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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 -
Nature Communications Aug 2023The gut microbiota is a crucial modulator of Plasmodium infection in mosquitoes, including the production of anti-Plasmodium effector proteins. But how the...
The gut microbiota is a crucial modulator of Plasmodium infection in mosquitoes, including the production of anti-Plasmodium effector proteins. But how the commensal-derived effectors are translocated into Plasmodium parasites remains obscure. Here we show that a natural Plasmodium blocking symbiotic bacterium Serratia ureilytica Su_YN1 delivers the effector lipase AmLip to Plasmodium parasites via outer membrane vesicles (OMVs). After a blood meal, host serum strongly induces Su_YN1 to release OMVs and the antimalarial effector protein AmLip into the mosquito gut. AmLip is first secreted into the extracellular space via the T1SS and then preferentially loaded on the OMVs that selectively target the malaria parasite, leading to targeted killing of the parasites. Notably, these serum-induced OMVs incorporate certain serum-derived lipids, such as phosphatidylcholine, which is critical for OMV uptake by Plasmodium via the phosphatidylcholine scavenging pathway. These findings reveal that this gut symbiotic bacterium evolved to deliver secreted effector molecules in the form of extracellular vesicles to selectively attack parasites and render mosquitoes refractory to Plasmodium infection. The discovery of the role of gut commensal-derived OMVs as carriers in cross-kingdom communication between mosquito microbiota and Plasmodium parasites offers a potential innovative strategy for blocking malaria transmission.
Topics: Animals; Phosphatidylcholines; Parasites; Plasmodium; Biological Transport; Culicidae
PubMed: 37620328
DOI: 10.1038/s41467-023-40887-6 -
Veterinary Parasitology Oct 2023Piroplasmida is an order of economically important blood parasites, including Babesia, Theileria, and Cytauxzoon, transmitted to mammals by ticks. Oxidative stress is a... (Review)
Review
Piroplasmida is an order of economically important blood parasites, including Babesia, Theileria, and Cytauxzoon, transmitted to mammals by ticks. Oxidative stress is a state in which the balance between oxidants and antioxidants is disturbed so that antioxidants cannot compensate for the harmful effects of oxidants. Due to the high concentration of oxygen and hemoglobin in red blood cells (RBCs), these are among the first cells exposed to oxidative damage. When RBCs are exposed to oxidative stress, their hemoglobin is oxidized, and lipid peroxidation leads to membrane instability, deformation, hemolysis, and anemia. Oxidative stress has a fundamental role in the pathogenesis of these parasites. In the present review article, we collected studies on the oxidative stress caused by Piroplasmida in domestic animals. What is obtained from the total review of studies conducted on piroplasmosis revealed that in these infections, the host faces oxidative stress, and the resultant oxidative injury plays a fundamental role in their pathogenicity. Further studies are needed to be carried out on the more precise role of oxidative stress, the use of more sensitive diagnostic biomarkers, and the possible therapeutic role of antioxidant agents in piroplasmosis.
Topics: Animals; Babesiosis; Animals, Domestic; Piroplasmida; Oxidative Stress; Antioxidants; Hemoglobins; Oxidants; Mammals
PubMed: 37643565
DOI: 10.1016/j.vetpar.2023.110011 -
Journal of Travel Medicine Dec 2023
Topics: Animals; Humans; Malaria; Primates; Plasmodium knowlesi
PubMed: 37856519
DOI: 10.1093/jtm/taad135 -
Nature Communications Feb 2024Mutations in a Plasmodium de-ubiquitinase UBP1 have been linked to antimalarial drug resistance. However, the UBP1-mediated drug-resistant mechanism remains unknown....
