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PubMed2006

The complete plastid genome sequence of the parasitic green alga Helicosporidium sp. is highly reduced and structured.

BACKGROUND: Loss of photosynthesis has occurred independently in several plant and algal lineages, and represents a major metabolic shift with potential consequences for the content and structure of plastid genomes. To investigate such changes, we sequenced the complete plastid genome of the parasitic, non-photosynthetic green alga, Helicosporidium. RESULTS: The Helicosporidium plastid genome is among the smallest known (37.5 kb), and like other plastids from non-photosynthetic organisms it lacks all genes for proteins that function in photosynthesis. Its reduced size results from more than just loss of genes, however; it has little non-coding DNA, with only one intron and tiny intergenic spaces, and no inverted repeat (no duplicated genes at all). It encodes precisely the minimal complement of tRNAs needed to translate the universal genetic code, and has eliminated all redundant isoacceptors. The Helicosporidium plastid genome is also highly structured, with each half of the circular genome containing nearly all genes on one strand. Helicosporidium is known to be related to trebouxiophyte green algae, but the genome is structured and compacted in a manner more reminiscent of the non-photosynthetic plastids of apicomplexan parasites. CONCLUSION: Helicosporidium contributes significantly to our understanding of the evolution of plastid DNA because it illustrates the highly ordered reduction that occurred following the loss of a major metabolic function. The convergence of plastid genome structure in Helicosporidium and the Apicomplexa raises the interesting possibility that there are common forces that shape plastid genomes, subsequent to the loss of photosynthesis in an organism.

Chlorophyta↗
PubMed2003

Mutation of an unusual mitochondrial targeting sequence of SODB2 produces multiple targeting fates in Toxoplasma gondii.

Proteins destined for the mitochondria travel an intricate pathway through two membranes, each with its own receptors and channels. These proteins interact with receptors via N-terminal presequences that form amphipathic helices. Generally, these helices contain abundant positive charges on one face and hydrophobic residues on the other, but share little primary sequence homology. While extensive research on mitochondrial import has been done in yeast and mammalian cells, little is known about import or contents of the single mitochondrion of Toxoplasma gondii, a parasite in the phylum Apicomplexa. We describe here the characterization of TgSODB2, a novel, mitochondrial superoxide dismutase in T. gondii with an unusual targeting sequence consisting of a hydrophobic segment resembling a signal peptide, followed by a presequence. We show that although the hydrophobic segment is competent to target a reporter protein to the secretory system, it is prevented from directing ER translocation when coupled with the presequence. When we mutated the only charged residue in the hydrophobic sequence, ER translocation is restored and the reporter targeted to the apicoplast, a chloroplast-like organelle found in most apicomplexans. The presequence that follows is predicted to form an amphipathic helix, but targeted the cytoplasm when the hydrophobic peptide is removed. In addition to having an unusual targeting sequence, TgSODB2 is only the second mitochondrially imported, iron-containing SOD to be described.

Amino Acid Sequence↗
PubMed2004

The Plasmodium falciparum Vps4 homolog mediates multivesicular body formation.

Members of the apicomplexan family of parasites contain morphologically unique secretory organelles termed rhoptries that are essential for host cell invasion. Rhoptries contain internal membranes, and thus resemble multivesicular bodies. To determine whether multivesicular body endosomal intermediates are formed in Apicomplexa, we used the Plasmodium falciparum homolog of the class E gene, Vps4, as a probe. Endogenous P. falciparum Vps4 (PfVps4) localized to the cytoplasm of P. falciparum trophozoites, and transgenic PfVps4 localized to the cytosol in P. falciparum, in the related parasite Toxoplasma gondii and in COS cells. When mutated to block ATP hydrolysis, transiently expressed PfVps4 localized instead to large vesicular structures in P. falciparum. The same construct, and another mutant blocked in ATP binding, generated large cholesterol-enriched multivesicular bodies in both COS cells and T. gondii. Mutant PfVps4 structures in T. gondii co-localized with markers for early endosomes. These results demonstrate a conservation of Vps4 function across wide phylogenetic boundaries, and indicate that endosomal multivesicular bodies form in both P. falciparum and T. gondii.

