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Frontiers in Cellular and Infection... 2022
Topics: Animals; Parasites; Trypanosoma cruzi; Host-Parasite Interactions
PubMed: 36601303
DOI: 10.3389/fcimb.2022.1054309 -
Cell Calcium Mar 2015Calcium ion (Ca(2+)) is an important second messenger in trypanosomatids and essential for their survival although prolonged high intracellular Ca(2+) levels lead to... (Review)
Review
Calcium ion (Ca(2+)) is an important second messenger in trypanosomatids and essential for their survival although prolonged high intracellular Ca(2+) levels lead to cell death. As other eukaryotic cells, trypanosomes use two sources of Ca(2+) for generating signals: Ca(2+) release from intracellular stores and Ca(2+) entry across the plasma membrane. Ca(2+) release from intracellular stores is controlled by the inositol 1,4,5-trisphosphate receptor (IP3R) that is located in acidocalcisomes, acidic organelles that are the primary Ca(2+) reservoir in these cells. A plasma membrane Ca(2+)-ATPase controls the cytosolic Ca(2+) levels and a number of pumps and exchangers are responsible for Ca(2+) uptake and release from intracellular compartments. The trypanosomatid genomes contain a wide variety of signaling and regulatory proteins that bind Ca(2+) as well as many Ca(2+)-binding proteins that await further characterization. The mitochondrial Ca(2+) transporters of trypanosomatids have an important role in the regulation of cell bioenergetics and flagellar Ca(2+) appears to have roles in sensing the environment. In trypanosomatids in which an intracellular life cycle is present, Ca(2+) signaling is important for host cell invasion.
Topics: Animals; Calcium Signaling; Humans; Parasites; Trypanosoma
PubMed: 25468729
DOI: 10.1016/j.ceca.2014.10.015 -
Trends in Parasitology Feb 2019Inheritance of the single mitochondrial nucleoid (kinetoplast) in the trypanosome requires numerous proteins, many of whose precise roles are unclear. By considering... (Review)
Review
Inheritance of the single mitochondrial nucleoid (kinetoplast) in the trypanosome requires numerous proteins, many of whose precise roles are unclear. By considering kinetoplast DNA (kDNA) as a template for cleavage into two equal-size networks, we predicted sets of mutant kinetoplasts associated with defects in each of the five steps in the kinetoplast cycle. Comparison of these kinetoplasts with those obtained after gene knockdowns enabled assignment of proteins to five classes - kDNA synthesis, site of scission selection, scission, separation, and partitioning. These studies highlight how analysis of mutant kinetoplast phenotypes may be used to predict functional categories of proteins involved in the biogenesis of kinetoplasts.
Topics: DNA, Kinetoplast; Mutation; Protozoan Proteins; Terminology as Topic; Trypanosoma
PubMed: 30638954
DOI: 10.1016/j.pt.2018.11.002 -
Genes Jun 2020Leishmaniasis ( species), sleeping sickness (), and Chagas disease () are devastating and globally spread diseases caused by trypanosomatid parasites. At present, drugs... (Review)
Review
Leishmaniasis ( species), sleeping sickness (), and Chagas disease () are devastating and globally spread diseases caused by trypanosomatid parasites. At present, drugs for treating trypanosomatid diseases are far from ideal due to host toxicity, elevated cost, limited access, and increasing rates of drug resistance. Technological advances in parasitology, chemistry, and genomics have unlocked new possibilities for novel drug concepts and compound screening technologies that were previously inaccessible. In this perspective, we discuss current models used in drug-discovery cascades targeting trypanosomatids (from in vitro to in vivo approaches), their use and limitations in a biological context, as well as different examples of recently discovered lead compounds.
