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Frontiers in Cellular and Infection... 2020Apicomplexan infections cause substantial morbidity and mortality, worldwide. New, improved therapies are needed. Herein, we create a next generation anti-apicomplexan...
Apicomplexan infections cause substantial morbidity and mortality, worldwide. New, improved therapies are needed. Herein, we create a next generation anti-apicomplexan lead compound, JAG21, a tetrahydroquinolone, with increased sp3-character to improve parasite selectivity. Relative to other cytochrome inhibitors, JAG21 has improved solubility and ADMET properties, without need for pro-drug. JAG21 significantly reduces tachyzoites and encysted bradyzoites , and in primary and established chronic murine infections. Moreover, JAG21 treatment leads to 100% survival. Further, JAG21 is efficacious against drug-resistant . Causal prophylaxis and radical cure are achieved after sporozoite infection with oral administration of a single dose (2.5 mg/kg) or 3 days treatment at reduced dose (0.625 mg/kg/day), eliminating parasitemia, and leading to 100% survival. Enzymatic, binding, and co-crystallography/pharmacophore studies demonstrate selectivity for apicomplexan relative to mammalian enzymes. JAG21 has significant promise as a pre-clinical candidate for prevention, treatment, and cure of toxoplasmosis and malaria.
Topics: Animals; Mice; Parasites; Plasmodium falciparum; Toxoplasma; Toxoplasmosis
PubMed: 32626661
DOI: 10.3389/fcimb.2020.00203 -
Biomolecules Jul 2020Fatty acids are essential components of biological membranes, important for the maintenance of cellular structures, especially in organisms with complex life cycles like...
Fatty acids are essential components of biological membranes, important for the maintenance of cellular structures, especially in organisms with complex life cycles like protozoan parasites. Apicomplexans are obligate parasites responsible for various deadly diseases of humans and livestock. We analyzed the fatty acids produced by the closest phototrophic relatives of parasitic apicomplexans, the chromerids and , and investigated the genes coding for enzymes involved in fatty acids biosynthesis in chromerids, in comparison to their parasitic relatives. Based on evidence from genomic and metabolomic data, we propose a model of fatty acid synthesis in chromerids: the plastid-localized FAS-II pathway is responsible for the de novo synthesis of fatty acids reaching the maximum length of 18 carbon units. Short saturated fatty acids (C14:0-C18:0) originate from the plastid are then elongated and desaturated in the cytosol and the endoplasmic reticulum. We identified giant FAS I-like multi-modular enzymes in both chromerids, which seem to be involved in polyketide synthesis and fatty acid elongation. This full-scale description of the biosynthesis of fatty acids and their derivatives provides important insights into the reductive evolutionary transition of a phototropic algal ancestor to obligate parasites.
Topics: Animals; Apicomplexa; Biosynthetic Pathways; Evolution, Molecular; Fatty Acid Desaturases; Fatty Acid Elongases; Fatty Acid Synthase, Type I; Fatty Acid Synthase, Type II; Fatty Acids; Humans; Phylogeny; Protozoan Infections; Protozoan Proteins; Species Specificity
PubMed: 32722284
DOI: 10.3390/biom10081102 -
Trends in Parasitology Jul 2021Apicomplexan parasites are unicellular eukaryotes that invade the cells in which they proliferate. The development of genetic tools in Toxoplasma, and then in... (Review)
Review
Apicomplexan parasites are unicellular eukaryotes that invade the cells in which they proliferate. The development of genetic tools in Toxoplasma, and then in Plasmodium, in the 1990s allowed the first description of the molecular machinery used for motility and invasion, revealing a crucial role for two different secretory organelles, micronemes and rhoptries. Rhoptry proteins are injected directly into the host cytoplasm not only to promote invasion but also to manipulate host functions. Nonetheless, the injection machinery has remained mysterious, a major conundrum in the field. Here we review recent progress in uncovering structural components and proteins implicated in rhoptry exocytosis and explain how revisiting early findings and considering the evolutionary origins of Apicomplexa contributed to some of these discoveries.