Adenosine Triphosphatases↗
PubMed2000

Toxoplasma gondii catalase: are there peroxisomes in toxoplasma?

The intracellular protozoan parasite Toxoplasma gondii, like all members of the phylum Apicomplexa, is known to possess many organelles: in addition to mitochondria and the compartments of the secretory pathway, there is a reduced chloroplast (the apicoplast) and the phylum-specific components of the apical complex: dense granules, micronemes and rhoptries. Conspicuously missing so far are microbodies, organelles that can be found in nearly all eukaryotic organisms. Microbodies show a large variation with regard to their size, number and contents, depending on the organism and cell type. One marker enzyme of this single membrane-bound organelle is catalase, which is responsible for the degradation of hydrogen peroxide to water and oxygen. The EST project in T. gondii revealed the existence of two overlapping clones which showed similarity with catalase, and these were used to clone the corresponding gene. The predicted sequence of T. gondii catalase has -AKM at the C terminus, which falls within the consensus of the PTS1 peroxisomal targeting signal. Southern blot analysis confirmed the presence of a single copy gene. Northern and western blot analyses showed that the catalase gene is transcribed and translated. Immunofluorescence assays using an antibody raised against a catalase peptide identified a distinct structure towards the apical end, but other catalase-specific antibodies failed to confirm this localisation. Cell fractionations indicated that the majority of the enzyme was in the cytosol. The fusion of the C-terminal twelve amino acids, including AKM, or the canonical peroxisomal targeting signal, -SKL, to GFP resulted in predominantly cytosolic localization in T. gondii. There was therefore no evidence for membrane-bound peroxisomes in Toxoplasma.

Amino Acids↗
PubMed2025

RNG2 tethers the conoid to the apical polar ring in Toxoplasma gondii to enable parasite motility and invasion.

The conoid is a dynamic, tubulin-based structure conserved across the Apicomplexa that undergoes extrusion during egress, gliding motility, and invasion in Toxoplasma gondii. This organelle traverses the apical polar ring (APR) in response to calcium waves and plays a critical role in controlling parasite motility. While the actomyosin-dependent extrusion of the conoid is beginning to be elucidated, the mechanism by which it remains apically anchored to the APR is still unclear. RNG2, a protein localized to both the conoid and the APR, has emerged as a strong candidate for mediating this connection. Biochemical analysis revealed that RNG2 is an unstable protein, undergoing extensive proteolytic cleavage both in the parasite and in heterologous expression systems. Its biochemical properties, with the presence of large coiled-coil domains, likely facilitate the formation of concatenated assemblies, enabling RNG2 to serve as a dynamic and resilient bridge between the conoid and the APR. Using a combination of iterative ultrastructure expansion microscopy and immunoelectron microscopy, we confirmed the localization of RNG2 to the 22 tethering elements bridging the APR and the conoid. Conditional depletion of RNG2 led to the striking detachment of the intact conoid organelle from the APR, supporting an essential role for RNG2 as a tether. Cryo-electron tomography of conoid-less parasites revealed that, in the absence of RNG2, the apical vesicle remains anchored to the plasma membrane, while the rhoptries follow the detached conoid. Although RNG2 depletion only mildly reduces microneme secretion, the parasites are immotile and exhibit impaired rhoptry discharge, highlighting the critical role of proper conoid anchorage in motility and host cell invasion. Comprehensive mutagenesis of RNG2 identified distinct regions responsible for binding to the conoid and the APR, and demonstrated that the full-length, intact protein is essential for bridging these two structures and for its functional activity. Altogether, RNG2 emerges as a pivotal protein that ensures conoid functionality and coordination in Coccidia.

Toxoplasma↗
PubMed2005

Identification of the moving junction complex of Toxoplasma gondii: a collaboration between distinct secretory organelles.