Mutations in a Plasmodium de-ubiquitinase UBP1 have been linked to antimalarial drug resistance. However, the UBP1-mediated drug-resistant mechanism remains unknown. Through drug selection, genetic mapping, allelic exchange, and functional characterization, here we show that simultaneous mutations of two amino acids (I1560N and P2874T) in the Plasmodium yoelii UBP1 can mediate high-level resistance to mefloquine, lumefantrine, and piperaquine. Mechanistically, the double mutations are shown to impair UBP1 cytoplasmic aggregation and de-ubiquitinating activity, leading to increased ubiquitination levels and altered protein localization, from the parasite digestive vacuole to the plasma membrane, of the P. yoelii multidrug resistance transporter 1 (MDR1). The MDR1 on the plasma membrane enhances the efflux of substrates/drugs out of the parasite cytoplasm to confer multidrug resistance, which can be reversed by inhibition of MDR1 transport. This study reveals a previously unknown drug-resistant mechanism mediated by UBP1 through altered MDR1 localization and substrate transport direction in a mouse model, providing a new malaria treatment strategy.
Topics: Animals; Mice; Plasmodium yoelii; Malaria, Falciparum; Plasmodium falciparum; Antimalarials; Drug Resistance, Multiple; Drug Resistance; Endopeptidases
PubMed: 38413566
DOI: 10.1038/s41467-024-46006-3 -
Molecular and Biochemical Parasitology Sep 2024Malaria, a parasitic infection caused by the genus Plasmodium, results to over 20 million reported cases annually worldwide. Most individuals exhibit various symptoms,... (Review)
Review
Malaria, a parasitic infection caused by the genus Plasmodium, results to over 20 million reported cases annually worldwide. Most individuals exhibit various symptoms, and blood analysis plays a crucial role in determining the appropriate treatment approach. This study discusses various hematologic complications associated with different Plasmodium species. A review of scientific databases including PubMed, Science Direct, Web of Science, Scopus, EMBASE, Magiran, SID, IranMedex was conducted using standard keywords such as Plasmodium, malaria, anemia and blood disorders (hematologic disorder) between 2000 and 2024. The review focused on articles pertaining to clinical trials, prospective cohort, retrospective, cross-sectional and case-control studies. Articles evaluating the effects of malaria on blood cells and indices, with target groups including human and animals, were included. Articles not written in English or Farsi were excluded. Our review revealed that, apart from iron deficiency anemia and vascular dysfunction contributed in part by adhesion of infected RBC to endothelium, decreases in hematocrit and hemoglobin levels, as part of pancytopenia and thrombocytopenia, are characteristic of Plasmodium infection. Additionally, the occurrence of inflammation due to the release of inflammatory cytokines and complement activation can complicate the clinical features of malaria in individuals with hematologic conditions.
Topics: Humans; Malaria; Animals; Plasmodium; Hematologic Diseases; Anemia
PubMed: 38857772
DOI: 10.1016/j.molbiopara.2024.111635 -
FASEB Journal : Official Publication of... Nov 2023Toxoplasma gondii is an obligate, intracellular apicomplexan protozoan parasite of both humans and animals that can cause fetal damage and abortion and severe disease in...
Toxoplasma gondii is an obligate, intracellular apicomplexan protozoan parasite of both humans and animals that can cause fetal damage and abortion and severe disease in the immunosuppressed. Sphingolipids have indispensable functions as signaling molecules and are essential and ubiquitous components of eukaryotic membranes that are both synthesized and scavenged by the Apicomplexa. Ceramide is the precursor for all sphingolipids, and here we report the identification, localization and analyses of the Toxoplasma ceramide synthases TgCerS1 and TgCerS2. Interestingly, we observed that while TgCerS1 was a fully functional orthologue of the yeast ceramide synthase (Lag1p) capable of catalyzing the conversion of sphinganine to ceramide, in contrast TgCerS2 was catalytically inactive. Furthermore, genomic deletion of TgCerS1 using CRISPR/Cas-9 led to viable but slow-growing parasites indicating its importance but not indispensability. In contrast, genomic knock out of TgCerS2 was only accessible utilizing the rapamycin-inducible Cre recombinase system. Surprisingly, the results demonstrated that this "pseudo" ceramide synthase, TgCerS2, has a considerably greater role in parasite fitness than its catalytically active orthologue (TgCerS1). Phylogenetic analyses indicated that, as in humans and plants, the ceramide synthase isoforms found in Toxoplasma and other Apicomplexa may have arisen through gene duplication. However, in the Apicomplexa the duplicated copy is hypothesized to have subsequently evolved into a non-functional "pseudo" ceramide synthase. This arrangement is unique to the Apicomplexa and further illustrates the unusual biology that characterize these protozoan parasites.
