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PubMed1985

Polymorphism of a high molecular weight schizont antigen of the human malaria parasite Plasmodium falciparum.

Intraspecies antigenic diversity in the blood stages of the human malaria parasite Plasmodium falciparum was investigated using a collection of murine monoclonal antibodies and clones of the parasite. The results were as follows: (a) The schizont and merozoite stages of the parasite express on their surface clonally restricted antigens detectable by strain-specific antibodies in indirect immunofluorescence tests. (b) These restricted antigens are phenotypically stable characteristics of clones grown in vitro. (c) The molecules carrying the specific antigens were isolated by immunoprecipitation and were found to be parasite proteins ranging in size from Mr 190,000 to 200,000 between clones. (d) Comparative immunoprecipitation and peptide mapping of these molecules showed that each parasite clone expresses a protein that is antigenically and structurally distinct from the equivalent products of several other clones. (e) The different clonal products are, however, immunologically interrelated, since they possess determinants in common with all tested isolates of the parasite. (f) These polymorphic molecules are closely related to a previously described schizont protein of P. falciparum that is posttranslationally cleaved into fragments located on the merozoite surface. These findings show the existence of a family of related polymorphic schizont antigens (PSA) of P. falciparum, whose expression is clonally restricted, and indicate that these proteins have regions of constant and variable antigenicity. We propose that a system of immunological classification of the parasite can be developed based on the polymorphism of these proteins.

Animals↗
PubMed1995

Transmission blocking immunity in Plasmodium vivax malaria: antibodies raised against a peptide block parasite development in the mosquito vector.

One approach towards the development of a vaccine against malaria is to immunize against the parasite sexual stages that mediate transmission of the parasite from man to mosquito. Antibodies against these stages, ingested with the blood meal, inhibit the parasite development in the mosquito vector, constituting "transmission blocking immunity." Most epitopes involved in transmission-blocking immunity depend on the tertiary conformational structure of surface antigens. However, one of the transmission-blocking monoclonal antibodies we have raised against Plasmodium vivax reacts with a linear epitope on both asexual stages and gametes. This monoclonal antibody (A12) is capable of totally blocking development of the parasite in the mosquito host when tested in membrane feeding assays with gametocytes from P. vivax-infected patients. Immune screening of a P. vivax lambda gt11 genomic expression library with A12 led to the isolation of a clone to which was mapped the six-amino acid epitope recognized by A12. Antisera raised in mice against a 12-mer synthetic peptide containing this epitope coupled to bovine serum albumin not only had high titers of antipeptide antibodies as measured by enzyme-linked immunosorbent assay, but in addition recognized the same 24- and 57-kD parasite components as A12 on Western blots and reacted with the parasite by immunofluorescence. When tested in membrane feeding assays, these antibodies have significant suppressive effects on parasite development in the mosquito.

Amino Acid Sequence↗
PubMed1995

Maintenance of the human malarial parasite, Plasmodium falciparum, in scid mice and transmission of gametocytes to mosquitoes.

The study of human malaria has been hampered by the lack of small animal models for the human-infecting malarial parasites. To approach this problem, the erythrocytic stages of the human malarial parasite Plasmodium falciparum were adapted to in vitro growth in the presence of ascites fluid from mice homozygous for the severe-combined immunodeficiency (scid) mutation. Human red blood cells (hRBCs) infected with these adapted parasites were then injected i.p. into nonobese diabetic scid/scid (NOD/LtSz-scid) mice. With daily supplemental intraperitoneal boosts of uninfected hRBCs, parasites were detected in the peripheral circulation of these mice for an average of 7 d after injection. Splenectomy of NOD/LtSz-scid mice increased both the level and duration of parasitemia in the periphery, and it also promoted the circulation of mature sexual stage parasites (gametocytes). When Anopheline mosquitoes were allowed to feed on the splenectomized mice, the gametocytes were ingested by the mosquitoes and developed into oocysts in the mosquito midguts. To our knowledge, these results are the first demonstration of human malarial parasite propagation in mice and transmission of these parasites to the invertebrate vector.

