scholarly journals Targeting SUMOylation in Plasmodium as a Potential Target for Malaria Therapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Daffiny Sumam de Oliveira ◽  
Thales Kronenberger ◽  
Giuseppe Palmisano ◽  
Carsten Wrenger ◽  
Edmarcia Elisa de Souza
Keyword(s):  
Life Cycle ◽  
Molecular Mechanisms ◽  
Gene Expression Regulation ◽  
Public Health Problem ◽  
Complex Life Cycle ◽  
Cellular Functions ◽  
Cellular Mechanisms ◽  
Malaria Parasites ◽  
Malaria Therapy ◽  
Lysine Residues

Malaria is a parasitic disease that represents a public health problem worldwide. Protozoans of the Plasmodium genus are responsible for causing malaria in humans. Plasmodium species have a complex life cycle that requires post-translational modifications (PTMs) to control cellular activities temporally and spatially and regulate the levels of critical proteins and cellular mechanisms for maintaining an efficient infection and immune evasion. SUMOylation is a PTM formed by the covalent linkage of a small ubiquitin-like modifier protein to the lysine residues on the protein substrate. This PTM is reversible and is triggered by the sequential action of three enzymes: E1-activating, E2-conjugating, and E3 ligase. On the other end, ubiquitin-like-protein-specific proteases in yeast and sentrin-specific proteases in mammals are responsible for processing SUMO peptides and for deconjugating SUMOylated moieties. Further studies are necessary to comprehend the molecular mechanisms and cellular functions of SUMO in Plasmodium. The emergence of drug-resistant malaria parasites prompts the discovery of new targets and antimalarial drugs with novel mechanisms of action. In this scenario, the conserved biological processes regulated by SUMOylation in the malaria parasites such as gene expression regulation, oxidative stress response, ubiquitylation, and proteasome pathways, suggest PfSUMO as a new potential drug target. This mini-review focuses on the current understanding of the mechanism of action of the PfSUMO during the coordinated multi-step life cycle of Plasmodium and discusses them as attractive new target proteins for the development of parasite-specific inhibitors and therapeutic intervention toward malaria disease.

scholarly journals Cellular functions and molecular mechanisms of non-lysine ubiquitination

Open Biology ◽  
2019 ◽  
Vol 9 (9) ◽  
pp. 190147 ◽  
Author(s):  
Amie J. McClellan ◽  
Sophie Heiden Laugesen ◽  
Lars Ellgaard
Keyword(s):  
Dna Repair ◽  
Molecular Mechanisms ◽  
Future Perspectives ◽  
Cellular Functions ◽  
The Past ◽  
Protein Ubiquitination ◽  
Open Questions ◽  
Lysine Residues ◽  
Molecular Machinery ◽  
Mechanistic Basis

Protein ubiquitination is of great cellular importance through its central role in processes such as degradation, DNA repair, endocytosis and inflammation. Canonical ubiquitination takes place on lysine residues, but in the past 15 years non-lysine ubiquitination on serine, threonine and cysteine has been firmly established. With the emerging importance of non-lysine ubiquitination, it is crucial to identify the responsible molecular machinery and understand the mechanistic basis for non-lysine ubiquitination. Here, we first provide an overview of the literature that has documented non-lysine ubiquitination. Informed by these examples, we then discuss the molecular mechanisms and cellular implications of non-lysine ubiquitination, and conclude by outlining open questions and future perspectives in the field.

scholarly journals What functional genomics has taught us about transcriptional regulation in malaria parasites

2019 ◽  
Vol 18 (5) ◽  
pp. 290-301 ◽  
Author(s):  
Christa G Toenhake ◽  
Richárd Bártfai
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Life Cycle ◽  
Functional Genomics ◽  
Expression Patterns ◽  
Regulatory Elements ◽  
Complex Life Cycle ◽  
Malaria Parasites ◽  
Gene Regulatory

