano

Pathogens 2023, 12(3), 467; https://doi.org/10.3390/pathogens12030467 - 16 Mar 2023

Viewed by 1454

Abstract

β-D-glucopyranosyloxymethiluracil (Base J) is a modified thymidine base found in kinetoplastids and some related organisms. Interestingly, Base J distribution into the genome can vary depending on the organism and its life stage. Base J is reported to be found mostly at telomeric repeats, on inactive variant surface glycoproteins (VSG’s) expression sites (e.g., T. brucei), in RNA polymerase II termination sites and sub-telomeric regions (e.g., Leishmania). This hypermodified nucleotide is synthesized in two steps with the participation of two distinct thymidine hydroxylases, J-binding protein 1 and 2 (JBP1 and JBP2, respectively) and a β-glucosyl transferase. A third J-binding protein, named JBP3, was recently identified as part of a multimeric complex. Although its structural similarities with JBP1, it seems not to be involved in J biosynthesis but to play roles in gene expression regulation in trypanosomatids. Over the years, with the characterization of JBP1 and JBP2 mutant lines, Base J functions have been targeted and shone a light on that matter, showing genus-specific features. This review aims to explore Base J’s reported participation as a regulator of RNA polymerase II transcription termination and to summarize the functional and structural characteristics and similarities of the remarkable JBP proteins in pathogenic trypanosomatids. Full article

(This article belongs to the Special Issue New Insights into Kinetoplastid Parasites: Molecular and Cellular Aspects)

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22 pages, 1368 KiB

Open AccessReview

The History of the ABC Proteins in Human Trypanosomiasis Pathogens

by Kelli Monteiro da Costa, Raphael do Carmo Valente, Leonardo Marques da Fonseca, Leonardo Freire-de-Lima, Jose Osvaldo Previato and Lucia Mendonça-Previato

Pathogens 2022, 11(9), 988; https://doi.org/10.3390/pathogens11090988 - 30 Aug 2022

Cited by 3 | Viewed by 2085

Abstract

Human trypanosomiasis affects nearly eight million people worldwide, causing great economic and social impact, mainly in endemic areas. T. cruzi and T. brucei are protozoan parasites that present efficient mechanisms of immune system evasion, leading to disease chronification. Currently, there is no vaccine, and chemotherapy is effective only in the absence of severe clinical manifestations. Nevertheless, resistant phenotypes to chemotherapy have been described in protozoan parasites, associated with cross-resistance to other chemically unrelated drugs. Multidrug resistance is multifactorial, involving: (i) drug entry, (ii) activation, (iii) metabolism and (iv) efflux pathways. In this context, ABC transporters, initially discovered in resistant tumor cells, have drawn attention in protozoan parasites, owing to their ability to decrease drug accumulation, thus mitigating their toxic effects. The discovery of these transporters in the Trypanosomatidae family started in the 1990s; however, few members were described and functionally characterized. This review contains a brief history of the main ABC transporters involved in resistance that propelled their investigation in Trypanosoma species, the main efflux modulators, as well as ABC genes described in T. cruzi and T. brucei according to the nomenclature HUGO. We hope to convey the importance that ABC transporters play in parasite physiology and chemotherapy resistance. Full article

(This article belongs to the Special Issue New Insights into Kinetoplastid Parasites: Molecular and Cellular Aspects)

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