Animals↗
PubMed2002

The mechanism and significance of deletion of parasite-specific CD4(+) T cells in malaria infection.

It is thought that both helper and effector functions of CD4(+) T cells contribute to protective immunity to blood stage malaria infection. However, malaria infection does not induce long-term immunity and its mechanisms are not defined. In this study, we show that protective parasite-specific CD4(+) T cells were depleted after infection with both lethal and nonlethal species of rodent PLASMODIUM: It is further shown that the depletion is confined to parasite-specific T cells because (a) ovalbumin (OVA)-specific CD4(+) T cells are not depleted after either malaria infection or direct OVA antigen challenge, and (b) the depletion of parasite-specific T cells during infection does not kill bystander OVA-specific T cells. A significant consequence of the depletion of malaria parasite-specific CD4(+) T cells is impaired immunity, demonstrated in mice that were less able to control parasitemia after depletion of transferred parasite-specific T cells. Using tumor necrosis factor (TNF)-RI knockout- and Fas-deficient mice, we demonstrate that the depletion of parasite-specific CD4(+) T cells is not via TNF or Fas pathways. However, in vivo administration of anti-interferon (IFN)-gamma antibody blocks depletion, suggesting that IFN-gamma is involved in the process. Taken together, these data suggest that long-term immunity to malaria infection may be affected by an IFN-gamma-mediated depletion of parasite-specific CD4(+) T cells during infection. This study provides further insight into the nature of immunity to malaria and may have a significant impact on approaches taken to develop a malaria vaccine.

Animals↗
PubMed2003

Leishmania major LACK antigen is required for efficient vertebrate parasitization.

The Leishmania major LACK antigen is a key target of the immune response in susceptible BALB/c mice and remains a viable vaccine candidate for human leishmaniasis. We describe the genomic organization of the four lack genes in the L. major diploid genome together with results of selected lack gene targeting. Parasites containing a single lack gene in either the upstream or downstream locus grew comparably to wild-type promastigotes in vitro, but failed to parasitize BALB/c mice efficiently, even in a T cell-deficient environment. The replication of single copy lack mutants as amastigotes was attenuated in macrophages in vitro, and parasites failed to increase in numbers in immunodeficient mice, despite their persistence over months. Complementation with an additional lack copy was sufficient to induce robust lesion development, which also occurred using parasites with two lack genes. Conversely, attempts to generate lack-null parasites failed, suggesting that LACK is required for parasite viability. These data suggest that LACK is critical for effective mammalian parasitization and thus represents a potential drug target for leishmaniasis.

Animals↗
PubMed2002

Daughter cell assembly in the protozoan parasite Toxoplasma gondii.

The phylum Apicomplexa includes thousands of species of obligate intracellular parasites, many of which are significant human and/or animal pathogens. Parasites in this phylum replicate by assembling daughters within the mother, using a cytoskeletal and membranous scaffolding termed the inner membrane complex. Most apicomplexan parasites, including Plasmodium sp. (which cause malaria), package many daughters within a single mother during mitosis, whereas Toxoplasma gondii typically packages only two. The comparatively simple pattern of T. gondii cell division, combined with its molecular genetic and cell biological accessibility, makes this an ideal system to study parasite cell division. A recombinant fusion between the fluorescent protein reporter YFP and the inner membrane complex protein IMC1 has been exploited to examine daughter scaffold formation in T. gondii. Time-lapse video microscopy permits the entire cell cycle of these parasites to be visualized in vivo. In addition to replication via endodyogeny (packaging two parasites at a time), T. gondii is also capable of forming multiple daughters, suggesting fundamental similarities between cell division in T. gondii and other apicomplexan parasites.

Animals↗
PubMed2002

Biogenesis of nanotubular network in Toxoplasma parasitophorous vacuole induced by parasite proteins.

