scholarly journals Discovery of HDAC inhibitors with potent activity against multiple malaria parasite life cycle stages

2014 ◽  
Vol 82 ◽  
pp. 204-213 ◽  
Author(s):  
Finn K. Hansen ◽  
Subathdrage D.M. Sumanadasa ◽  
Katharina Stenzel ◽  
Sandra Duffy ◽  
Stephan Meister ◽  
...  
Keyword(s):  
Life Cycle ◽  
Malaria Parasite ◽  
Hdac Inhibitors ◽  
Parasite Life Cycle ◽  
Life Cycle Stages

scholarly journals The Malaria Parasite Cyclic GMP-Dependent Protein Kinase Plays a Central Role in Blood-Stage Schizogony

2009 ◽  
Vol 9 (1) ◽  
pp. 37-45 ◽  
Author(s):  
Helen M. Taylor ◽  
Louisa McRobert ◽  
Munira Grainger ◽  
Audrey Sicard ◽  
Anton R. Dluzewski ◽  
...  
Keyword(s):  
Life Cycle ◽  
Protein Kinase ◽  
Cyclic Gmp ◽  
Malaria Parasite ◽  
Kinase Inhibitor ◽  
Blood Stage ◽  
Parasite Life Cycle ◽  
Dependent Protein Kinase ◽  
Asexual Blood Stage ◽  
Dependent Protein

ABSTRACT A role for the Plasmodium falciparum cyclic GMP (cGMP)-dependent protein kinase (PfPKG) in gametogenesis in the malaria parasite was elucidated previously. In the present study we examined the role of PfPKG in the asexual blood-stage of the parasite life cycle, the stage that causes malaria pathology. A specific PKG inhibitor (compound 1, a trisubstituted pyrrole) prevented the progression of P. falciparum schizonts through to ring stages in erythrocyte invasion assays. Addition of compound 1 to ring-stage parasites allowed normal development up to 30 h postinvasion, and segmented schizonts were able to form. However, synchronized schizonts treated with compound 1 for ≥6 h became large and dysmorphic and were unable to rupture or liberate merozoites. To conclusively demonstrate that the effect of compound 1 on schizogony was due to its selective action on PfPKG, we utilized genetically manipulated P. falciparum parasites expressing a compound 1-insensitive PfPKG. The mutant parasites were able to complete schizogony in the presence of compound 1 but not in the presence of the broad-spectrum protein kinase inhibitor staurosporine. This shows that PfPKG is the primary target of compound 1 during schizogony and provides direct evidence of a role for PfPKG in this process. Discovery of essential roles for the P. falciparum PKG in both asexual and sexual development demonstrates that cGMP signaling is a key regulator of both of these crucial life cycle phases and defines this molecule as an exciting potential drug target for both therapeutic and transmission blocking action against malaria.

scholarly journals Dual Plasmepsin-Targeting Antimalarial Agents Disrupt Multiple Stages of the Malaria Parasite Life Cycle

2020 ◽  
Vol 27 (4) ◽  
pp. 642-658.e12 ◽  
Author(s):  
Paola Favuzza ◽  
Manuel de Lera Ruiz ◽  
Jennifer K. Thompson ◽  
Tony Triglia ◽  
Anna Ngo ◽  
...  
Keyword(s):  
Life Cycle ◽  
Malaria Parasite ◽  
Parasite Life Cycle ◽  
Antimalarial Agents ◽  
Multiple Stages

scholarly journals Calcium in the Backstage of Malaria Parasite Biology

2021 ◽  
Vol 11 ◽  
Author(s):  
Lucas Silva de Oliveira ◽  
Marcos Rodrigo Alborghetti ◽  
Renata Garcia Carneiro ◽  
Izabela Marques Dourado Bastos ◽  
Rogerio Amino ◽  
...  
Keyword(s):  
Life Cycle ◽  
Protein Kinases ◽  
Malaria Parasite ◽  
Developmental Stages ◽  
Receptor Gene ◽  
Food Vacuole ◽  
Parasite Development ◽  
Cell Infection ◽  
Parasite Life Cycle ◽  
Downstream Signaling

