scholarly journals The Functioning of Na+-ATPases from Protozoan Parasites: Are These Pumps Targets for Antiparasitic Drugs?

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2225
Author(s):  
Claudia F. Dick ◽  
José Roberto Meyer-Fernandes ◽  
Adalberto Vieyra
Keyword(s):  
Plasmodium Falciparum ◽  
Toxoplasma Gondii ◽  
Mammalian Cells ◽  
Life Cycles ◽  
Therapeutic Interventions ◽  
Potential Candidate ◽  
Protozoan Parasites ◽  
Antiparasitic Drugs ◽  
P Type ◽  
Structural Homologue

The ENA ATPases (from exitus natru: the exit of sodium) belonging to the P-type ATPases are structurally very similar to the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA); they exchange Na+ for H+ and, therefore, are also known as Na+-ATPases. ENA ATPases are required in alkaline milieu, as in the case for Aspergillus, where other transporters cannot mediate an uphill Na+ efflux. They are also important for salt tolerance, as described for Arabidopsis. During their life cycles, protozoan parasites might encounter a high pH environment, thus allowing consideration of ENA ATPases as possible targets for controlling certain severe parasitic diseases, such as Chagas’ Disease. Phylogenetic analysis has now shown that, besides the types IIA, IIB, IIC, and IID P-type ATPases, there exists a 5th subgroup of ATPases classified as ATP4-type ATPases, found in Plasmodium falciparum and Toxoplasma gondii. In malaria, for example, some drugs targeting PfATP4 destroy Na+ homeostasis; these drugs, which include spiroindolones, are now in clinical trials. The ENA P-type (IID P-type ATPase) and ATP4-type ATPases have no structural homologue in mammalian cells, appearing only in fungi, plants, and protozoan parasites, e.g., Trypanosoma cruzi, Leishmania sp., Toxoplasma gondii, and Plasmodium falciparum. This exclusivity makes Na+-ATPase a potential candidate for the biologically-based design of new therapeutic interventions; for this reason, Na+-ATPases deserves more attention.

scholarly journals Intracellular Ca2+ Signaling in Protozoan Parasites: An Overview with a Focus on Mitochondria

2021 ◽  
Vol 22 (1) ◽  
pp. 469
Author(s):  
Pedro H. Scarpelli ◽  
Mateus F. Pecenin ◽  
Celia R. S. Garcia
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Plasmodium Falciparum ◽  
Toxoplasma Gondii ◽  
Trypanosoma Cruzi ◽  
Cell Cycle Control ◽  
Endoplasmatic Reticulum ◽  
Protozoan Parasites ◽  
Cellular Functions ◽  
Higher Eukaryotes

Ca2+ signaling has been involved in controling critical cellular functions such as activation of proteases, cell death, and cell cycle control. The endoplasmatic reticulum plays a significant role in Ca2+ storage inside the cell, but mitochondria have long been recognized as a fundamental Ca2+ pool. Protozoan parasites such as Plasmodium falciparum, Toxoplasma gondii, and Trypanosoma cruzi display a Ca2+ signaling toolkit with similarities to higher eukaryotes, including the participation of mitochondria in Ca2+-dependent signaling events. This review summarizes the most recent knowledge in mitochondrial Ca2+ signaling in protozoan parasites, focusing on the mechanism involved in mitochondrial Ca2+ uptake by pathogenic protists.

scholarly journals Upstream Open Reading Frames (uORFs) in the Apicomplexan Parasites Plasmodium falciparum and Toxoplasma gondii: Small yet Powerful Regulators of Translation

2021 ◽  
Author(s):  
Chhaminder Kaur ◽  
Swati Patankar
Keyword(s):  
Gene Expression ◽  
Plasmodium Falciparum ◽  
Toxoplasma Gondii ◽  
Translational Regulation ◽  
Life Cycles ◽  
Ribosome Profiling ◽  
Open Reading Frames ◽  
Apicomplexan Parasites ◽  
Upstream Open Reading Frames ◽  
Reading Frames

During their complex life cycles, the Apicomplexan parasites, Plasmodium falciparum and Toxoplasma gondii employ several genetic switches to regulate their gene expression. One such switch is mediated at the level of translation through upstream Open Reading Frames (uORFs). As uORFs are found in the upstream regions of a majority of genes in both the parasites, it is essential that their roles in translational regulation be appreciated to a greater extent. This review provides a comprehensive summary of studies that show uORF-mediated gene regulation in these parasites and highlights examples of clinically and physiologically relevant proteins that exhibit uORF-mediated regulation. In addition to these examples, several studies that use bioinformatics, transcriptomics, proteomics, and ribosome profiling also indicate the possibility of widespread translational regulation by uORFs. Further analysis of genome-wide datasets will reveal novel genes involved in key biological pathways such as cell-cycle progression, stress-response, and pathogenicity. The cumulative evidence from studies presented in this review suggests that uORFs will play crucial roles in regulating gene expression during clinical disease caused by these important human pathogens.