The intracellular parasite Toxoplasma gondii develops within a nonfusogenic vacuole containing a network of elongated nanotubules that form connections with the vacuolar membrane. Parasite secretory proteins discharged from dense granules (known as GRA proteins) decorate this intravacuolar network after invasion. Herein, we show using specific gene knockout mutants, that the unique nanotubule conformation of the network is induced by the parasite secretory protein GRA2 and further stabilized by GRA6. The vacuolar compartment generated by GRA2 knockout parasites was dramatically disorganized, and the normally tubular network was replaced by small aggregated material. The defect observed in Deltagra2 parasites was evident from the initial stages of network formation when a prominent cluster of multilamellar vesicles forms at a posterior invagination of the parasite. The secretory protein GRA6 failed to localize properly to this posterior organizing center in Deltagra2 cells, indicating that this early conformation is essential to proper assembly of the network. Construction of a Deltagra6 mutant also led to an altered mature network characterized by small vesicles instead of elongated nanotubules; however, the initial formation of the posterior organizing center was normal. Complementation of the Deltagra2 knockout with mutated forms of GRA2 showed that the integrity of both amphipathic alpha-helices of the protein is required for correct formation of the network. The induction of nanotubues by the parasite protein GRA2 may be a conserved feature of amphipathic alpha-helical regions, which have also been implicated in the organization of Golgi nanotubules and endocytic vesicles in mammalian cells.

Animals↗
PubMed2005

Unusual kinetic and structural properties control rapid assembly and turnover of actin in the parasite Toxoplasma gondii.

Toxoplasma is a protozoan parasite in the phylum Apicomplexa, which contains a number of medically important parasites that rely on a highly unusual form of motility termed gliding to actively penetrate their host cells. Parasite actin filaments regulate gliding motility, yet paradoxically filamentous actin is rarely detected in these parasites. To investigate the kinetics of this unusual parasite actin, we expressed TgACT1 in baculovirus and purified it to homogeneity. Biochemical analysis showed that Toxoplasma actin (TgACT1) rapidly polymerized into filaments at a critical concentration that was 3-4-fold lower than conventional actins, yet it failed to copolymerize with mammalian actin. Electron microscopic analysis revealed that TgACT1 filaments were 10 times shorter and less stable than rabbit actin. Phylogenetic comparison of actins revealed a limited number of apicomplexan-specific residues that likely govern the unusual behavior of parasite actin. Molecular modeling identified several key alterations that affect interactions between monomers and that are predicted to destabilize filaments. Our findings suggest that conserved molecular differences in parasite actin favor rapid cycles of assembly and disassembly that govern the unusual form of gliding motility utilized by apicomplexans.

Actin Cytoskeleton↗
PubMed2002

Host-symbiont conflicts: positive selection on an outer membrane protein of parasitic but not mutualistic Rickettsiaceae.

The Rickettsiaceae is a family of intracellular bacterial symbionts that includes both vertically transmitted parasites that spread by manipulating the reproduction of their host (Wolbachia in arthropods) and horizontally transmitted parasites (represented by Cowdria ruminantium), and mutualists (Wolbachia pipientis in nematode worms). We have investigated the nature of natural selection acting on an outer membrane protein, the wsp gene in Wolbachia and its homologue map1 in Cowdria, thought likely to be involved in host-parasite interactions in these bacteria. The ratio of nonsynonymous to synonymous substitution rates (d(N)/d(S)) at individual amino acid sites or at lineages within the gene's phylogeny was estimated using maximum likelihood models of codon substitution. The first hypothesis we tested was that this protein is under positive selection in the parasitic but not in the mutualistic Rickettsiaceae. This hypothesis was supported as positive selection and was detected in Cowdria and arthropod Wolbachia sequence evolution but not in the evolution of Wolbachia sequences from nematodes. Furthermore, this selection was concentrated outside the transmembrane region of the protein and, therefore, in the regions of the protein that may interact with the host. The second hypothesis tested was that positive selection would be stronger in the strains of arthropod Wolbachia that distort the host sex ratio than in those that induce cytoplasmic incompatibility. However, we found no support for this hypothesis. In conclusion, our results are consistent with the hypothesis that antagonistic coevolution causes faster evolution of surface protein sequences in parasites than in mutualists. Confirmation of this conclusion awaits the replication of these results both in additional genes and across more bacterial taxa. The regions of the wsp and map1 genes we identified as likely to be involved in host-parasite arms races should be examined in future studies of parasite virulence and host immune responses, and during the design of vaccines.

