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Science Translational Medicine Jul 2023There are no licensed vaccines against . We conducted two phase 1/2a clinical trials to assess two vaccines targeting Duffy-binding protein region II (PvDBPII)....
There are no licensed vaccines against . We conducted two phase 1/2a clinical trials to assess two vaccines targeting Duffy-binding protein region II (PvDBPII). Recombinant viral vaccines using chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) vectors as well as a protein and adjuvant formulation (PvDBPII/Matrix-M) were tested in both a standard and a delayed dosing regimen. Volunteers underwent controlled human malaria infection (CHMI) after their last vaccination, alongside unvaccinated controls. Efficacy was assessed by comparisons of parasite multiplication rates in the blood. PvDBPII/Matrix-M, given in a delayed dosing regimen, elicited the highest antibody responses and reduced the mean parasite multiplication rate after CHMI by 51% ( = 6) compared with unvaccinated controls ( = 13), whereas no other vaccine or regimen affected parasite growth. Both viral-vectored and protein vaccines were well tolerated and elicited expected, short-lived adverse events. Together, these results support further clinical evaluation of the PvDBPII/Matrix-M vaccine.
Topics: Humans; Animals; Parasites; Plasmodium vivax; Vaccination; Malaria
PubMed: 37437014
DOI: 10.1126/scitranslmed.adf1782 -
Trends in Parasitology Feb 2024The dissemination of protozoan and metazoan parasites through host tissues is hindered by cellular barriers, dense extracellular matrices, and fluid forces in the... (Review)
Review
The dissemination of protozoan and metazoan parasites through host tissues is hindered by cellular barriers, dense extracellular matrices, and fluid forces in the bloodstream. To overcome these diverse biophysical impediments, parasites implement versatile migratory strategies. Parasite-exerted mechanical forces and upregulation of the host's cellular contractile machinery are the motors for these strategies, and these are comparably better characterized for protozoa than for helminths. Using the examples of the protozoans, Toxoplasma gondii and Plasmodium, and the metazoan, Schistosoma mansoni, we highlight how quantitative tools such as traction force and reflection interference contrast microscopies have improved our understanding of how parasites alter host mechanobiology to promote their migration.
Topics: Animals; Parasites; Biomechanical Phenomena; Helminths; Toxoplasma; Plasmodium
PubMed: 38172015
DOI: 10.1016/j.pt.2023.12.001 -
Nature Communications Aug 2023Invasion of red blood cells (RBCs) by Plasmodium merozoites is critical to their continued survival within the host. Two major protein families, the Duffy binding-like...
Invasion of red blood cells (RBCs) by Plasmodium merozoites is critical to their continued survival within the host. Two major protein families, the Duffy binding-like proteins (DBPs/EBAs) and the reticulocyte binding like proteins (RBLs/RHs) have been studied extensively in P. falciparum and are hypothesized to have overlapping, but critical roles just prior to host cell entry. The zoonotic malaria parasite, P. knowlesi, has larger invasive merozoites and contains a smaller, less redundant, DBP and RBL repertoire than P. falciparum. One DBP (DBPα) and one RBL, normocyte binding protein Xa (NBPXa) are essential for invasion of human RBCs. Taking advantage of the unique biological features of P. knowlesi and iterative CRISPR-Cas9 genome editing, we determine the precise order of key invasion milestones and demonstrate distinct roles for each family. These distinct roles support a mechanism for phased commitment to invasion and can be targeted synergistically with invasion inhibitory antibodies.
Topics: Animals; Humans; Carrier Proteins; Parasites; Malaria; Plasmodium knowlesi; Protozoan Proteins; Erythrocytes; Merozoites; Plasmodium falciparum
PubMed: 37528099
DOI: 10.1038/s41467-023-40357-z -
Science (New York, N.Y.) May 2024Natural infections are distinct from those of laboratory-or zombie-strains.
Natural infections are distinct from those of laboratory-or zombie-strains.
Topics: Animals; Humans; Malaria; Plasmodium
PubMed: 38696584
DOI: 10.1126/science.adp0001 -
Nature Microbiology Nov 2023Malaria-associated pathogenesis such as parasite invasion, egress, host cell remodelling and antigenic variation requires concerted action by many proteins, but the...