Apicomplexan parasites, including Toxoplasma gondii and Plasmodium sp., are obligate intracellular protozoa. They enter into a host cell by attaching to and then creating an invagination in the host cell plasma membrane. Contact between parasite and host plasma membranes occurs in the form of a ring-shaped moving junction that begins at the anterior end of the parasite and then migrates posteriorly. The resulting invagination of host plasma membrane creates a parasitophorous vacuole that completely envelops the now intracellular parasite. At the start of this process, apical membrane antigen 1 (AMA1) is released onto the parasite surface from specialized secretory organelles called micronemes. The T. gondii version of this protein, TgAMA1, has been shown to be essential for invasion but its exact role has not previously been determined. We identify here a trio of proteins that associate with TgAMA1, at least one of which associates with TgAMA1 at the moving junction. Surprisingly, these new proteins derive not from micronemes, but from the anterior secretory organelles known as rhoptries and specifically, for at least two, from the neck portion of these club-shaped structures. Homologues for these AMA1-associated proteins are found throughout the Apicomplexa strongly suggesting that this moving junction apparatus is a conserved feature of this important class of parasites. Differences between the contributing proteins in different species may, in part, be the result of selective pressure from the different niches occupied by these parasites.

Animals↗
PubMed2004

Genotyping of Cryptosporidium parvum with microsatellite markers.

Recent outbreaks of cryptosporidiosis caused by Cryptosporidium parvum in the United States and other countries, as well as the emergence of cryptosporidiosis as a frequent cause of morbidity and mortality in immunodeficient individuals, have raised the interest of the research community in this parasite. The genus Cryptosporidium, phylum Apicomplexa, comprises an undefined number of species, of which only C. parvum is of public health concern. Cryptosporidiosis is contracted through the ingestion of oocysts, the stage of the parasite produced in large numbers by infected hosts. Because the oocysts are small, typically about 5 microm in diameter, and lack species-specific morphological features, there is a need for molecular markers to distinguish between human-infectious C. parvum and other species that do not (or only infrequently) cause disease in humans. Genetic characterization of Cryptosporidium oocysts using restriction fragment length or sequence polymorphism has revealed host-associated genotypes, that are often referred to as species. In addition, C. parvum was found to include two genotypes, designated type 1 and type 2. Type 1 is almost exclusively found in humans, whereas type 2 infects humans and various mammalian hosts. The frequent occurrence of Cryptosporidium oocysts in untreated surface water and the potential for contamination of drinking water have emphasized the need for molecular markers to track the source of oocysts within a watershed or water distribution system, and to discriminate between oocysts infectious to humans and nonpathogenic species. Genetic markers are also needed to study the taxonomy of Cryptosporidium. Several laboratories have identified microsatellites in the genome of C. parvum and have investigated the level of polymorphism at these loci. For instance, 10 alleles of marker 5B12 have been found to date among C. parvum isolates from various geographical and host origins. Multilocus haplotypes based on such markers are suitable for discriminating individual isolates of C. parvum. In an attempt to develop rapid and cost-effective methods for typing isolates of C. parvum, we have pursued two methods, a traditional polymerase chain reaction (PCR) method followed by gel electrophoresis, and real-time PCR using SYBR Green I melting curve analysis for allele identification.

Animals↗
PubMed2005

The plastid-derived organelle of protozoan human parasites as a target of established and emerging drugs.

Human diseases like malaria, toxoplasmosis or cryptosporidiosis are caused by intracellular protozoan parasites of the phylum Apicomplexa and are still a major health problem worldwide. In the case of Plasmodium falciparum, the causative agent of tropical malaria, resistance against previously highly effective drugs is widespread and requires the continued development of new and affordable drugs. Most apicomplexan parasites possess a single plastid-derived organelle called apicoplast, which offers the great opportunity to tailor highly specific inhibitors against vital metabolic pathways resident in this compartment. This is due to the fact that several of these pathways, being of bacterial or algal origin, are absent in the mammalian host. In fact, the targets of several antibiotics already in use for years against some of these diseases can now be traced to the apicoplast and by knowing the molecular entities which are affected by these substances, improved drugs or drug combinations can be envisaged to emerge from this knowledge. Likewise, apicoplast-resident pathways like fatty acid or isoprenoid biosynthesis have already been proven to be the likely targets of the next drug generation. In this review the current knowledge on the different targets and available inhibitors (both established and experimental) will be summarised and an overview of the clinical efficacy of drugs that inhibit functions in the apicoplast and which have been tested in humans so far will be given.

Animals↗
PubMedDate not supplied

Regional variation in toxoplasmosis seronegativity in the São Paulo metropolitan region.