Amino Acid Sequence↗
PubMed2003

A profile of putative parasitism genes expressed in the esophageal gland cells of the root-knot nematode Meloidogyne incognita.

Identifying parasitism genes encoding proteins secreted from a nematode's esophageal gland cells and injected through its stylet into plant tissue is the key to understanding the molecular basis of nematode parasitism of plants. Meloidogyne incognita parasitism genes were cloned by microaspirating the cytoplasm from the esophageal gland cells of different parasitic stages to provide mRNA to create a gland cell-specific cDNA library by long-distance reverse-transcriptase polymerase chain reaction. Of 2,452 cDNA clones sequenced, deduced protein sequences of 185 cDNAs had a signal peptide for secretion and, thus, could have a role in root-knot nematode parasitism of plants. High-throughput in situ hybridization with cDNA clones encoding signal peptides resulted in probes of 37 unique clones specifically hybridizing to transcripts accumulating within the subventral (13 clones) or dorsal (24 clones) esophageal gland cells of M. incognita. In BLASTP analyses, 73% of the predicted proteins were novel proteins. Those with similarities to known proteins included a pectate lyase, acid phosphatase, and hypothetical proteins from other organisms. Our cell-specific analysis of genes encoding secretory proteins provided, for the first time, a profile of putative parasitism genes expressed in the M. incognita esophageal gland cells throughout the parasitic cycle.

Animals↗
PubMed2000

Malaria research: host-parasite interactions and new developments in chemotherapy, immunology and vaccinology.

Malaria remains the major parasitic disease, with 300-500 million new infections each year. This survey covers recent advances in the field of parasite-host interactions, focusing on Plasmodium falciparum, the most virulent of the human parasites. Rapid progress in genomic research is creating a basis for the development of new drugs and vaccines. Identification of drug-resistance mutations facilitates evaluation of improved drug policies, and attempts are being made to develop new compounds that inhibit metabolic pathways that are specific to the parasite. Cytoadherence of parasitized erythrocytes to microvascular endothelium is responsible for the sequestration of parasites, causing pathology and severe disease. Newly identified molecular fine structures that mediate cytoadherence may provide new targets for specific therapies. Humoral and cell-mediated immunity induced by the parasite may be protective, but may also be harmful by generating imbalance in cytokine responses. Efforts are made to determine the pathways that give rise to protection, with vaccination being the principal goal for achieving malaria control. Different vaccine constructs are being evaluated in preclinical and clinical trials, including modified viral vectors, synthetic peptides, DNA and new adjuvants.

Journal Article↗
PubMed2001

The energetic grooming costs imposed by a parasitic mite (Spinturnix myoti) upon its bat host (Myotis myotis).

Parasites often exert severe negative effects upon their host's fitness. Natural selection has therefore prompted the evolution of anti-parasite mechanisms such as grooming. Grooming is efficient at reducing parasitic loads in both birds and mammals, but the energetic costs it entails have not been properly quantified. We measured both the energetic metabolism and behaviour of greater mouse-eared bats submitted to three different parasite loads (no, 20 and 40 mites) during whole daily cycles. Mites greatly affected their time and energy budgets. They caused increased grooming activity, reduced the overall time devoted to resting and provoked a dramatic shortening of resting bout duration. Correspondingly, the bats' overall metabolism (oxygen consumption) increased drastically with parasite intensity and, during the course of experiments, the bats lost more weight when infested with 40 rather than 20 or no parasites. The short-term energetic constraints induced by anti-parasite grooming are probably associated with long-term detrimental effects such as a decrease in survival and overall reproductive value.

Animals↗
PubMed2004

Exploiting a mutualism: parasite specialization on cultivars within the fungus-growing ant symbiosis.