Topics: Animals; Anthelmintics; Cheminformatics; Drug Discovery; Genome, Protozoan; Genomics; Humans; Trypanosoma; Trypanosomiasis
PubMed: 32610603
DOI: 10.3390/genes11070722 -
PLoS Pathogens Sep 2021Trypanosoma brucei is a protozoan parasite that causes human and animal African trypanosomiases (HAT and AAT). In the mammalian host, the parasite lives entirely... (Review)
Review
Trypanosoma brucei is a protozoan parasite that causes human and animal African trypanosomiases (HAT and AAT). In the mammalian host, the parasite lives entirely extracellularly, in both the blood and interstitial spaces in tissues. Although most T. brucei research has focused on the biology of blood- and central nervous system (CNS)-resident parasites, a number of recent studies have highlighted parasite reservoirs in the dermis and adipose tissue, leading to a renewed interest in tissue-resident parasite populations. In light of this renewed interest, work describing tissue-resident parasites can serve as a valuable resource to inform future investigations of tissue-resident T. brucei. Here, we review this body of literature, which describes infections in humans, natural hosts, and experimental animal models, providing a wealth of information on the distribution and biology of extravascular parasites, the corresponding immune response in each tissue, and resulting host pathology. We discuss the implications of these studies and future questions in the study of extravascular T. brucei.
Topics: Animals; Host-Parasite Interactions; Humans; Trypanosoma brucei brucei; Trypanosomiasis, African
PubMed: 34529724
DOI: 10.1371/journal.ppat.1009866 -
Trends in Parasitology Mar 2020African trypanosomes are mainly transmitted by tsetse flies. In recent years there has been good progress in understanding how the parasites prepare for transmission,... (Review)
Review
African trypanosomes are mainly transmitted by tsetse flies. In recent years there has been good progress in understanding how the parasites prepare for transmission, detect their changed environment through the perception of different environmental cues, and respond by changing their developmental gene expression. In this review, we discuss the different signals and signaling mechanisms used by the parasites to carry out the early events necessary for their establishment in the fly. We also compare Trypanosoma brucei and Trypanosoma congolense, parasites that share a common pathway in the early stages of fly colonization but apparently use different mechanisms to achieve this.
Topics: Animals; Environment; Gene Expression Regulation, Developmental; Humans; Signal Transduction; Trypanosoma; Trypanosomiasis, African
PubMed: 32014419
DOI: 10.1016/j.pt.2019.12.011 -
International Journal For Parasitology.... Dec 2021Kinetoplastid parasites are the causative agents of Chagas disease (CD), leishmaniasis and human African trypanosomiasis (HAT). Despite a sustained decrease in the...
Kinetoplastid parasites are the causative agents of Chagas disease (CD), leishmaniasis and human African trypanosomiasis (HAT). Despite a sustained decrease in the number of HAT cases, more efforts are needed to discover safe and effective therapies against CD and leishmaniasis. Kinetoplastid parasites lack the capability to biosynthesize purines de novo and thus critically depend on uptake and processing of purines from host cells. As such, modified purine nucleoside analogues may act as broad-spectrum antikinetoplastid agents. This study assessed the in vitro activity profile of 7-modified 6-methyl tubercidin derivatives against Trypanosoma cruzi, Leishmania infantum, Trypanosoma brucei brucei and T. b. rhodesiense, and led to the identification of analogues that display activity against all these species, such as 7-ethyl (13) and 7-chloro (7) analogues. These selected analogues also proved sufficiently stable in liver microsomes to warrant in vivo follow-up evaluation.