Toxoplasmosis is a highly prevalent zoonotic human infection caused by the Apicomplexa protozoon Toxoplasma gondii. The acute disease is usually mild or asymptomatic, except for foetal infection transmitted by acutely infected pregnant women, which courses as a devastating disease. In order to determine possible regional variations in risk factors, we studied the frequency of seronegativity in areas of the São Paulo Metropolitan Region, comparing titers and age groups. The prevalence of seronegativity was determined retrospectively in 1286 pregnant women receiving prenatal care at public health services in four selected areas of the São Paulo Metropolitan Region of similar socioeconomic background. The São Paulo City area had the higher frequency of seronegativity (41.1%), followed by the Northwest (31.5%) and Southwest (29.9%) areas, with similar intermediate levels, and by the Northeast (22.5%) area with the lowest frequency (p < 0.001). A rough estimate disclosed about 280 infected infants/year in the São Paulo Metropolitan Region. Serological titers analyzed by age group suggested a decline in antibody levels with age, as shown by a lower frequency of higher titers in older groups. Our study emphasizes the importance of determining the regional prevalence of toxoplasmosis for proper planning of public health prenatal care.

Adolescent↗
PubMed1992

Molecular approaches to malaria and babesiosis diagnosis.

The development of additional methods for detecting and identifying Babesia and Plasmodium infections may be useful in disease monitoring, management and control efforts. The preliminary evaluate synthetic peptide-based serodiagnosis, a hydrophilic sequence (DDESEFDKEK) was selected from the published BabR gene of B. bovis. Immunization of rabbits and cattle with the hemocyanin-conjugated peptide elicited antibody responses that specifically detected both P. falciparum and B. bovis antigens by immunofluorescence and Western blots. Using a dot-ELISA with this peptide, antisera from immunized and naturally-infected cattle, and immunized rodents, were specifically detected. Reactivity was weak and correlated with peptide immunization or infection. DNA-based detection using repetitive DNA was species-specific in dot-blot formats for B. bovis DNA, and in both dot-blot and in situ formats for P. falciparum; a streamlined enzyme-linked synthetic DNA assay for P. falciparum detected 30 parasites/mm3 from patient blood using either colorimetric (2-15 h color development) or chemiluminescent detection (0.5-6-min exposures). Serodiagnostic and DNA hybridization methods may be complementary in the respective detection of both chronic and acute infections. However, recent improvements in the polymerase chain reaction (PCR) make feasible a more sensitive and uniform approach to the diagnosis of these and other infectious disease complexes, with appropriate primers and processing methods. An analysis of ribosomal DNA genes of Plasmodium and Toxoplasma identified Apicomplexa-conserved sequence regions. Specific and distinctive PCR profiles were obtained for primers spanning the internal transcribed spacer locus for each of several Plasmodium and Babesia species.

Amino Acid Sequence↗
PubMed2003

Enzootic Babesia microti in Maine.

Human babesiosis in the northeastern United States caused by Babesia microti (Apicomplexa: Piroplasmida) is mainly reported from coastal New England sites, where deer ticks (Ixodes dammini) are common. However, the piroplasm has been detected in microtine rodents elsewhere in association with I. angustus or other nidicolous ticks, suggesting that the agent is widely distributed but zoonotically significant only where a human-biting "bridge" vector is present. To determine whether this piroplasm may be enzootic in areas where I. dammini is absent, we surveyed small mammals collected from 2 sites in Maine, where I. angustus or I. muris is common but I. dammini is not. Of 43 chipmunks, voles, deer mice, and shrews examined, 3 (6.9, 95% confidence interval 0 to 14.5) were parasitemic, as determined by blood smear or polymerase chain reaction targeting a piroplasm-specific portion of the 18S ribosomal DNA gene. Phylogenetic analysis of the sequenced amplification products demonstrates the presence of 2 forms of B. microti. We conclude that B. microti may be enzootic in the absence of I. dammini but that human risk relates to dense infestations of this human-biting tick.

Animals↗
PubMed2005

Molecular characterization of isosporoid coccidia (Isospora and Atoxoplasma spp.) in passerine birds.

