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PubMed1991

Direct access to serum macromolecules by intraerythrocytic malaria parasites.

Trafficking pathways in malaria-infected erythrocytes are complex because the internal parasite is separated from the serum by the erythrocyte and parasitophorous vacuolar membranes. Intraerythrocytic Plasmodium falciparum parasites can endocytose dextrans, protein A and an IgG2a antibody. Here we show that these macromolecules do not cross the erythrocyte or parasitophorous vacuolar membranes, but rather gain direct access to the aqueous space surrounding the parasite through a parasitophorous duct. Evidence for this structure includes visualization of membranes that are continuous between the parasitophorous vacuolar and erythrocyte membranes, and surface labelling of the parasite with fluorescent macromolecules under conditions that block endocytosis. The parasite can internalize by fluid-phase endocytosis macromolecules from the aqueous compartment surrounding it. Thus, surface antigens on trophozoites and schizonts should be considered as targets for antibody-directed parasiticidal agents.

Animals↗
PubMed1997

A plastid organelle as a drug target in apicomplexan parasites.

Parasites of the phylum Apicomplexa include many important human and veterinary pathogens such as Plasmodium (malaria), Toxoplasma (a leading opportunistic infection associated with AIDS and congenital neurological birth defects), and Eimeria (an economically significant disease of poultry and cattle). Recent studies have identified an unusual organelle in these parasites: a plastid that appears to have been acquired by secondary endosymbiosis of a green alga. Here we show that replication of the apicomplexan plastid (apicoplast) genome in Toxoplasma gondii tachyzoites can be specifically inhibited using ciprofloxacin, and that this inhibition blocks parasite replication. Moreover, parasite death occurs with peculiar kinetics that are identical to those observed after exposure to clindamycin and macrolide antibiotics, which have been proposed to target protein synthesis in the apicoplast. Conversely, clindamycin (and functionally related compounds) immediately inhibits plastid replication upon drug application-the earliest effect so far described for these antibiotics. Our results directly link apicoplast function with parasite survival, validating this intriguing organelle as an effective target for parasiticidal drug design.

Animals↗
PubMed2003

Artemisinins target the SERCA of Plasmodium falciparum.

Artemisinins are extracted from sweet wormwood (Artemisia annua) and are the most potent antimalarials available, rapidly killing all asexual stages of Plasmodium falciparum. Artemisinins are sesquiterpene lactones widely used to treat multidrug-resistant malaria, a disease that annually claims 1 million lives. Despite extensive clinical and laboratory experience their molecular target is not yet identified. Activated artemisinins form adducts with a variety of biological macromolecules, including haem, translationally controlled tumour protein (TCTP) and other higher-molecular-weight proteins. Here we show that artemisinins, but not quinine or chloroquine, inhibit the SERCA orthologue (PfATP6) of Plasmodium falciparum in Xenopus oocytes with similar potency to thapsigargin (another sesquiterpene lactone and highly specific SERCA inhibitor). As predicted, thapsigargin also antagonizes the parasiticidal activity of artemisinin. Desoxyartemisinin lacks an endoperoxide bridge and is ineffective both as an inhibitor of PfATP6 and as an antimalarial. Chelation of iron by desferrioxamine abrogates the antiparasitic activity of artemisinins and correspondingly attenuates inhibition of PfATP6. Imaging of parasites with BODIPY-thapsigargin labels the cytosolic compartment and is competed by artemisinin. Fluorescent artemisinin labels parasites similarly and irreversibly in an Fe2+-dependent manner. These data provide compelling evidence that artemisinins act by inhibiting PfATP6 outside the food vacuole after activation by iron.

Animals↗
PubMed2004

Identification of an antimalarial synthetic trioxolane drug development candidate.

