Research

14 pages, 2638 KiB

Open AccessArticle

Identification and Validation of Toxoplasma gondii Mitoribosomal Large Subunit Components

by Shikha Shikha, Mariana Ferreira Silva and Lilach Sheiner

Microorganisms 2022, 10(5), 863; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms10050863 - 21 Apr 2022

Cited by 2 | Viewed by 1949

Mitochondrial ribosomes are fundamental to mitochondrial function, and thus survival, of nearly all eukaryotes. Despite their common ancestry, mitoribosomes have evolved divergent features in different eukaryotic lineages. In apicomplexans, the mitochondrial rRNA is extremely fragmented raising questions about its evolution, protein composition and [...] Read more.

Mitochondrial ribosomes are fundamental to mitochondrial function, and thus survival, of nearly all eukaryotes. Despite their common ancestry, mitoribosomes have evolved divergent features in different eukaryotic lineages. In apicomplexans, the mitochondrial rRNA is extremely fragmented raising questions about its evolution, protein composition and structure. Apicomplexan mitochondrial translation and the mitoribosomes are essential in all parasites and life stages studied, highlighting mitoribosomes as a promising target for drugs. Still, the apicomplexan mitoribosome is understudied, with one of the obstacles being that its composition is unknown. Here, to facilitate the study of apicomplexan mitoribosomes, we identified and validated components of the mitoribosomal large subunit in the model apicomplexan Toxoplasma gondii. Full article

(This article belongs to the Special Issue The Molecular Life of Apicomplexa)

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17 pages, 8742 KiB

Open AccessArticle

Thiosemicarbazone Copper Chelator BLT-1 Blocks Apicomplexan Parasite Replication by Selective Inhibition of Scavenger Receptor B Type 1 (SR-BI)

by Camilo Larrazabal, Sara López-Osorio, Zahady D. Velásquez, Carlos Hermosilla, Anja Taubert and Liliana M. R. Silva

Microorganisms 2021, 9(11), 2372; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms9112372 - 17 Nov 2021

Cited by 1 | Viewed by 1887

Abstract

Coccidian parasites are obligate intracellular pathogens that affect humans and animals. Apicomplexans are defective in de novo synthesis of cholesterol, which is required for membrane biosynthesis and offspring formation. In consequence, cholesterol has to be scavenged from host cells. It is mainly taken [...] Read more.

Coccidian parasites are obligate intracellular pathogens that affect humans and animals. Apicomplexans are defective in de novo synthesis of cholesterol, which is required for membrane biosynthesis and offspring formation. In consequence, cholesterol has to be scavenged from host cells. It is mainly taken up from extracellular sources via LDL particles; however, little is known on the role of HDL and its receptor SR-BI in this process. Here, we studied effects of the SR-BI-specific blocker BLT-1 on the development of different fast (Toxoplasma gondii, Neospora caninum, Besnoitia besnoiti) and slow (Eimeria bovis and Eimeria arloingi) replicating coccidian species. Overall, development of all these parasites was significantly inhibited by BLT-1 treatment indicating a common SR-BI-related key mechanism in the replication process. However, SR-BI gene transcription was not affected by T. gondii, N. caninum and B. besnoiti infections. Interestingly, BLT-1 treatment of infective stages reduced invasive capacities of all fast replicating parasites paralleled by a sustained increase in cytoplasmic Ca⁺⁺ levels. Moreover, BLT1-mediated blockage of SR-BI led to enhanced host cell lipid droplet abundance and neutral lipid content, thereby confirming the importance of this receptor in general lipid metabolism. Finally, the current data suggest a conserved role of SR-BI for successful coccidian infections. Full article

(This article belongs to the Special Issue The Molecular Life of Apicomplexa)

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20 pages, 6926 KiB

Open AccessArticle

Expansion Microscopy Reveals Plasmodium falciparum Blood-Stage Parasites Undergo Anaphase with A Chromatin Bridge in the Absence of Mini-Chromosome Maintenance Complex Binding Protein

by Benjamin Liffner and Sabrina Absalon

Microorganisms 2021, 9(11), 2306; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms9112306 - 06 Nov 2021

Cited by 32 | Viewed by 4870

Abstract

The malaria parasite Plasmodium falciparum undergoes closed mitosis, which occurs within an intact nuclear envelope, and differs significantly from its human host. Mitosis is underpinned by the dynamics of microtubules and the nuclear envelope. To date, our ability to study P. falciparum [...] Read more.