Fungus-growing ants, their cultivated fungi and the cultivar-attacking parasite Escovopsis coevolve as a complex community. Higher-level phylogenetic congruence of the symbionts suggests specialized long-term associations of host-parasite clades but reveals little about parasite specificity at finer scales of species-species and genotype-genotype interactions. By coupling sequence and amplified fragment length polymorphism genotyping analyses with experimental evidence, we examine (i) the host specificity of Escovopsis strains infecting colonies of three closely related ant species in the genus Cyphomyrmex, and (ii) potential mechanisms constraining the Escovopsis host range. Incongruence of cultivar and ant relationships across the three focal Cyphomyrmex spp. allows us to test whether Escovopsis strains track their cultivar or the ant hosts. Phylogenetic analyses demonstrate that the Escovopsis phylogeny matches the cultivar phylogeny but not the ant phylogeny, indicating that the parasites are cultivar specific. Cross-infection experiments establish that ant gardens can be infected by parasite strains with which they are not typically associated in the field, but that infection is more likely when gardens are inoculated with their typical parasite strains. Thus, Escovopsis specialization is shaped by the parasite's ability to overcome only a narrow range of garden-specific defences, but specialization is probably additionally constrained by ecological factors, including the other symbionts (i.e. ants and their antibiotic-producing bacteria) within the coevolved fungus-growing ant symbiosis.

Analysis of Variance↗
PubMed2004

Survival costs of reproduction in the blue tit (Parus caeruleus): a role for blood parasites?

One of the central tenets in life-history theory is that there is a trade-off between current and future reproduction (i.e. a cost of reproduction). The mechanism for this cost of reproduction is, however, largely unknown. One hypothesis is that the high workload during reproduction compromises resistance to parasites and that the resulting increase in parasitaemia has negative effects on the prospects of future survival. Although empirical evidence for a negative relationship between reproductive effort and parasite resistance exists, the causal relationships between reproductive effort, parasite resistance and future reproduction are still unclear. We use a path analytical approach to investigate whether a change in parasite resistance (as measured by intensities of infections by the blood parasite Haemoproteus) after manipulation of reproductive effort, translates into altered survival in female blue tits. Our results show a negative relationship between reproductive effort and parasite resistance, although evident only in first-year breeders. Moreover, we found survival costs of reproduction in first-year breeders. These costs were, however, not mediated by the blood parasite studied.

Analysis of Variance↗
PubMed2006

Prevalence and evolutionary relationships of haematozoan parasites in native versus introduced populations of common myna Acridotheres tristis.

The success of introduced species is frequently explained by their escape from natural enemies in the introduced region. We tested the enemy release hypothesis with respect to two well studied blood parasite genera (Plasmodium and Haemoproteus) in native and six introduced populations of the common myna Acridotheres tristis. Not all comparisons of introduced populations to the native population were consistent with expectations of the enemy release hypothesis. Native populations show greater overall parasite prevalence than introduced populations, but the lower prevalence in introduced populations is driven by low prevalence in two populations on oceanic islands (Fiji and Hawaii). When these are excluded, prevalence does not differ significantly. We found a similar number of parasite lineages in native populations compared to all introduced populations. Although there is some evidence that common mynas may have carried parasite lineages from native to introduced locations, and also that introduced populations may have become infected with novel parasite lineages, it may be difficult to differentiate between parasites that are native and introduced, because malarial parasite lineages often do not show regional or host specificity.

Animals↗
PubMed2005

Origin and diversification of the human parasite Schistosoma mansoni.