Topics: Antiprotozoal Agents; Humans; Nucleosides; Purines; Structure-Activity Relationship; Trypanosoma brucei brucei; Trypanosoma cruzi
PubMed: 34375904
DOI: 10.1016/j.ijpddr.2021.08.001 -
The Journal of Eukaryotic Microbiology Nov 2019CRISPR/Cas9 technology has revolutionized biology. This prokaryotic defense system against foreign DNA has been repurposed for genome editing in a broad range of cell... (Review)
Review
CRISPR/Cas9 technology has revolutionized biology. This prokaryotic defense system against foreign DNA has been repurposed for genome editing in a broad range of cell tissues and organisms. Trypanosomatids are flagellated protozoa belonging to the order Kinetoplastida. Some of its most representative members cause important human diseases affecting millions of people worldwide, such as Chagas disease, sleeping sickness and different forms of leishmaniases. Trypanosomatid infections represent an enormous burden for public health and there are no effective treatments for most of the diseases they cause. Since the emergence of the CRISPR/Cas9 technology, the genetic manipulation of these parasites has notably improved. As a consequence, genome editing is now playing a key role in the functional study of proteins, in the characterization of metabolic pathways, in the validation of alternative targets for antiparasitic interventions, and in the study of parasite biology and pathogenesis. In this work we review the different strategies that have been used to adapt the CRISPR/Cas9 system to Trypanosoma cruzi, Trypanosoma brucei, and Leishmania spp., as well as the research progress achieved using these approaches. Thereby, we will present the state-of-the-art molecular tools available for genome editing in trypanosomatids to finally point out the future perspectives in the field.
Topics: CRISPR-Cas Systems; Gene Editing; Genome, Protozoan; Leishmania; Trypanosoma
PubMed: 31211904
DOI: 10.1111/jeu.12747 -
Mathematical Biosciences and... Jun 2022In this paper, an insect-parasite-host model with logistic growth of triatomine bugs is formulated to study the transmission between hosts and vectors of the Chagas...
In this paper, an insect-parasite-host model with logistic growth of triatomine bugs is formulated to study the transmission between hosts and vectors of the Chagas disease by using dynamical system approach. We derive the basic reproduction numbers for triatomine bugs and as two thresholds. The local and global stability of the vector-free equilibrium, parasite-free equilibrium and parasite-positive equilibrium is investigated through the derived two thresholds. Forward bifurcation, saddle-node bifurcation and Hopf bifurcation are proved analytically and illustrated numerically. We show that the model can lose the stability of the vector-free equilibrium and exhibit a supercritical Hopf bifurcation, indicating the occurrence of a stable limit cycle. We also find it unlikely to have backward bifurcation and Bogdanov-Takens bifurcation of the parasite-positive equilibrium. However, the sustained oscillations of infected vector population suggest that will persist in all the populations, posing a significant challenge for the prevention and control of Chagas disease.
Topics: Animals; Chagas Disease; Disease Vectors; Rhodnius; Trypanosoma cruzi; Trypanosoma rangeli
PubMed: 35801473
DOI: 10.3934/mbe.2022393 -
ELife May 2023African trypanosomes proliferate as bloodstream forms (BSFs) and procyclic forms in the mammal and tsetse fly midgut, respectively. This allows them to colonise the host...
African trypanosomes proliferate as bloodstream forms (BSFs) and procyclic forms in the mammal and tsetse fly midgut, respectively. This allows them to colonise the host environment upon infection and ensure life cycle progression. Yet, understanding of the mechanisms that regulate and drive the cell replication cycle of these forms is limited. Using single-cell transcriptomics on unsynchronised cell populations, we have obtained high resolution cell cycle regulated (CCR) transcriptomes of both procyclic and slender BSF without prior cell sorting or synchronisation. Additionally, we describe an efficient freeze-thawing protocol that allows single-cell transcriptomic analysis of cryopreserved . Computational reconstruction of the cell cycle using periodic pseudotime inference allowed the dynamic expression patterns of cycling genes to be profiled for both life cycle forms. Comparative analyses identify a core cycling transcriptome highly conserved between forms, as well as several genes where transcript levels dynamics are form specific. Comparing transcript expression patterns with protein abundance revealed that the majority of genes with periodic cycling transcript and protein levels exhibit a relative delay between peak transcript and protein expression. This work reveals novel detail of the CCR transcriptomes of both forms, which are available for further interrogation via an interactive webtool.
Topics: Trypanosoma; Single-Cell Gene Expression Analysis; Cryopreservation; RNA, Protozoan; Protozoan Proteins
PubMed: 37166108
DOI: 10.7554/eLife.86325