Topics: Animals; Apicomplexa; Cells; Exocytosis; Host-Parasite Interactions; Humans; Organelles; Protozoan Proteins
PubMed: 34045149
DOI: 10.1016/j.pt.2021.04.011 -
Trends in Parasitology Sep 2018Increased parasite burden is linked to the severity of clinical disease caused by Apicomplexa parasites such as Toxoplasma gondii, Plasmodium spp, and Cryptosporidium.... (Review)
Review
Increased parasite burden is linked to the severity of clinical disease caused by Apicomplexa parasites such as Toxoplasma gondii, Plasmodium spp, and Cryptosporidium. Pathogenesis of apicomplexan infections is greatly affected by the growth rate of the parasite asexual stages. This review discusses recent advances in deciphering the mitotic structures and cell cycle regulatory factors required by Apicomplexa parasites to replicate. As the molecular details become clearer, it is evident that the highly unconventional cell cycles of these parasites is a blending of many ancient and borrowed elements, which were then adapted to enable apicomplexan proliferation in a wide variety of different animal hosts.
Topics: Apicomplexa; Cell Cycle; Host-Parasite Interactions; Protozoan Infections
PubMed: 30078701
DOI: 10.1016/j.pt.2018.07.006 -
Current Opinion in Microbiology Aug 2015Pore-forming proteins (PFPs) encompass a broad family of proteins that are used for virulence or immune defense. Members of the cholesterol-dependent cytolysins (CDCs)... (Review)
Review
Pore-forming proteins (PFPs) encompass a broad family of proteins that are used for virulence or immune defense. Members of the cholesterol-dependent cytolysins (CDCs) and membrane attack complex/perforin (MACPF) family of PFPs form large β-barrel pores in the membrane. The CDC/MACPF proteins contain a characteristic four-stranded β-sheet that is flanked by two α-helical bundles, which unfold to form two transmembrane β-hairpins. Apicomplexan eukaryotic parasites express CDC/MACPFs termed perforin-like proteins (PLPs). Here we review recent studies that provide key insights into the assembly and regulation of the Apicomplexan PLP (ApiMACPF) molecular pore-forming mechanisms, which are necessary for the osmotically driven rupture of the parasitophorous vacuole and host cell membrane, and cell traversal by these parasites.
Topics: Apicomplexa; Host-Pathogen Interactions; Macromolecular Substances; Perforin; Protein Conformation; Protein Multimerization
PubMed: 26025132
DOI: 10.1016/j.mib.2015.05.001 -
Biomedical Journal Feb 2017Apicomplexan parasites are responsible for a number of important human pathologies. Obviously, as Eukaryotes they share a number of cellular features and pathways with... (Review)
Review
Apicomplexan parasites are responsible for a number of important human pathologies. Obviously, as Eukaryotes they share a number of cellular features and pathways with their respective host cells. One of them is autophagy, a process involved in the degradation of the cell's own components. These intracellular parasites nonetheless seem to present a number of original features compared to their very evolutionarily distant host cells. In mammals and other metazoans, autophagy has been identified as an important contributor to the defence against microbial pathogens. Thus, host autophagy also likely plays a key role in the control of apicomplexan parasites, although its potential manipulation and subversion by intracellular parasites creates a complex interplay in the regulation of host and parasite autophagy. In this mini-review, we summarise current knowledge on autophagy in both parasites and their host cells, in the context of infection by three Apicomplexa: Plasmodium, Toxoplasma, and Theileria.
Topics: Animals; Autophagy; Host-Parasite Interactions; Humans; Parasites; Plasmodium; Theileria; Toxoplasma
PubMed: 28411879
DOI: 10.1016/j.bj.2017.01.001 -
Trends in Parasitology Dec 2017Apicomplexan parasites Toxoplasma gondii and Plasmodium spp. use latent stages to persist in the host, facilitate transmission, and thwart treatment of infected... (Review)
Review
Apicomplexan parasites Toxoplasma gondii and Plasmodium spp. use latent stages to persist in the host, facilitate transmission, and thwart treatment of infected patients. Therefore, it is important to understand the processes driving parasite differentiation to and from quiescent stages. Here, we discuss how a family of protein kinases that phosphorylate the eukaryotic initiation factor-2 (eIF2) function in translational control and drive differentiation. This translational control culminates in reprogramming of the transcriptome to facilitate parasite transition towards latency. We also discuss how eIF2 phosphorylation contributes to the maintenance of latency and provides a crucial role in the timing of reactivation of latent parasites towards proliferative stages.