Malaria-associated pathogenesis such as parasite invasion, egress, host cell remodelling and antigenic variation requires concerted action by many proteins, but the molecular regulation is poorly understood. Here we have characterized an essential Plasmodium-specific Apicomplexan AP2 transcription factor in Plasmodium falciparum (PfAP2-P; pathogenesis) during the blood-stage development with two peaks of expression. An inducible knockout of gene function showed that PfAP2-P is essential for trophozoite development, and critical for var gene regulation, merozoite development and parasite egress. Chromatin immunoprecipitation sequencing data collected at timepoints matching the two peaks of pfap2-p expression demonstrate PfAP2-P binding to promoters of genes controlling trophozoite development, host cell remodelling, antigenic variation and pathogenicity. Single-cell RNA sequencing and fluorescence-activated cell sorting revealed de-repression of most var genes in Δpfap2-p parasites. Δpfap2-p parasites also overexpress early gametocyte marker genes, indicating a regulatory role in sexual stage conversion. We conclude that PfAP2-P is an essential upstream transcriptional regulator at two distinct stages of the intra-erythrocytic development cycle.
Topics: Animals; Parasites; Malaria; Gene Expression Regulation; Plasmodium falciparum; Plasmodium
PubMed: 37884813
DOI: 10.1038/s41564-023-01497-6 -
Chembiochem : a European Journal of... Sep 2023Natural product discovery has traditionally relied on the isolation of small molecules from producing species, but genome-sequencing technology and advances in molecular... (Review)
Review
Natural product discovery has traditionally relied on the isolation of small molecules from producing species, but genome-sequencing technology and advances in molecular biology techniques have expanded efforts to a wider array of organisms. Protists represent an underexplored kingdom for specialized metabolite searches despite bioinformatic analysis that suggests they harbor distinct biologically active small molecules. Specifically, pathogenic apicomplexan parasites, responsible for billions of global infections, have been found to possess multiple biosynthetic gene clusters, which hints at their capacity to produce polyketide metabolites. Biochemical studies have revealed unique features of apicomplexan polyketide synthases, but to date, the identity and function of the polyketides synthesized by these megaenzymes remains unknown. Herein, we discuss the potential for specialized metabolite production in protists and the possible evolution of polyketide biosynthetic gene clusters in apicomplexan parasites. We then focus on a polyketide synthase from the apicomplexan Toxoplasma gondii to discuss the unique domain architecture and properties of these proteins when compared to previously characterized systems, and further speculate on the possible functions for polyketides in these pathogenic parasites.
Topics: Secondary Metabolism; Polyketide Synthases; Computational Biology; Apicomplexa; Polyketides
PubMed: 37171468
DOI: 10.1002/cbic.202300263 -
Advanced Science (Weinheim,... Apr 2024Macrophage therapy for liver fibrosis is on the cusp of meaningful clinical utility. Due to the heterogeneities of macrophages, it is urgent to develop safer macrophages...
Macrophage therapy for liver fibrosis is on the cusp of meaningful clinical utility. Due to the heterogeneities of macrophages, it is urgent to develop safer macrophages with a more stable and defined phenotype for the treatment of liver fibrosis. Herein, a new macrophage-based immunotherapy using macrophages stably expressing a pivotal cytokine from Toxoplasma gondii, a parasite that infects ≈ 2 billion people is developed. It is found that Toxoplasma gondii macrophage migration inhibitory factor-transgenic macrophage (Mφ) shows stable fibrinolysis and strong chemotactic capacity. Mφ effectively ameliorates liver fibrosis and deactivates aHSCs by recruiting Ly6C macrophages via paracrine CCL2 and polarizing them into the restorative Ly6C macrophage through the secretion of CX3CL1. Remarkably, Mφ exhibits even higher chemotactic potential, lower grade of inflammation, and better therapeutic effects than LPS/IFN-γ-treated macrophages, making macrophage-based immune therapy more efficient and safer. Mechanistically, TgMIF promotes CCL2 expression by activating the ERK/HMGB1/NF-κB pathway, and this event is associated with recruiting endogenous macrophages into the fibrosis liver. The findings do not merely identify viable immunotherapy for liver fibrosis but also suggest a therapeutic strategy based on the evolutionarily designed immunomodulator to treat human diseases by modifying the immune microenvironment.
