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EMBO Reports Jul 2023Eukaryotic cell adhesion and migration rely on surface adhesins connecting extracellular ligands to the intracellular actin cytoskeleton. Plasmodium sporozoites are...
Eukaryotic cell adhesion and migration rely on surface adhesins connecting extracellular ligands to the intracellular actin cytoskeleton. Plasmodium sporozoites are transmitted by mosquitoes and rely on adhesion and gliding motility to colonize the salivary glands and to reach the liver after transmission. During gliding, the essential sporozoite adhesin TRAP engages actin filaments in the cytoplasm of the parasite, while binding ligands on the substrate through its inserted (I) domain. Crystal structures of TRAP from different Plasmodium species reveal the I domain in closed and open conformations. Here, we probe the importance of these two conformational states by generating parasites expressing versions of TRAP with the I domain stabilized in either the open or closed state with disulfide bonds. Strikingly, both mutations impact sporozoite gliding, mosquito salivary gland entry, and transmission. Absence of gliding in sporozoites expressing the open TRAP I domain can be partially rescued by adding a reducing agent. This suggests that dynamic conformational change is required for ligand binding, gliding motility, and organ invasion and hence sporozoite transmission from mosquito to mammal.
Topics: Animals; Sporozoites; Ligands; Plasmodium; Culicidae; Liver; Protozoan Proteins; Plasmodium berghei; Mammals
PubMed: 37306042
DOI: 10.15252/embr.202357064 -
Frontiers in Cellular and Infection... 2021Malaria is a parasitic disease that represents a public health problem worldwide. Protozoans of the genus are responsible for causing malaria in humans. species have a... (Review)
Review
Malaria is a parasitic disease that represents a public health problem worldwide. Protozoans of the genus are responsible for causing malaria in humans. 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 . 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 SUMO as a new potential drug target. This mini-review focuses on the current understanding of the mechanism of action of the SUMO during the coordinated multi-step life cycle of and discusses them as attractive new target proteins for the development of parasite-specific inhibitors and therapeutic intervention toward malaria disease.
Topics: Animals; Antimalarials; Humans; Malaria; Plasmodium; Plasmodium falciparum; Sumoylation
PubMed: 34178724
DOI: 10.3389/fcimb.2021.685866 -
Current Opinion in Microbiology Dec 2017Non-human primates harbor diverse species of malaria parasites, including the progenitors of Plasmodium falciparum and Plasmodium vivax. Cross-species transmission of... (Review)
Review
Non-human primates harbor diverse species of malaria parasites, including the progenitors of Plasmodium falciparum and Plasmodium vivax. Cross-species transmission of some malaria parasites-most notably the macaque parasite, Plasmodium knowlesi-continues to this day, compelling the scientific community to ask whether these zoonoses could impede malaria control efforts by acting as a source of recurrent human infection. Host-restriction varies considerably among parasite species and is governed by both ecological and molecular variables. In particular, the efficiency of red blood cell invasion constitutes a prominent barrier to zoonotic emergence. Although proteins expressed upon the erythrocyte surface exhibit considerable diversity both within and among hosts, malaria parasites have adapted to this heterogeneity via the expansion of protein families associated with invasion, offering redundant mechanisms of host cell entry. This molecular toolkit may enable some parasites to circumvent host barriers, potentially yielding host shifts upon subsequent adaptation. Recent studies have begun to elucidate the molecular determinants of host-specificity, as well as the mechanisms that malaria parasites use to overcome these restrictions. We review recent studies concerning host tropism in the context of erythrocyte invasion by focusing on three malaria parasites that span the zoonotic spectrum: P. falciparum, P. knowlesi, and P. vivax.
Topics: Animals; Erythrocytes; Host Specificity; Humans; Malaria; Plasmodium; Protozoan Proteins
PubMed: 29096194
DOI: 10.1016/j.mib.2017.10.006 -
Journal of Immunology Research 2016Dendritic cells (DCs) play a central role in the initiation of adaptive immune responses, efficiently presenting antigens to T cells. This ability relies on the presence... (Review)
Review
Dendritic cells (DCs) play a central role in the initiation of adaptive immune responses, efficiently presenting antigens to T cells. This ability relies on the presence of numerous surface and intracellular receptors capable of sensing microbial components as well as inflammation and on a very efficient machinery for antigen presentation. In this way, DCs sense the presence of a myriad of pathogens, including Plasmodium spp., the causative agent of malaria. Despite many efforts to control this infection, malaria is still responsible for high rates of morbidity and mortality. Different groups have shown that DCs act during Plasmodium infection, and data suggest that the phenotypically distinct DCs subsets are key factors in the regulation of immunity during infection. In this review, we will discuss the importance of DCs for the induction of immunity against the different stages of Plasmodium, the outcomes of DCs activation, and also what is currently known about Plasmodium components that trigger such activation.