The calcium ion (Ca2+) is a ubiquitous second messenger involved in key biological processes in prokaryotes and eukaryotes. In Plasmodium species, Ca2+ signaling plays a central role in the parasite life cycle. It has been associated with parasite development, fertilization, locomotion, and host cell infection. Despite the lack of a canonical inositol-1,4,5-triphosphate receptor gene in the Plasmodium genome, pharmacological evidence indicates that inositol-1,4,5-triphosphate triggers Ca2+ mobilization from the endoplasmic reticulum. Other structures such as acidocalcisomes, food vacuole and mitochondria are proposed to act as supplementary intracellular Ca2+ reservoirs. Several Ca2+-binding proteins (CaBPs) trigger downstream signaling. Other proteins with no EF-hand motifs, but apparently involved with CaBPs, are depicted as playing an important role in the erythrocyte invasion and egress. It is also proposed that a cross-talk among kinases, which are not members of the family of Ca2+-dependent protein kinases, such as protein kinases G, A and B, play additional roles mediated indirectly by Ca2+ regulation. This statement may be extended for proteins directly related to invasion or egress, such as SUB1, ERC, IMC1I, IMC1g, GAP45 and EBA175. In this review, we update our understanding of aspects of Ca2+-mediated signaling correlated to the developmental stages of the malaria parasite life cycle.

scholarly journals The dimerisable Cre recombinase allows conditional genome editing in the mosquito stages of Plasmodium berghei

2020 ◽  
Author(s):  
Priyanka Fernandes ◽  
Sylvie Briquet ◽  
Delphine Patarot ◽  
Manon Loubens ◽  
Bénédicte Hoareau-Coudert ◽  
...  
Keyword(s):  
Life Cycle ◽  
Dna Sequences ◽  
Malaria Parasite ◽  
Reverse Genetics ◽  
High Efficiency ◽  
Parasite Life Cycle ◽  
Asexual Blood Stage ◽  
Functional Studies ◽  
Powerful Approach ◽  
Regulatable Promoters

ABSTRACTAsexual blood stages of the malaria parasite are readily amenable to genetic modification via homologous recombination, allowing functional studies of parasite genes that are not essential in this part of the life cycle. However, conventional reverse genetics cannot be applied for the functional analysis of genes that are essential during asexual blood-stage replication. Various strategies have been developed for conditional mutagenesis of Plasmodium, including recombinase-based gene deletion, regulatable promoters, and mRNA or protein destabilization systems. Among these, the dimerisable Cre (DiCre) recombinase system has emerged as a powerful approach for conditional gene targeting in P. falciparum. In this system, the bacteriophage Cre is expressed in the form of two separate, enzymatically inactive polypeptides, each fused to a different rapamycin-binding protein. Rapamycin-induced heterodimerization of the two components restores recombinase activity. We have implemented the DiCre system in the rodent malaria parasite P. berghei, and show that rapamycin-induced excision of floxed DNA sequences can be achieved with very high efficiency in both mammalian and mosquito parasite stages. This tool can be used to investigate the function of essential genes not only in asexual blood stages, but also in other parts of the malaria parasite life cycle.

scholarly journals The Schistosoma mansoni genome encodes thousands of long non-coding RNAs predicted to be functional at different parasite life-cycle stages

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Elton J. R. Vasconcelos ◽  
Lucas F. daSilva ◽  
David S. Pires ◽  
Guilherme M. Lavezzo ◽  
Adriana S. A. Pereira ◽  
...  
Keyword(s):  
Life Cycle ◽  
Schistosoma Mansoni ◽  
Parasite Life Cycle ◽  
Life Cycle Stages ◽  
Non Coding Rnas

scholarly journals Monoclonal Antibodies to Intracellular Stages ofCryptosporidium parvumDefine Life Cycle ProgressionIn Vitro

mSphere ◽  
2018 ◽  
Vol 3 (3) ◽  
Author(s):  
Georgia Wilke ◽  
Soumya Ravindran ◽  
Lisa Funkhouser-Jones ◽  
Jennifer Barks ◽  
Qiuling Wang ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Life Cycle ◽  
Gastrointestinal Disease ◽  
Epithelial Cell Line ◽  
Type I ◽  
Parasite Life Cycle ◽  
Major Barrier ◽  
Content Type ◽  
Life Cycle Stages