Abstract Malaria parasites are characterized by a complex life cycle that is accompanied by dynamic gene expression patterns. The factors and mechanisms that regulate gene expression in these parasites have been searched for even before the advent of next generation sequencing technologies. Functional genomics approaches have substantially boosted this area of research and have yielded significant insights into the interplay between epigenetic, transcriptional and post-transcriptional mechanisms. Recently, considerable progress has been made in identifying sequence-specific transcription factors and DNA-encoded regulatory elements. Here, we review the insights obtained from these efforts including the characterization of core promoters, the involvement of sequence-specific transcription factors in life cycle progression and the mapping of gene regulatory elements. Furthermore, we discuss recent developments in the field of functional genomics and how they might contribute to further characterization of this complex gene regulatory network.

scholarly journals Generation of Transgenic Human Malaria Parasites With Strong Fluorescence in the Transmission Stages

2018 ◽  
Author(s):  
Kyle J McLean ◽  
Judith Straimer ◽  
Christine S Hopp ◽  
Joel Vega-Rodriguez ◽  
Abhai Tripathi ◽  
...  
Keyword(s):  
Life Cycle ◽  
Integration Site ◽  
Complex Life Cycle ◽  
Phenotypic Characterization ◽  
Malaria Parasites ◽  
Genome Expression ◽  
High Infection ◽  
Parasite Plasmodium ◽  
Parasite Plasmodium Falciparum ◽  
Marker Free

Malaria parasites have a complex life cycle that includes specialized stages for transmission between their mosquito and human hosts. These stages are an understudied part of the lifecycle yet targeting them is an essential component of the effort to shrink the malaria map. The human parasite Plasmodium falciparum is responsible for the majority of deaths due to malaria. Our goal was to generate transgenic P. falciparum lines that could complete the lifecycle and produce fluorescent transmission stages for more in-depth and high-throughput studies. Using zinc-finger nuclease technology to engineer a marker-free integration site, we generated three transgenic P. falciparum lines in which tdtomato or gfp were stably integrated into the genome. Expression was driven by either stage-specific peg4 and csp promoters or the constitutive ef1a promoter. Phenotypic characterization of these lines demonstrates that they complete the life cycle with high infection rates and give rise to fluorescent mosquito stages. The transmission stages are sufficiently bright for intra-vital imaging, flow cytometry and scalable screening of chemical inhibitors and potentially inhibitory antibodies.

scholarly journals Parasites are Particularly Problematic

2018 ◽  
Vol 2 ◽  
pp. e25604
Author(s):  
Susan Perkins
Keyword(s):  
Life Cycle ◽  
Intermediate Host ◽  
Information Content ◽  
Definitive Host ◽  
Complex Life Cycle ◽  
Phylogenetic Study ◽  
Biodiversity Informatics ◽  
Malaria Parasites ◽  
Parasitic Organism

Although they are hyperdiverse and intensively studied, parasites present major challenges when it comes to phylogenetics, taxonomy, and biodiversity informatics. The collection of any parasitic organism entails the linking of at least two specimens - the parasite and the host. If the parasite has a complex life cycle, then this becomes further complicated by requiring the linking of three or more hosts, such as the parasite, its intermediate host (vector) and its definitive host(s). Parasites are sometimes collected as byproduct of another collection event and are not studied immediately - which has the potential to disconnect them further in terms of information content and continuity- and the converse if also common - parasites can be collected by parasitologists, who do not necessarily take host vouchers or incorporate host taxonomy, let alone other metadata for these events. Using the specific example of the malaria parasites (Order Haemosporida) I will present examples of the specific challenges that have accompanied the study of these parasites including issues of delimiting species, phylogenetic study, including genetic oddities that are unique to these organisms, and taxonomic quandries that we now find ourselves in, along with other problems with maintaining continuity of information in a group that is both diverse biologically and important medically.

scholarly journals The ApiAP2 factor PfAP2-HC is an integral component of heterochromatin in the malaria parasite Plasmodium falciparum

2020 ◽  
Author(s):  
Eilidh Carrington ◽  
Roel H. M. Cooijmans ◽  
Dominique Keller ◽  
Christa G. Toenhake ◽  
Richárd Bártfai ◽  
...  
Keyword(s):  
Gene Expression ◽  
Plasmodium Falciparum ◽  
Life Cycle ◽  
Dna Binding ◽  
Regulation Of Gene Expression ◽  
Complex Life Cycle ◽  
Parasite Development ◽  
Specific Gene ◽  
Mosquito Vector ◽  
Malaria Parasites