Topics: Antigen Presentation; Dendritic Cells; Humans; Immunologic Tests; Life Cycle Stages; Malaria; Plasmodium; T-Lymphocytes
PubMed: 27110574
DOI: 10.1155/2016/2926436 -
Trends in Parasitology May 2019Malaria infection is often accompanied by periodic fevers, triggered by synchronous cycles of parasite replication within the host. The degree of synchrony in parasite... (Review)
Review
Malaria infection is often accompanied by periodic fevers, triggered by synchronous cycles of parasite replication within the host. The degree of synchrony in parasite development influences the efficacy of drugs and immune defenses and is therefore relevant to host health and infectiousness. Synchrony is thought to vary over the course of infection and across different host-parasite genotype or species combinations, but the evolutionary significance - if any - of this diversity remains elusive. Standardized methods are lacking, but the most common metric for quantifying synchrony is the percentage of parasites in a particular developmental stage. We use a heuristic model to show that this metric is often unacceptably biased. Methodological challenges must be addressed to characterize diverse patterns of synchrony and their consequences for disease severity and spread.
Topics: Humans; Life Cycle Stages; Malaria; Parasitology; Plasmodium
PubMed: 30952484
DOI: 10.1016/j.pt.2019.03.002 -
International Journal of Medical... Jan 2018Plasmodium parasites, the causative agents of malaria, display a well-regulated lipid metabolism required to ensure their survival in the human host as well as in the... (Review)
Review
Plasmodium parasites, the causative agents of malaria, display a well-regulated lipid metabolism required to ensure their survival in the human host as well as in the mosquito vector. The fine-tuning of lipid metabolic pathways is particularly important for the parasites during the rapid erythrocytic infection cycles, and thus enzymes involved in lipid metabolic processes represent prime targets for malaria chemotherapeutics. While plasmodial enzymes involved in lipid synthesis and acquisition have been studied in the past, to date not much is known about the roles of phospholipases for proliferation and transmission of the malaria parasite. These phospholipid-hydrolyzing esterases are crucial for membrane dynamics during host cell infection and egress by the parasite as well as for replication and cell signaling, and thus they are considered important virulence factors. In this review, we provide a comprehensive bioinformatic analysis of plasmodial phospholipases identified to date. We further summarize previous findings on the lipid metabolism of Plasmodium, highlight the roles of phospholipases during parasite life-cycle progression, and discuss the plasmodial phospholipases as potential targets for malaria therapy.
Topics: Animals; Erythrocytes; Humans; Intracellular Membranes; Lipid Metabolism; Malaria; Phospholipases; Plasmodium; Protozoan Proteins; Virulence Factors
PubMed: 28988696
DOI: 10.1016/j.ijmm.2017.09.015 -
Malaria Journal Sep 2017Insect vectors, namely mosquitoes (Diptera: Culicidae), are compulsory for malaria parasites (Plasmodium spp.) to complete their life cycle. Despite this, little is...
BACKGROUND
Insect vectors, namely mosquitoes (Diptera: Culicidae), are compulsory for malaria parasites (Plasmodium spp.) to complete their life cycle. Despite this, little is known about vector competence of different mosquito species for the transmission of avian malaria parasites.
METHODS
In this study, nested PCR was used to determine Plasmodium spp. occurrence in pools of whole individuals, as well as the diversity of mitochondrial cytochrome b gene sequences in wild-caught mosquitoes sampled across Eastern Austria in 2013-2015.