The malaria parasite Plasmodium falciparum undergoes closed mitosis, which occurs within an intact nuclear envelope, and differs significantly from its human host. Mitosis is underpinned by the dynamics of microtubules and the nuclear envelope. To date, our ability to study P. falciparum mitosis by microscopy has been hindered by the small size of the P. falciparum nuclei. Ultrastructure expansion microscopy (U-ExM) has recently been developed for P. falciparum, allowing the visualization of mitosis at the individual nucleus level. Using U-ExM, three intranuclear microtubule structures are observed: hemispindles, mitotic spindles, and interpolar spindles. A previous study demonstrated that the mini-chromosome maintenance complex binding-protein (MCMBP) depletion caused abnormal nuclear morphology and microtubule defects. To investigate the role of microtubules following MCMBP depletion and study the nuclear envelope in these parasites, we developed the first nuclear stain enabled by U-ExM in P. falciparum. MCMBP-deficient parasites show aberrant hemispindles and mitotic spindles. Moreover, anaphase chromatin bridges and individual nuclei containing multiple microtubule structures were observed following MCMBP knockdown. Collectively, this study refines our understanding of MCMBP-deficient parasites and highlights the utility of U-ExM coupled with a nuclear envelope stain for studying mitosis in P. falciparum. Full article

(This article belongs to the Special Issue The Molecular Life of Apicomplexa)

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Review

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17 pages, 642 KiB

Open AccessReview

Role of Host Small GTPases in Apicomplexan Parasite Infection

by Silvio Paone and Anna Olivieri

Microorganisms 2022, 10(7), 1370; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms10071370 - 07 Jul 2022

Cited by 3 | Viewed by 2432

Abstract

The Apicomplexa are obligate intracellular parasites responsible for several important human diseases. These protozoan organisms have evolved several strategies to modify the host cell environment to create a favorable niche for their survival. The host cytoskeleton is widely manipulated during all phases of [...] Read more.

The Apicomplexa are obligate intracellular parasites responsible for several important human diseases. These protozoan organisms have evolved several strategies to modify the host cell environment to create a favorable niche for their survival. The host cytoskeleton is widely manipulated during all phases of apicomplexan intracellular infection. Moreover, the localization and organization of host organelles are altered in order to scavenge nutrients from the host. Small GTPases are a class of proteins widely involved in intracellular pathways governing different processes, from cytoskeletal and organelle organization to gene transcription and intracellular trafficking. These proteins are already known to be involved in infection by several intracellular pathogens, including viruses, bacteria and protozoan parasites. In this review, we recapitulate the mechanisms by which apicomplexan parasites manipulate the host cell during infection, focusing on the role of host small GTPases. We also discuss the possibility of considering small GTPases as potential targets for the development of novel host-targeted therapies against apicomplexan infections. Full article

(This article belongs to the Special Issue The Molecular Life of Apicomplexa)

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19 pages, 1306 KiB

Open AccessReview

An Uninvited Seat at the Dinner Table: How Apicomplexan Parasites Scavenge Nutrients from the Host

by Federica Piro, Riccardo Focaia, Zhicheng Dou, Silvia Masci, David Smith and Manlio Di Cristina

Microorganisms 2021, 9(12), 2592; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms9122592 - 15 Dec 2021

Cited by 6 | Viewed by 2896

Abstract

Obligate intracellular parasites have evolved a remarkable assortment of strategies to scavenge nutrients from the host cells they parasitize. Most apicomplexans form a parasitophorous vacuole (PV) within the invaded cell, a replicative niche within which they survive and multiply. As well as providing [...] Read more.

Obligate intracellular parasites have evolved a remarkable assortment of strategies to scavenge nutrients from the host cells they parasitize. Most apicomplexans form a parasitophorous vacuole (PV) within the invaded cell, a replicative niche within which they survive and multiply. As well as providing a physical barrier against host cell defense mechanisms, the PV membrane (PVM) is also an important site of nutrient uptake that is essential for the parasites to sustain their metabolism. This means nutrients in the extracellular milieu are separated from parasite metabolic machinery by three different membranes, the host plasma membrane, the PVM, and the parasite plasma membrane (PPM). In order to facilitate nutrient transport from the extracellular environment into the parasite itself, transporters on the host cell membrane of invaded cells can be modified by secreted and exported parasite proteins to maximize uptake of key substrates to meet their metabolic demand. To overcome the second barrier, the PVM, apicomplexan parasites secrete proteins contained in the dense granules that remodel the vacuole and make the membrane permissive to important nutrients. This bulk flow of host nutrients is followed by a more selective uptake of substrates at the PPM that is operated by specific transporters of this third barrier. In this review, we recapitulate and compare the strategies developed by Apicomplexa to scavenge nutrients from their hosts, with particular emphasis on transporters at the parasite plasma membrane and vacuolar solute transporters on the parasite intracellular digestive organelle. Full article

(This article belongs to the Special Issue The Molecular Life of Apicomplexa)

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19 pages, 646 KiB

Open AccessReview

Toxoplasmosis: Current and Emerging Parasite Druggable Targets

by Rana El Hajj, Lina Tawk, Shaymaa Itani, Maguy Hamie, Jana Ezzeddine, Marwan El Sabban and Hiba El Hajj

Microorganisms 2021, 9(12), 2531; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms9122531 - 07 Dec 2021

Cited by 19 | Viewed by 4712

Abstract

Toxoplasmosis is a prevalent disease affecting a wide range of hosts including approximately one-third of the human population. It is caused by the sporozoan parasite Toxoplasma gondii (T. gondii), which instigates a range of symptoms, manifesting as acute and chronic forms [...] Read more.