AbstractMalaria parasites undergo a highly complex life cycle in the human host and the mosquito vector. The ApiAP2 family of sequence-specific DNA-binding proteins plays a dominant role in parasite development and life cycle progression. Of the ApiAP2 factors studied to date, most act as transcription factors regulating stage-specific gene expression. Here, we characterised a new ApiAP2 factor in Plasmodium falciparum (PF3D7_1456000) that we termed PfAP2-HC. Via detailed investigation of several single or double genetically engineered parasite lines, we demonstrate that PfAP2-HC specifically binds to heterochromatin throughout the genome. Intriguingly, PfAP2-HC does not bind DNA in vivo and recruitment of PfAP2-HC to heterochromatin is independent of its DNA-binding domain but strictly dependent on heterochromatin protein 1. Furthermore, our results suggest that PfAP2-HC functions neither in the regulation of gene expression nor in heterochromatin formation or maintenance. In summary, our findings reveal that PfAP2-HC constitutes a core component of heterochromatin in malaria parasites. They furthermore identify unexpected properties of ApiAP2 factors and suggest substantial functional divergence among the members of this important family of regulatory proteins.

scholarly journals Generation of Transmission-Competent Human Malaria Parasites with Chromosomally-Integrated Fluorescent Reporters

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Kyle Jarrod McLean ◽  
Judith Straimer ◽  
Christine S. Hopp ◽  
Joel Vega-Rodriguez ◽  
Jennifer L. Small-Saunders ◽  
...  
Keyword(s):  
Life Cycle ◽  
Integration Site ◽  
Complex Life Cycle ◽  
Phenotypic Characterization ◽  
Malaria Parasites ◽  
Fluorescent Reporters ◽  
Genome Expression ◽  
Chemical Inhibitors ◽  
High Infection

Abstract Malaria parasites have a complex life cycle that includes specialized stages for transmission between their mosquito and human hosts. These stages are an understudied part of the lifecycle yet targeting them is an essential component of the effort to shrink the malaria map. The human parasite Plasmodium falciparum is responsible for the majority of deaths due to malaria. Our goal was to generate transgenic P. falciparum lines that could complete the lifecycle and produce fluorescent transmission stages for more in-depth and high-throughput studies. Using zinc-finger nuclease technology to engineer an integration site, we generated three transgenic P. falciparum lines in which tdtomato or gfp were stably integrated into the genome. Expression was driven by either stage-specific peg4 and csp promoters or the constitutive ef1a promoter. Phenotypic characterization of these lines demonstrates that they complete the life cycle with high infection rates and give rise to fluorescent mosquito stages. The transmission stages are sufficiently bright for intra-vital imaging, flow cytometry and scalable screening of chemical inhibitors and inhibitory antibodies.

scholarly journals Malaria parasite egress at a glance

2021 ◽  
Vol 134 (5) ◽  
pp. jcs257345
Author(s):  
Michele S. Y Tan ◽  
Michael J. Blackman
Keyword(s):  
Life Cycle ◽  
Malaria Control ◽  
Cyst Wall ◽  
Malaria Parasite ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Complex Life Cycle ◽  
Intracellular Pathogens ◽  
Parasite Egress ◽  
Intracellular Vacuole

ABSTRACTAll intracellular pathogens must escape (egress) from the confines of their host cell to disseminate and proliferate. The malaria parasite only replicates in an intracellular vacuole or in a cyst, and must undergo egress at four distinct phases during its complex life cycle, each time disrupting, in a highly regulated manner, the membranes or cyst wall that entrap the parasites. This Cell Science at a Glance article and accompanying poster summarises our current knowledge of the morphological features of egress across the Plasmodium life cycle, the molecular mechanisms that govern the process, and how researchers are working to exploit this knowledge to develop much-needed new approaches to malaria control.