scholarly journals Lipid and fatty acid metabolism in trypanosomatids

2021 ◽  
Vol 8 (11) ◽  
pp. 262-275
Author(s):  
Giovana Parreira de Aquino ◽  
Marco Antonio Mendes Gomes ◽  
Roberto Köpke Salinas ◽  
Maria Fernanda Laranjeira-Silva
Keyword(s):  
De Novo ◽  
Neglected Tropical Diseases ◽  
Treatment Options ◽  
Life Cycles ◽  
Protozoan Parasites ◽  
Life Cycle Stages ◽  
Leishmania Spp ◽  
Causative Agents ◽  
Major Energy Source ◽  
Antiparasitic Drugs

Trypanosomiases and leishmaniases are neglected tropical diseases that have been spreading to previously non-affected areas in recent years. Identification of new chemotherapeutics is needed as there are no vaccines and the currently available treatment options are highly toxic and often ineffective. The causative agents for these diseases are the protozoan parasites of the Trypanosomatidae family, and they alternate between invertebrate and vertebrate hosts during their life cycles. Hence, these parasites must be able to adapt to different environments and compete with their hosts for several essential compounds, such as amino acids, vitamins, ions, carbohydrates, and lipids. Among these nutrients, lipids and fatty acids (FAs) are essential for parasite survival. Trypanosomatids require massive amounts of FAs, and they can either synthesize FAs de novo or scavenge them from the host. Moreover, FAs are the major energy source during specific life cycle stages of T. brucei, T. cruzi, and Leishmania. Therefore, considering the distinctive features of FAs metabolism in trypanosomatids, these pathways could be exploited for the development of novel antiparasitic drugs. In this review, we highlight specific aspects of lipid and FA metabolism in the protozoan parasites T. brucei, T. cruzi, and Leishmania spp., as well as the pathways that have been explored for the development of new chemotherapies.

scholarly journals Pathomechanisms in the Kidneys in Selected Protozoan Parasitic Infections

2021 ◽  
Vol 22 (8) ◽  
pp. 4209
Author(s):  
Karolina Kot ◽  
Natalia Łanocha-Arendarczyk ◽  
Michał Ptak ◽  
Aleksandra Łanocha ◽  
Elżbieta Kalisińska ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Molecular Mechanisms ◽  
Kidney Injury ◽  
Therapeutic Interventions ◽  
Parasitic Infections ◽  
Injury Mechanisms ◽  
Kidney Involvement ◽  
Leishmania Spp ◽  
Apoptosis Process ◽  
Insight Into

Leishmaniasis, malaria, toxoplasmosis, and acanthamoebiasis are protozoan parasitic infections. They remain important contributors to the development of kidney disease, which is associated with increased patients’ morbidity and mortality. Kidney injury mechanisms are not fully understood in protozoan parasitic diseases, bringing major difficulties to specific therapeutic interventions. The aim of this review is to present the biochemical and molecular mechanisms in kidneys infected with Leishmania spp., Plasmodium spp., Toxoplasma gondii, and Acanthamoeba spp. We present available mechanisms of an immune response, oxidative stress, apoptosis process, hypoxia, biomarkers of renal injury in the serum or urine, and the histopathological changes of kidneys infected with the selected parasites. Pathomechanisms of Leishmania spp. and Plasmodium spp. infections have been deeply investigated, while Toxoplasma gondii and Acanthamoeba spp. infections in the kidneys are not well known yet. Deeper knowledge of kidney involvement in leishmaniasis and malaria by presenting their mechanisms provides insight into how to create novel and effective treatments. Additionally, the presented work shows gaps in the pathophysiology of renal toxoplasmosis and acanthamoebiasis, which need further research.

scholarly journals Correction: The PH domain from the Toxoplasma gondii PH-containing protein-1 (TgPH1) serves as an ectopic reporter of phosphatidylinositol 3-phosphate in mammalian cells

PLoS ONE ◽  
2018 ◽  
Vol 13 (7) ◽  
pp. e0201800 ◽  
Author(s):  
Krishna Chintaluri ◽  
Brady D. Goulden ◽  
Camilyn Clemenza ◽  
Golam Saffi ◽  
Emily Miraglia ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Mammalian Cells ◽  
Ph Domain ◽  
Phosphatidylinositol 3

scholarly journals Apicortin, a Constituent of Apicomplexan Conoid/Apical Complex and Its Tentative Role in Pathogen—Host Interaction

2021 ◽  
Vol 6 (3) ◽  
pp. 118
Author(s):  
Ferenc Orosz
Keyword(s):  
Plasmodium Falciparum ◽  
Toxoplasma Gondii ◽  
Therapeutic Target ◽  
In Silico ◽  
Free Living ◽  
Binding Properties ◽  
Host Interactions ◽  
Trichoplax Adhaerens ◽  
Host Interaction ◽  
Apical Complex

In 2009, apicortin was identified in silico as a characteristic protein of apicomplexans that also occurs in the placozoa, Trichoplax adhaerens. Since then, it has been found that apicortin also occurs in free-living cousins of apicomplexans (chromerids) and in flagellated fungi. It contains a partial p25-α domain and a doublecortin (DCX) domain, both of which have tubulin/microtubule binding properties. Apicortin has been studied experimentally in two very important apicomplexan pathogens, Toxoplasma gondii and Plasmodium falciparum. It is localized in the apical complex in both parasites. In T. gondii, apicortin plays a key role in shaping the structure of a special tubulin polymer, conoid. In both parasites, its absence or downregulation has been shown to impair pathogen–host interactions. Based on these facts, it has been suggested as a therapeutic target for treatment of malaria and toxoplasmosis.