Schistosoma mansoni is the most widespread of the human-infecting schistosomes, present in 54 countries, predominantly in Africa, but also in Madagascar, the Arabian Peninsula, and the Neotropics. Adult-stage parasites that infect humans are also occasionally recovered from baboons, rodents, and other mammals. Larval stages of the parasite are dependent upon certain species of freshwater snails in the genus Biomphalaria, which largely determine the parasite's geographical range. How S. mansoni genetic diversity is distributed geographically and among isolates using different hosts has never been examined with DNA sequence data. Here we describe the global phylogeography of S. mansoni using more than 2500 bp of mitochondrial DNA (mtDNA) from 143 parasites collected in 53 geographically widespread localities. Considerable within-species mtDNA diversity was found, with 85 unique haplotypes grouping into five distinct lineages. Geographical separation, and not host use, appears to be the most important factor in the diversification of the parasite. East African specimens showed a remarkable amount of variation, comprising three clades and basal members of a fourth, strongly suggesting an East African origin for the parasite 0.30-0.43 million years ago, a time frame that follows the arrival of its snail host. Less but still substantial variation was found in the rest of Africa. A recent colonization of the New World is supported by finding only seven closely related New World haplotypes which have West African affinities. All Brazilian isolates have nearly identical mtDNA haplotypes, suggesting a founder effect from the establishment and spread of the parasite in this large country.

Africa↗
PubMed1986

Analysis of B cell and T cell proliferative responses induced by monomorphic and pleomorphic Trypanosoma brucei parasites in mice.

Cells collected from C57B1/6 mice infected with monomorphic and pleomorphic clones of Trypanosoma brucei parasites (ILTat 1.4 and GUTat 3.1) were analysed for the incorporation of 125I-Iododeoxyuridine into DNA of total splenic lymphocytes and of B and T lymphocytes isolated on a fluorescence activated cell sorter. The monomorphic T. brucei ILTat 1.4 parasites triggered delayed and low splenic DNA synthetic responses in comparison to those arising in mice infected with the pleomorphic T. brucei GUTat 3.1 organisms. Mice infected with both parasite clones mounted splenic DNA synthetic responses similar to those arising in animals infected with the pleomorphic organisms alone and similar responses were induced by lethally irradiated T. bruceiGUTat 3.1 and T. brucei ILTat 1.4 parasites. In mice infected with the pleomorphic parasites, DNA synthesis was first detected in the T cell population and B cell DNA synthetic responses were detected between 1 and 2 days later. In contrast only T cell DNA synthetic responses were detected after infection with the monomorphic T. brucei ILTat 1.4 parasites. It is suggested that the previously reported failure of monomorphic T. brucei parasites to trigger antibody production in infected mice is a result of their inability to stimulate B lymphocytes.

Animals↗
PubMed1987

Schistosoma mansoni: autoradiographic tracking studies of isotopically-labelled challenge parasites in naive and vaccinated CBA/Ca mice.

The migration of isotopically-labelled challenge parasites of Schistosoma mansoni in naive CBA/Ca mice, and CBA/Ca mice vaccinated 4 weeks previously with about 600 radiation-attenuated cercariae, has been followed by means of compressed organ autoradiography. In naive mice, only 16% of the challenge parasites failed to migrate from the skin to the lungs, whereas up to half of the individuals that succeeded in reaching the pulmonary vasculature did not move on to the liver. The tracking technique thus revealed a total loss of 58% of the challenge parasites, which correlated well with the fact that only 50% of the challenge was recovered as adult worms by retrograde perfusion of the hepatic portal system. Challenge migration in vaccinated mice initially proceeded more slowly than in naive mice, but peak numbers of foci were eventually recorded in the lungs on the same day in both groups of individuals. We did not therefore recognize a delay in parasite migration in vaccinated mice. In the present experiments, 58.5% of the challenge failed to reach the lungs of vaccinated rodents, and 25% of those parasites that did attain the pulmonary vasculature were not recruited to the liver. The tracking technique thus accounted for a total loss of 83.5% of the parasites, which again correlated well with the fact that we recovered only 22% of the challenge as adult worms at portal perfusion. The data presented here prove conclusively that the major phase of immune-dependent challenge elimination in vaccinated CBA/Ca mice occurs in the cutaneous tissues, and that only a small proportion of the parasites are lost in the lungs. These data are entirely consistent with those we have published elsewhere for the CBA/Ca mouse using a multiplicity of different techniques; they differ however, from results reported by others for the C57 Black strain of mouse. Possible reasons for these discrepancies are discussed.

Animals↗