Commit, hide and escape: the story ofPlasmodiumgametocytes

Parasitology ◽  
2018 ◽  
Vol 145 (13) ◽  
pp. 1772-1782 ◽  
Author(s):  
Divya Beri ◽  
Balu Balan ◽  
Utpal Tatu
Keyword(s):  
Life Cycle ◽  
Causative Agent ◽  
Malaria Elimination ◽  
Molecular Mechanisms ◽  
Modern Technology ◽  
Vital Role ◽  
Complex Life Cycle ◽  
Sexual Stage ◽  
Mortality And Morbidity ◽  
Human Host

AbstractMalaria is the major cause of mortality and morbidity in tropical countries. The causative agent,Plasmodiumsp., has a complex life cycle and is armed with various mechanisms which ensure its continuous transmission. Gametocytes represent the sexual stage of the parasite and are indispensable for the transmission of the parasite from the human host to the mosquito. Despite its vital role in the parasite's success, it is the least understood stage in the parasite's life cycle. The presence of gametocytes in asymptomatic populations and induction of gametocytogenesis by most antimalarial drugs warrants further investigation into its biology. With a renewed focus on malaria elimination and advent of modern technology available to biologists today, the field of gametocyte biology has developed swiftly, providing crucial insights into the molecular mechanisms driving sexual commitment. This review will summarise key current findings in the field of gametocyte biology and address the associated challenges faced in malaria detection, control and elimination.

Ultrastructural analysis of “Sensory” surface nerve endings and “putative” neurotransmitter sites in Schistosoma mansoni Miracidia

1989 ◽  
Vol 47 ◽  
pp. 962-963
Author(s):  
Betty Ruth Jones ◽  
Steve Chi-Tang Pan
Keyword(s):  
Nervous System ◽  
Life Cycle ◽  
Schistosoma Mansoni ◽  
Snail Host ◽  
Complex Life Cycle ◽  
Rational Approach ◽  
Effective Control ◽  
The Social ◽  
Social And Economic Development ◽  
Basic Biology

INTRODUCTION: Schistosomiasis has been described as “one of the most devastating diseases of mankind, second only to malaria in its deleterious effects on the social and economic development of populations in many warm areas of the world.” The disease is worldwide and is probably spreading faster and becoming more intense than the overall research efforts designed to provide the basis for countering it. Moreover, there are indications that the development of water resources and the demands for increasing cultivation and food in developing countries may prevent adequate control of the disease and thus the number of infections are increasing.Our knowledge of the basic biology of the parasites causing the disease is far from adequate. Such knowledge is essential if we are to develop a rational approach to the effective control of human schistosomiasis. The miracidium is the first infective stage in the complex life cycle of schistosomes. The future of the entire life cycle depends on the capacity and ability of this organism to locate and enter a suitable snail host for further development, Little is known about the nervous system of the miracidium of Schistosoma mansoni and of other trematodes. Studies indicate that miracidia contain a well developed and complex nervous system that may aid the larvae in locating and entering a susceptible snail host (Wilson, 1970; Brooker, 1972; Chernin, 1974; Pan, 1980; Mehlhorn, 1988; and Jones, 1987-1988).

Natural Products for Regulating Macrophages M2 Polarization

2020 ◽  
Vol 15 (7) ◽  
pp. 559-569 ◽  
Author(s):  
Zhen Chang ◽  
Youhan Wang ◽  
Chang Liu ◽  
Wanli Smith ◽  
Lingbo Kong
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Therapeutic Strategies ◽  
Research Progress ◽  
Cellular Mechanisms ◽  
Pharmacological Activities ◽  
Current Review ◽  
M2 Polarization ◽  
Macrophages Polarization ◽  
Herbal Plants

Macrophages M2 polarization have been taken as an anti-inflammatory progression during inflammation. Natural plant-derived products, with potential therapeutic and preventive activities against inflammatory diseases, have received increasing attention in recent years because of their whole regulative effects and specific pharmacological activities. However, the molecular mechanisms about how different kinds of natural compounds regulate macrophages polarization still unclear. Therefore, in the current review, we summarized the detailed research progress on the active compounds derived from herbal plants with regulating effects on macrophages, especially M2 polarization. These natural occurring compounds including flavonoids, terpenoids, glycosides, lignans, coumarins, alkaloids, polyphenols and quinones. In addition, we extensively discussed the cellular mechanisms underlying the M2 polarization for each compound, which could provide potential therapeutic strategies aiming macrophages M2 polarization.

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