RESULTS
A total of 45,749 mosquitoes in 2628 pools were collected, of which 169 pools (6.43%) comprising 9 mosquito species were positive for avian Plasmodium, with the majority of positives in mosquitoes of Culex pipiens s.l./Culex torrentium. Six different avian Plasmodium lineages were found, the most common were Plasmodium vaughani SYAT05, Plasmodium sp. Linn1 and Plasmodium relictum SGS1. In 2014, mosquitoes of the Culex pipiens complex were genetically identified and Culex pipiens f. pipiens presented with the highest number of avian Plasmodium positives (n = 37; 16.74%). Despite this, the minimum infection rate (MIR) was highest in Culex torrentium (5.36%) and Culex pipiens f. pipiens/f. molestus hybrids (5.26%). During 2014 and 2015, seasonal and annual changes in Plasmodium lineage distribution were also observed. In both years P. vaughani SYAT05 dominated at the beginning of the sampling period to be replaced later in the year by P. relictum SGS1 (2014) and Plasmodium sp. Linn1 (2015).
CONCLUSIONS
This is the first large-scale study of avian Plasmodium parasites in Austrian mosquitoes. These results are of special interest, because molecular identification of the taxa of the Cx. pipiens complex and Cx. torrentium enabled the determination of Plasmodium prevalence in the different mosquito taxa and hybrids of this complex. Since pools of whole insects were used, it is not possible to assert any vector competence in any of the examined mosquitoes, but the results are nonetheless valuable in providing an overview of avian Plasmodium species and lineages present in Austria.
Topics: Animals; Austria; Culex; Insect Vectors; Malaria, Avian; Plasmodium; Sequence Analysis, DNA
PubMed: 28962620
DOI: 10.1186/s12936-017-2035-1 -
Trends in Parasitology Aug 2022The conserved plasmodial surface anion channel (PSAC) mediates nutrient uptake by bloodstream malaria parasites and is an antimalarial target. This pathogen-associated... (Review)
Review
The conserved plasmodial surface anion channel (PSAC) mediates nutrient uptake by bloodstream malaria parasites and is an antimalarial target. This pathogen-associated channel is linked to the clag multigene family, which is variably expanded in Plasmodium spp. Member genes are under complex epigenetic regulation, with the clag3 genes of the human P. falciparum pathogen exhibiting monoallelic transcription and mutually exclusive surface exposure on infected erythrocytes. While other multigene families use monoallelic expression to evade host immunity, the reasons of epigenetic control of clag genes are unclear. I consider existing models and their implications for nutrient acquisition and immune evasion. Understanding the reasons for epigenetic regulation of PSAC-mediated nutrient uptake will help clarify host-pathogen interactions and guide development of therapies resistant to allele switching.
Topics: Animals; Epigenesis, Genetic; Erythrocytes; Humans; Malaria; Malaria, Falciparum; Nutrients; Plasmodium; Plasmodium falciparum; Protozoan Proteins
PubMed: 35641406
DOI: 10.1016/j.pt.2022.05.005 -
Parasitology International Dec 2022Rodent malaria parasites have been widely used in all aspects of malaria research to study parasite development within rodent and insect hosts, drug resistance, disease... (Review)
Review
Rodent malaria parasites have been widely used in all aspects of malaria research to study parasite development within rodent and insect hosts, drug resistance, disease pathogenesis, host immune response, and vaccine efficacy. Rodent malaria parasites were isolated from African thicket rats and initially characterized by scientists at the University of Edinburgh, UK, particularly by Drs. Richard Carter, David Walliker, and colleagues. Through their efforts and elegant work, many rodent malaria parasite species, subspecies, and strains are now available. Because of the ease of maintaining these parasites in laboratory mice, genetic crosses can be performed to map the parasite and host genes contributing to parasite growth and disease severity. Recombinant DNA technologies are now available to manipulate the parasite genomes and to study gene functions efficiently. In this chapter, we provide a brief history of the isolation and species identification of rodent malaria parasites. We also discuss some recent studies to further characterize the different developing stages of the parasites including parasite genomes and chromosomes. Although there are differences between rodent and human malaria parasite infections, the knowledge gained from studies of rodent malaria parasites has contributed greatly to our understanding of and the fight against human malaria.
Topics: Animals; Humans; Malaria; Mice; Parasites; Plasmodium; Plasmodium berghei; Plasmodium yoelii; Rats; Rodentia
PubMed: 35926694
DOI: 10.1016/j.parint.2022.102636 -
PLoS Pathogens Dec 2019
Review
Topics: Animals; Humans; Malaria; Plasmodium; Protozoan Proteins; RNA, Protozoan
PubMed: 31877193
DOI: 10.1371/journal.ppat.1008095