ABSTRACTAmong the obstacles hinderingCryptosporidiumresearch is the lack of anin vitroculture system that supports complete life development and propagation. This major barrier has led to a shortage of widely available anti-Cryptosporidiumantibodies and a lack of markers for staging developmental progression. Previously developed antibodies againstCryptosporidiumwere raised against extracellular stages or recombinant proteins, leading to antibodies with limited reactivity across the parasite life cycle. Here we sought to create antibodies that recognize novel epitopes that could be used to define intracellular development. We identified a mouse epithelial cell line that supportedC. parvumgrowth, enabling immunization of mice with infected cells to create a bank of monoclonal antibodies (MAbs) against intracellular parasite stages while avoiding the development of host-specific antibodies. From this bank, we identified 12 antibodies with a range of reactivities across the parasite life cycle. Importantly, we identified specific MAbs that can distinguish different life cycle stages, such as trophozoites, merozoites, type I versus II meronts, and macrogamonts. These MAbs provide valuable tools for theCryptosporidiumresearch community and will facilitate future investigation into parasite biology.IMPORTANCECryptosporidiumis a protozoan parasite that causes gastrointestinal disease in humans and animals. Currently, there is a limited array of antibodies available against the parasite, which hinders imaging studies and makes it difficult to visualize the parasite life cycle in different culture systems. In order to alleviate this reagent gap, we created a library of novel antibodies against the intracellular life cycle stages ofCryptosporidium. We identified antibodies that recognize specific life cycle stages in distinctive ways, enabling unambiguous description of the parasite life cycle. These MAbs will aid future investigation intoCryptosporidiumbiology and help illuminate growth differences between various culture platforms.

scholarly journals Kinesin-8B controls basal body function and flagellum formation and is key to malaria parasite transmission

2019 ◽  
Author(s):  
Mohammad Zeeshan ◽  
David J. P. Ferguson ◽  
Steven Abel ◽  
Alana Burrrell ◽  
Edward Rea ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Life Cycle ◽  
Live Cell Imaging ◽  
Malaria Parasite ◽  
Cell Imaging ◽  
Male Gamete ◽  
Live Cell ◽  
Basal Bodies ◽  
Parasite Transmission ◽  
Parasite Life Cycle

AbstractEukaryotic flagella are conserved microtubule-based organelles that drive cell motility. Plasmodium, the causative agent of malaria, has a single flagellate stage: the male gamete in the mosquito. Three rounds of endomitotic division together with an unusual mode of flagellum assembly rapidly produce eight motile gametes. These processes are tightly coordinated but their regulation is poorly understood. To understand this important developmental stage, we studied the function and location of the microtubule-based motor kinesin-8B, using gene-targeting, electron microscopy and live cell imaging. Deletion of the kinesin-8B gene showed no effect on mitosis but disrupted 9+2 axoneme assembly and flagellum formation during male gamete development and also completely ablated parasite transmission. Live cell imaging showed that kinesin-8B-GFP did not colocalise with kinetochores in the nucleus but instead revealed dynamic, cytoplasmic localisation with the basal bodies and the assembling axoneme during flagellum formation. We thus uncovered an unexpected role for kinesin-8B in parasite flagellum formation that is vital for the parasite life cycle.

scholarly journals Targeting the Malaria Parasite cGMP-Dependent Protein Kinase to Develop New Drugs

2020 ◽  
Vol 11 ◽  
Author(s):  
David A. Baker ◽  
Alexios N. Matralis ◽  
Simon A. Osborne ◽  
Jonathan M. Large ◽  
Maria Penzo
Keyword(s):  
Life Cycle ◽  
Protein Kinase ◽  
Malaria Parasite ◽  
Public Health Problem ◽  
Major Public Health Problem ◽  
Parasite Life Cycle ◽  
Dependent Protein Kinase ◽  
Cgmp Dependent Protein Kinase ◽  
Cgmp Signaling ◽  
Dependent Protein

The single-celled apicomplexan parasite Plasmodium falciparum is responsible for the majority of deaths due to malaria each year. The selection of drug resistance has been a recurring theme over the decades with each new drug that is developed. It is therefore crucial that future generations of drugs are explored to tackle this major public health problem. Cyclic GMP (cGMP) signaling is one of the biochemical pathways that is being explored as a potential target for new antimalarial drugs. It has been shown that this pathway is essential for all of the key developmental stages of the complex malaria parasite life cycle. This gives hope that targeting cGMP signaling might give rise to drugs that treat disease, block its transmission and even prevent the establishment of infection. Here we review previous work that has been carried out to develop and optimize inhibitors of the cGMP-dependent protein kinase (PKG) which is a critical regulator of the malaria parasite life cycle.

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