Prevalence and disease caused by isosporoid coccidia in passerine birds are well recognized, but confusion about the life cycles of the parasites has led to taxonomic inconsistencies. In this study, we characterized segments of the chromosomal small and large-subunit ribosomal RNA (rRNA) genes of coccidial parasites from 23 species of passerine birds, as well as heat shock protein 70, apicoplast rRNA, and chromosomal 5.8s rRNA genes from a subgroup of these animals, and we correlated genetic data with morphologic findings for different parasite developmental stages, host phylogeny, and overall taxonomic relations within the phylum Apicomplexa. Our findings indicate that isosporoid coccidia of passerine birds are monophyletic but exhibit substantial diversity, with most avian species having one or several unique parasite lineages that underwent synchronous speciation with their hosts, interrupted by sporadic episodes of lateral transmission across species and families. Molecular analyses support a homoxenous life cycle, with sexual forms occurring chiefly in the intestines and asexual merozoites present systemically. Rarely, extraintestinal sexual stages can occur. The passerine coccidia are genetically most closely related to species of Eimeria rather than Isospora. We suggest that these parasites, whether identified from blood merozoite stages or fecal oocysts, be provisionally grouped as a homogeneous clade of individual species in a single taxon and formally named when reliable criteria allowing reclassification of related genera in the suborder Eimeriina are clarified.

Animals↗
PubMed2025

Plasmodium ARK1 regulates spindle formation during atypical mitosis and forms a divergent chromosomal passenger complex.

Mitosis in Plasmodium spp., the causative agent of malaria, is fundamentally different from model eukaryotes, proceeding via a bipartite microtubule organising centre (MTOC) and lacking canonical regulators such as Polo and Bub1 kinases. During schizogony, asynchronous nuclear replication produces a multinucleate schizont, while rapid male gametogony generates an octaploid nucleus before gamete formation. Here, we identify Aurora-related kinase 1 (ARK1) as a key component of inner MTOC and spindle formation, controlling kinetochore dynamics and driving mitotic progression. Conditional ARK1 depletion disrupts spindle biogenesis, kinetochore segregation, karyokinesis and cytokinesis in both stages, and affects parasite transmission. Interactome analysis reveals ARK1 as the catalytic core of a non-canonical chromosomal passenger complex (CPC) containing two divergent inner centromere proteins (INCENPs) but lacking Survivin and Borealin. Comparative genomics indicates this CPC architecture arose early in Apicomplexa, replacing canonical centromere-targeting modules. These findings uncover a distinct mitotic machinery in Plasmodium and identify the ARK1-INCENP interface as a potential multistage target for malaria therapeutic intervention.

Aurora kinase↗
PubMed2005

Drug-induced expansion and differentiation of V gamma 9V delta 2 T cells in vivo: the role of exogenous IL-2.

Human Vgamma9Vdelta2 T cells recognize nonpeptidic Ags generated by the 1-deoxy-d-xylulose 5-phosphate (many eubacteria, algae, plants, and Apicomplexa) and mevalonate (eukaryotes, archaebacteria, and certain eubacteria) pathways of isoprenoid synthesis. The potent Vgamma9Vdelta2 T cell reactivity 1) against certain cancer cells or 2) induced by infectious agents indicates that therapeutic augmentations of Vgamma9Vdelta2 T cell activities may be clinically beneficial. The functional characteristics of Vgamma9Vdelta2 T cells from Macaca fascicularis (cynomolgus monkey) are very similar to those from Homo sapiens. We have found that the i.v. administration of nitrogen-containing bisphosphonate or pyrophosphomonoester drugs into cynomolgus monkeys combined with s.c. low-dose (6 x 10(5) U/animal) IL-2 induces a large pool of CD27+ and CD27- effector/memory T cells in the peripheral blood of treated animals. The administration of these drugs in the absence of IL-2 is substantially less effective, indicating the importance of additional exogenous costimuli. Shortly after the costimulatory IL-2 treatment, only gammadelta (but not alphabeta) T cells expressed the CD69 activation marker, indicating that Vgamma9Vdelta2 T lymphocytes are more responsive to low-dose IL-2 than alphabeta T cells. Up to 100-fold increases in the numbers of peripheral blood Vgamma9Vdelta2 T cells were observed in animals receiving the gammadelta stimulatory drug plus IL-2. Moreover, the expanded Vgamma9Vdelta2 T cells were potent Th1 effectors capable of releasing large amounts of IFN-gamma. These results may be relevant for designing novel (or modifying current) immunotherapeutic trials with nitrogen-containing bisphosphonate or pyrophosphomonoester drugs.