Topics: Humans; Animals; Toxoplasma; Parasites; Gene Duplication; Phylogeny; Sphingolipids; Ceramides; Protozoan Proteins
PubMed: 37795915
DOI: 10.1096/fj.202201603RRR -
Antimicrobial Agents and Chemotherapy Aug 2023Malaria parasites in the blood stage express a single transmembrane transport protein for the release of the glycolytic end product l-lactate/H from the cell. This...
Malaria parasites in the blood stage express a single transmembrane transport protein for the release of the glycolytic end product l-lactate/H from the cell. This transporter is a member of the strictly microbial formate-nitrite transporter (FNT) family and a novel putative drug target. Small, drug-like FNT inhibitors potently block lactate transport and kill Plasmodium falciparum parasites in culture. The protein structure of Plasmodium falciparum FNT (PfFNT) in complex with the inhibitor has been resolved and confirms its previously predicted binding site and its mode of action as a substrate analog. Here, we investigated the mutational plasticity and essentiality of the PfFNT target on a genetic level, and established its druggability using mouse malaria models. We found that, besides a previously identified PfFNT G107S resistance mutation, selection of parasites at 3 × IC (50% inhibitory concentration) gave rise to two new point mutations affecting inhibitor binding: G21E and V196L. Conditional knockout and mutation of the PfFNT gene showed essentiality in the blood stage, whereas no phenotypic defects in sexual development were observed. PfFNT inhibitors mainly targeted the trophozoite stage and exhibited high potency in P. berghei- and P. falciparum-infected mice. Their activity profiles were comparable to that of artesunate, demonstrating strong potential for the further development of PfFNT inhibitors as novel antimalarials.
Topics: Animals; Mice; Monocarboxylic Acid Transporters; Plasmodium falciparum; Malaria, Falciparum; Antimalarials; Parasites; Lactates; Plasmodium berghei; Protozoan Proteins
PubMed: 37428074
DOI: 10.1128/aac.00356-23 -
European Journal of Medicinal Chemistry Nov 2023Reviewing the advancements in malaria treatment, the emergence of triazole hybrid compounds stands out as a groundbreaking development. Combining the advantages of... (Review)
Review
Reviewing the advancements in malaria treatment, the emergence of triazole hybrid compounds stands out as a groundbreaking development. Combining the advantages of triazole and other moieties, these hybrid compounds offer a new frontier in the battle against malaria. Their potential as effective antimalarial agents has captured the attention of researchers and holds promise for overcoming the challenges posed by drug-resistant malaria strains. We focused on their broad spectrum of antimalarial activity of diverse hybridized 1,2,3-triazoles and 1,2,4-triazoles, structure-activity relationship (SAR), drug-likeness, bioavailability and pharmacokinetic properties reported since 2018 targeting multiple stages of the Plasmodium life cycle. This versatility makes them highly effective against both drug-sensitive and drug-resistant strains of P. falciparum, making them invaluable tools in regions where resistance is prevalent. The synergistic effects of combining the triazole moiety with other pharmacophores have resulted in even greater antimalarial potency. This approach has the potential to circumvent existing resistance mechanisms and provide a more sustainable solution to malaria treatment. While triazole hybrid compounds show great promise, further research and clinical trials are warranted to fully evaluate their safety, efficacy and long-term effects. As research progresses, these compounds can potentially revolutionize the field and contribute to global efforts to eradicate malaria, ultimately saving countless lives worldwide.
Topics: Humans; Antimalarials; Triazoles; Plasmodium falciparum; Malaria; Plasmodium; Malaria, Falciparum
PubMed: 37556947
DOI: 10.1016/j.ejmech.2023.115694 -
British Journal of Haematology Feb 2024
Topics: Humans; Monocytes; Malaria; Plasmodium falciparum
PubMed: 38111310
DOI: 10.1111/bjh.19259