Topics: Apicomplexa; Eukaryotic Initiation Factor-2; Host-Parasite Interactions; Humans; Life Cycle Stages; Phosphorylation; Protozoan Proteins; Transcriptome
PubMed: 28942109
DOI: 10.1016/j.pt.2017.08.006 -
Molecular Microbiology May 2021Babesia species are tick-borne intracellular parasites that infect the red blood cells of their mammalian host, leading to severe or fatal disease. Babesia spp. infect a... (Review)
Review
Babesia species are tick-borne intracellular parasites that infect the red blood cells of their mammalian host, leading to severe or fatal disease. Babesia spp. infect a wide range of mammalian species and cause a significant economic burden globally, predominantly through disease in cattle. Several Babesia spp. are increasingly being recognized as zoonotic pathogens of humans. Babesia spp. have complex life cycles involving multiple stages in the tick and the mammalian host. The parasite utilizes complex signaling pathways during replication, egress, and invasion in each of these stages. They must also rapidly respond to their environment when switching between the mammalian and tick stages. This review will focus on the signaling pathways and environmental stimuli that Babesia spp. utilize in the bloodstream and for transmission to the tick, with an emphasis on the role of phosphorylation- and calcium-based signaling during egress and invasion. The expanding availability of in vitro and in vivo culture systems, genomes, transcriptomes, and transgenic systems available for a range of Babesia spp. should encourage further biological and translational studies of these ubiquitous parasites.
Topics: Animals; Babesia; Babesiosis; Humans; Life Cycle Stages; Protozoan Proteins; Signal Transduction; Ticks
PubMed: 33274587
DOI: 10.1111/mmi.14650 -
The Journal of Biological Chemistry Jan 2020The Apicomplexa phylum comprises diverse parasitic organisms that have evolved from a free-living ancestor. These obligate intracellular parasites exhibit versatile... (Review)
Review
The Apicomplexa phylum comprises diverse parasitic organisms that have evolved from a free-living ancestor. These obligate intracellular parasites exhibit versatile metabolic capabilities reflecting their capacity to survive and grow in different hosts and varying niches. Determined by nutrient availability, they either use their biosynthesis machineries or largely depend on their host for metabolite acquisition. Because vitamins cannot be synthesized by the mammalian host, the enzymes required for their synthesis in apicomplexan parasites represent a large repertoire of potential therapeutic targets. Here, we review recent advances in metabolic reconstruction and functional studies coupled to metabolomics that unravel the interplay between biosynthesis and salvage of vitamins and cofactors in apicomplexans. A particular emphasis is placed on , during both its acute and latent stages of infection.
Topics: Apicomplexa; Coenzymes; Host-Parasite Interactions; Humans; Metabolic Networks and Pathways; Protein Biosynthesis; Toxoplasma; Toxoplasmosis; Vitamins
PubMed: 31767680
DOI: 10.1074/jbc.AW119.008150 -
Molecular Microbiology Mar 2022Apicomplexan parasites encompass diverse pathogens for humans and animals, including the causative agents of malaria and toxoplasmosis, Plasmodium spp. and Toxoplasma... (Review)
Review
Apicomplexan parasites encompass diverse pathogens for humans and animals, including the causative agents of malaria and toxoplasmosis, Plasmodium spp. and Toxoplasma gondii. Genetic manipulation of these parasites has become central to explore parasite biology, unravel gene function and identify new targets for therapeutic strategies. Tremendous progress has been achieved over the past years with the advent of next generation sequencing and powerful genome editing methods. In particular, various methods for conditional gene expression have been developed in both Plasmodium and Toxoplasma to knockout or knockdown essential genes, or for inducible expression of master developmental regulators or mutant versions of proteins. Conditional gene expression can be achieved at three distinct levels. At the DNA level, inducible site-specific recombinases allow conditional genome editing. At the RNA level, regulation can be achieved during transcription, using stage-specific or regulatable promoters, or post-transcriptionally through alteration of mRNA stability or translation. At the protein level, several systems have been developed for inducible degradation or displacement of a protein of interest. In this review, we provide an overview of current systems for conditional control of gene expression in Plasmodium and Toxoplasma parasites, highlighting the advantages and limitations of each approach.
Topics: Animals; Gene Expression; Genes, Essential; Parasites; Plasmodium; Toxoplasma
PubMed: 34564906
DOI: 10.1111/mmi.14821