Actomyosin motor in the merozoite of the malaria parasite, Plasmodium falciparum: implications for red cell invasion

1998 ◽  
Vol 111 (13) ◽  
pp. 1831-1839 ◽  
Author(s):  
J.C. Pinder ◽  
R.E. Fowler ◽  
A.R. Dluzewski ◽  
L.H. Bannister ◽  
F.M. Lavin ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Plasma Membrane ◽  
Toxoplasma Gondii ◽  
Malaria Parasite ◽  
Cellular Protein ◽  
Red Cell ◽  
Parasite Protein ◽  
Ionic Detergent ◽  
Parasite Plasmodium ◽  
Parasite Plasmodium Falciparum

The genome of the malaria parasite, Plasmodium falciparum, contains a myosin gene sequence, which bears a close homology to one of the myosin genes found in another apicomplexan parasite, Toxoplasma gondii. A polyclonal antibody was generated against an expressed polypeptide of molecular mass 27,000, based on part of the deduced sequence of this myosin. The antibody reacted with the cognate antigen and with a component of the total parasite protein on immunoblots, but not with vertebrate striated or smooth muscle myosins. It did, however, recognise two components in the cellular protein of Toxoplasma gondii. The antibody was used to investigate stage-specificity of expression of the myosin (here designated Pf-myo1) in P. falciparum. The results showed that the protein is synthesised in mature schizonts and is present in merozoites, but vanishes after the parasite enters the red cell. Pf-myo1 was found to be largely, though not entirely, associated with the particulate parasite cell fraction and is thus presumably mainly membrane bound. It was not solubilised by media that would be expected to dissociate actomyosin or myosin filaments, or by non-ionic detergent. Immunofluorescence revealed that in the merozoite and mature schizont Pf-myo1 is predominantly located around the periphery of the cell. Immuno-gold electron microscopy also showed the presence of the myosin around almost the entire parasite periphery, and especially in the region surrounding the apical prominence. Labelling was concentrated under the plasma membrane but was not seen in the apical prominence itself. This suggests that Pf-myo1 is associated with the plasma membrane or with the outer membrane of the subplasmalemmal cisterna, which forms a lining to the plasma membrane, with a gap at the apical prominence. The results lead to a conjectural model of the invasion mechanism.

Associations between varied susceptibilities of PfATP4 inhibitors and genotypes in Ugandan Plasmodium falciparum isolates

2021 ◽  
Author(s):  
Oriana Kreutzfeld ◽  
Stephanie A. Rasmussen ◽  
Aarti A. Ramanathan ◽  
Patrick K. Tumwebaze ◽  
Oswald Byaruhanga ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Single Nucleotide Polymorphisms ◽  
Ex Vivo ◽  
Nucleotide Polymorphisms ◽  
Wild Type ◽  
Single Nucleotide ◽  
Field Isolates ◽  
Frequent Mutations ◽  
Mixed Field ◽  
P Type

Among novel compounds under recent investigation as potential new antimalarial drugs are three independently developed inhibitors of the Plasmodium falciparum P-type ATPase (PfATP4): KAE609 (cipargamin), PA92, and SJ733. We assessed ex vivo susceptibilities to these compounds of 374 fresh P. falciparum isolates collected in Tororo and Busia districts, Uganda from 2016-2019. Median IC 50 s were 65 nM for SJ733, 9.1 nM for PA92, and 0.5 nM for KAE609. Sequencing of pfatp4 for 218 of these isolates demonstrated many non-synonymous single nucleotide polymorphisms; the most frequent mutations were G1128R (69% of isolates mixed or mutant), Q1081K/R (68%), G223S (25%), N1045K (16%) and D1116G/N/Y (16%). The G223S mutation was associated with decreased susceptibility to SJ733, PA92 and KAE609. The D1116G/N/Y mutations were associated with decreased susceptibility to SJ733, and the presence of mutations at both codons 223 and 1116 was associated with decreased susceptibility to PA92 and SJ733. In all of these cases, absolute differences in susceptibilities of wild type (WT) and mutant parasites were modest. Analysis of clones separated from mixed field isolates consistently identified mutant clones as less susceptible than WT. Analysis of isolates from other sites demonstrated presence of the G223S and D1116G/N/Y mutations across Uganda. Our results indicate that malaria parasites circulating in Uganda have a number of polymorphisms in PfATP4 and that modestly decreased susceptibility to PfATP4 inhibitors is associated with some mutations now present in Ugandan parasites.

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