Toxoplasmosis is a prevalent disease affecting a wide range of hosts including approximately one-third of the human population. It is caused by the sporozoan parasite Toxoplasma gondii (T. gondii), which instigates a range of symptoms, manifesting as acute and chronic forms and varying from ocular to deleterious congenital or neuro-toxoplasmosis. Toxoplasmosis may cause serious health problems in fetuses, newborns, and immunocompromised patients. Recently, associations between toxoplasmosis and various neuropathies and different types of cancer were documented. In the veterinary sector, toxoplasmosis results in recurring abortions, leading to significant economic losses. Treatment of toxoplasmosis remains intricate and encompasses general antiparasitic and antibacterial drugs. The efficacy of these drugs is hindered by intolerance, side effects, and emergence of parasite resistance. Furthermore, all currently used drugs in the clinic target acute toxoplasmosis, with no or little effect on the chronic form. In this review, we will provide a comprehensive overview on the currently used and emergent drugs and their respective parasitic targets to combat toxoplasmosis. We will also abridge the repurposing of certain drugs, their targets, and highlight future druggable targets to enhance the therapeutic efficacy against toxoplasmosis, hence lessening its burden and potentially alleviating the complications of its associated diseases. Full article

(This article belongs to the Special Issue The Molecular Life of Apicomplexa)

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19 pages, 1506 KiB

Open AccessReview

Structural and Functional Insights into the Microtubule Organizing Centers of Toxoplasma gondii and Plasmodium spp.

by Ramiro Tomasina, Fabiana C. González and Maria E. Francia

Microorganisms 2021, 9(12), 2503; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms9122503 - 03 Dec 2021

Cited by 15 | Viewed by 3503

Abstract

Microtubule organizing centers (MTOCs) perform critical cellular tasks by nucleating, stabilizing, and anchoring microtubule’s minus ends. These capacities impact tremendously a wide array of cellular functions ranging from ascribing cell shape to orchestrating cell division and generating motile structures, among others. The phylum [...] Read more.

Microtubule organizing centers (MTOCs) perform critical cellular tasks by nucleating, stabilizing, and anchoring microtubule’s minus ends. These capacities impact tremendously a wide array of cellular functions ranging from ascribing cell shape to orchestrating cell division and generating motile structures, among others. The phylum Apicomplexa comprises over 6000 single-celled obligate intracellular parasitic species. Many of the apicomplexan are well known pathogens such as Toxoplasma gondii and the Plasmodium species, causative agents of toxoplasmosis and malaria, respectively. Microtubule organization in these parasites is critical for organizing the cortical cytoskeleton, enabling host cell penetration and the positioning of large organelles, driving cell division and directing the formation of flagella in sexual life stages. Apicomplexans are a prime example of MTOC diversity displaying multiple functional and structural MTOCs combinations within a single species. This diversity can only be fully understood in light of each organism’s specific MT nucleation requirements and their evolutionary history. Insight into apicomplexan MTOCs had traditionally been limited to classical ultrastructural work by transmission electron microscopy. However, in the past few years, a large body of molecular insight has emerged. In this work we describe the latest insights into nuclear MTOC biology in two major human and animal disease causing Apicomplexans: Toxoplasma gondii and Plasmodium spp. Full article

(This article belongs to the Special Issue The Molecular Life of Apicomplexa)

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Other

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12 pages, 1315 KiB

Open AccessCommentary

Babesia, Theileria, Plasmodium and Hemoglobin

by Daniel Sojka, Marie Jalovecká and Jan Perner

Microorganisms 2022, 10(8), 1651; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms10081651 - 15 Aug 2022

Cited by 10 | Viewed by 3914

Abstract

The Propagation of Plasmodium spp. and Babesia/Theileria spp. vertebrate blood stages relies on the mediated acquisition of nutrients available within the host’s red blood cell (RBC). The cellular processes of uptake, trafficking and metabolic processing of host RBC proteins are thus [...] Read more.

The Propagation of Plasmodium spp. and Babesia/Theileria spp. vertebrate blood stages relies on the mediated acquisition of nutrients available within the host’s red blood cell (RBC). The cellular processes of uptake, trafficking and metabolic processing of host RBC proteins are thus crucial for the intraerythrocytic development of these parasites. In contrast to malarial Plasmodia, the molecular mechanisms of uptake and processing of the major RBC cytoplasmic protein hemoglobin remain widely unexplored in intraerythrocytic Babesia/Theileria species. In the paper, we thus provide an updated comparison of the intraerythrocytic stage feeding mechanisms of these two distantly related groups of parasitic Apicomplexa. As the associated metabolic pathways including proteolytic degradation and networks facilitating heme homeostasis represent attractive targets for diverse antimalarials, and alterations in these pathways underpin several mechanisms of malaria drug resistance, our ambition is to highlight some fundamental differences resulting in different implications for parasite management with the potential for novel interventions against Babesia/Theileria infections. Full article

(This article belongs to the Special Issue The Molecular Life of Apicomplexa)

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