Topics: Humans; Macrophages; Liver Cirrhosis; Toxoplasma; Inflammation; Phenotype
PubMed: 38247166
DOI: 10.1002/advs.202308750 -
Journal of Cancer Research and Clinical... Aug 2023Parasites and cancers have some common antigens. Much scientific evidence in the human population, animal models, and in vitro experiments exhibit that parasites have... (Review)
Review
Parasites and cancers have some common antigens. Much scientific evidence in the human population, animal models, and in vitro experiments exhibit that parasites have significant anti-cancer effects. The larval stage of the tapeworm Echinococcus granulosus, Toxoplasma gondii, Trypanosoma cruzy, Plasmodium's, and Trichinella spiralis are among the parasites that have been subjects of anti-cancer research in the last decades. Anti-tumor effects of parasites may be due to the direct impact of the parasites per se or indirectly due to the immune response raised against common antigens between malignant cells and parasites. This manuscript reviews the anti-cancer effects of parasites and possible mechanisms of these effects. Options for using parasites or their antigens for cancer treatment in the future have been discussed.
Topics: Animals; Humans; Parasites; Toxoplasma; Neoplasms; Immunotherapy
PubMed: 36949175
DOI: 10.1007/s00432-023-04694-2 -
International Journal For Parasitology Sep 2023The horse genotype is one of three common Cryptosporidium spp. in equine animals and has been identified in some human cases. The species status of Cryptosporidium horse...
The horse genotype is one of three common Cryptosporidium spp. in equine animals and has been identified in some human cases. The species status of Cryptosporidium horse genotype remains unclear due to the lack of extensive morphological, biological, and genetic data. In the present study, we have conducted biological and whole genome sequence analyses of an isolate of the genotype from hedgehogs and proposed to name it Cryptosporidium equi n. sp. to reflect its common occurrence in equine animals. Oocysts of C. equi measured 5.12 ± 0.36 μm × 4.46 ± 0.21 μm with a shape index of 1.15 ± 0.08 (n = 50). Cryptosporidium equi was infectious to 3-week-old four-toed hedgehogs (Atelerix albiventris) and mice, with a prepatent period of 2-9 days and a patent period of 30-40 days in hedgehogs. It was not infectious to rats and rabbits. Phylogenetic analyses of small subunit rRNA, 70 kDa heat shock protein, actin, 60 kDa glycoprotein and 100 other orthologous genes revealed that C. equi is genetically distinct from other known Cryptosporidium species and genotypes. The sequence identity between C. equi and Cryptosporidium parvum genomes is 97.9%. Compared with C. parvum, C. equi has lost two MEDLE genes and one insulinase-like protease gene and gained one SKSR gene. In addition, 60 genes have highly divergent sequences (sequence differences ≥ 5.0%), including those encoding mucin-like glycoproteins, insulinase-like peptidases, and MEDLE and SKSR proteins. The genetic uniqueness of C. equi supports its increasing host range and the naming of it as a valid Cryptosporidium species. This is the first known use of whole genome sequence data in delineating new Cryptosporidium species.
Topics: Animals; Horses; Mice; Rats; Humans; Rabbits; Cryptosporidium; Cryptosporidiosis; Cryptosporidiidae; Phylogeny; Hedgehogs; Insulysin; Genotype; Feces
PubMed: 37150475
DOI: 10.1016/j.ijpara.2023.02.008 -
Communications Biology Aug 2023Microneme protein 2 (MIC2) and MIC2-associated protein (M2AP) play crucial roles in the gliding motility and host cell invasion of Toxoplasma gondii. Complex formation...
Microneme protein 2 (MIC2) and MIC2-associated protein (M2AP) play crucial roles in the gliding motility and host cell invasion of Toxoplasma gondii. Complex formation between MIC2 and M2AP is required for maturation and transport from the microneme to the parasite surface. Previous studies showed that M2AP associates with the 6 TSR domain of MIC2 (TSR6), but the detailed interaction remains unclear. In this study, we report crystal structures of M2AP alone and in complex with TSR6. TSR domains have an unusually thin, long structure with a layer of intercalated residues on one side. The non-layered side of TSR6 with hotspot residue His-620 at the center binds to M2AP. Remarkably, we show that TSR6 residue Y602 is dynamic; it equilibrates between being part of the layer (the layered state) and in a flipped-out state in the absence of M2AP. However, when bound to M2AP, Y602 shifts to the flipped-out state. Our findings provide insights into the association and stabilization of MIC2-M2AP complex, and may be used to develop new therapies to prevent infections caused by this parasite.
Topics: Humans; Toxoplasma; Recognition, Psychology; Research Personnel
PubMed: 37652989
DOI: 10.1038/s42003-023-05277-0