2,3-Diphosphoglycerate↗
PubMed1985

Detection of Plasmodium falciparum using a synthetic DNA probe.

A labeled synthetic polynucleotide representing a repetitive sequence from Plasmodium falciparum was hybridized with genomic DNA spotted on nitrocellulose. After an overnight exposure, 0.1 ng of P. falciparum DNA was specifically detected and 0.01 ng was detected after an exposure of 1 week. The synthetic probe showed no cross-hybridization with host DNA or with DNA isolated from other species in the phylum Apicomplexa, P. vivax and Babesia species. Since synthetic DNA is easily prepared, the observed sensitivity and specificity suggests that synthetic DNA probes would be generally useful in diagnosis.

Animals↗
PubMed1995

Cyst wall ultrastructure of two Sarcocystis spp. from European mouflon (Ovis ammon musimon) in Germany compared with domestic sheep.

Muscle samples from six wild and two captive European mouflons (Ovis ammon musimon) in Germany as well as one domestic sheep from a German zoo were infected with sarcocysts (Sarcocystis: Sarcocystidae, Apicomplexa). Sarcocystis tenella and S. arieticanis were identified by light and electron microscopy. Both species are determined for the first time from wild sheep, and this is the first description of S. arieticanis from wild sheep.

Animals↗
PubMed1999

Active isoprenoid pathway in the intra-erythrocytic stages of Plasmodium falciparum: presence of dolichols of 11 and 12 isoprene units.

N-glycosylation of proteins is required for the intra-erythrocytic schizogony of Plasmodium falciparum. In eukaryotic cells, this process involves the transfer of oligosaccharides from a dolichyl pyrophosphate derivative to asparagine residues. We have identified dolichol, dolichyl phosphate and dolichyl pyrophosphate species of 11 and 12 isoprenoid residues by metabolic labelling with [(3)H]farnesyl pyrophosphate, [(3)H]geranylgeranyl pyrophosphate and [(14)C]acetate in the different intra-erythrocytic stages of P. falciparum. This is the first demonstration of short-chain dolichols in the phylum Apicomplexa. The results demonstrate the presence of an active isoprenoid pathway in the intra-erythrocytic stages of P. falciparum. Parasites treated with mevastatin, a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, show depressed biosynthesis of dolichol, dolichyl phosphate and isoprenoid pyrophosphate. This effect is observed in all intra-erythrocytic stages of the parasite life cycle, but is most pronounced in the ring stage. N-linked glycosylation of proteins was inhibited in the ring and young-trophozoite stages after mevastatin treatment of parasite cultures. Therefore the isoprenoid pathway may represent a different approach to the development of new anti-malarial drugs.

Animals↗
PubMedDate not supplied

[The taxonomic rank and place of Colpodellida in the system of the Protista].

The analysis of ultrastructure organisation and divergent processes in Colpodellida, Perkinsida, Gregarinea and Coccidea has confirmed the presence of unique basic structures in all of these organisms and the necessity to combine them into the single phylum Sporozoa. A taxonomic rank and place of Colpodellida in the system of living organisms is represented as follows: phylum Sporozoa Leuckart, 1879; em. Krylov, Mylnikov, 1986. (Syn.: Apicomplexa Levine, 1970). Predators or parasites. Common basic structure: pellicular membranes, subpellicular microtubules, micropores, conoid, rhoptries and micronemes, tubular mitochondrial cristae. Class Perkinsea Levine, 1978. Predators or parasites, vegetative stages with two heterodynamic flagella. Subclass 1. Colpodellia nom. nov. (Syn.: Spiromonadia Krylov, Mylnikov, 1986). Predators, two heterodynamic flagella with string-like mastigonemes (if present), division is exclusively within a cyst, with 2-4 daughter cells being produced, extrusomes are trichocyst-like. Subclass 2. Perkinsia Levine, 1978. Parasites, zoospores with two heterodynamic flagella, mastigonemes (if present) bristle-like or string-like.

Animals↗