The discovery of artemisinin more than 30 years ago provided a completely new antimalarial structural prototype; that is, a molecule with a pharmacophoric peroxide bond in a unique 1,2,4-trioxane heterocycle. Available evidence suggests that artemisinin and related peroxidic antimalarial drugs exert their parasiticidal activity subsequent to reductive activation by haem, released as a result of haemoglobin digestion by the malaria-causing parasite. This irreversible redox reaction produces carbon-centred free radicals, leading to alkylation of haem and proteins (enzymes), one of which--the sarcoplasmic-endoplasmic reticulum ATPase PfATP6 (ref. 7)--may be critical to parasite survival. Notably, there is no evidence of drug resistance to any member of the artemisinin family of drugs. The chemotherapy of malaria has benefited greatly from the semi-synthetic artemisinins artemether and artesunate as they rapidly reduce parasite burden, have good therapeutic indices and provide for successful treatment outcomes. However, as a drug class, the artemisinins suffer from chemical (semi-synthetic availability, purity and cost), biopharmaceutical (poor bioavailability and limiting pharmacokinetics) and treatment (non-compliance with long treatment regimens and recrudescence) issues that limit their therapeutic potential. Here we describe how a synthetic peroxide antimalarial drug development candidate was identified in a collaborative drug discovery project.

Animals↗
PubMed2001

Interleukin-12 stimulation of lymphoproliferative responses in Trypanosoma cruzi infection.

The cytokine interleukin-12 (IL-12) is essential for resistance to Trypanosoma cruzi infection because it stimulates the synthesis of interferon-gamma (IFN-gamma), a major activator of the parasiticidal effect of macrophages. A less studied property of IL-12 is its ability to amplify the proliferation of T or natural killer (NK) lymphocytes. We investigated the role of endogenously produced IL-12 in the maintenance of parasite antigen (T-Ag)-specific lymphoproliferative responses during the acute phase of T. cruzi infection. We also studied whether treatment with recombinant IL-12 (rIL-12) would stimulate T-Ag-specific or concanavalin A (Con A)-stimulated lymphoproliferation and abrogate the suppression that is characteristic of the acute phase of infection. Production of IL-12 by spleen-cell cultures during T. cruzi infection increased in the first days of infection (days 3-5) and decreased as infection progressed beyond day 7. The growth-promoting activity of endogenous IL-12 on T-Ag-specific proliferation was observed on day 5 of infection. Treatment of cultures with rIL-12 promoted a significant increase in Con A-stimulated proliferation by spleen cells from normal or infected mice. Enhanced T-Ag-specific proliferation by rIL-12 was seen in spleen cell cultures from infected mice providing that nitric oxide production was inhibited by treatment with the competitive inhibitor NG-monomethyl-L-arginine (NMMA). Enhancement of proliferation promoted by IL-12 occurred in the presence of neutralizing anti-interleukin-2 (IL-2) antibody, suggesting that this activity of IL-12 was partly independent of endogenous IL-2. Thymidine incorporation levels achieved with rIL-12 treatment of the cultures were approximately 50% of those stimulated by rIL-2 in the same cultures.

Acute Disease↗
PubMed2003

Resistant mice lacking interleukin-12 become susceptible to Trypanosoma cruzi infection but fail to mount a T helper type 2 response.

Interleukin-12 (IL-12) is essential to resistance to Trypanosoma cruzi infection because it stimulates the synthesis of interferon-gamma (IFN-gamma) that activates macrophages to a parasiticidal effect. Investigation of mice deprived of IL-12 genes (IL-12 knockout mice) has confirmed the important role of IL-12 and IFN-gamma in controlling parasitism in T. cruzi infection. However, it has not yet been addressed whether a shift towards a T helper type 2 (Th2) pattern of cytokine response occurred in these mice that might have contributed to the aggravation of the infection caused by IL-12 deprivation. We examined the course of T. cruzi (Y strain) infection and the regulation of cytokine responses and nitric oxide production in C57BL/6 IL-12 p40-knockout mice. The mutant mice were extremely susceptible to the infection as evidenced by increased parasitaemia, tissue parasitism and mortality in comparison with the control C57BL/6 mouse strain (wild-type) that is resistant to T. cruzi. A severe depletion of parasite-antigen-specific IFN-gamma response, without an increase in IL-4 or IL-10 production, accompanied by reduced levels of nitric oxide production was observed in IL-12 knockout mice. We found no evidence of a shift towards a Th2-type cytokine response. In IL-12 knockout mice, the residual IFN-gamma production is down-regulated by IL-10 but not by IL-4 and nitric oxide production is stimulated by tumour necrosis factor-alpha. Parasite-specific immunoglobulin G1 antibody levels were similar in IL-12 knockout and wild-type mice, whereas IL-12 knockout mice had much higher levels of immunoglobulin G2b.

Acute Disease↗
PubMed1993

The knowledge base of health visitors and district nurses regarding products in the proposed formulary for nurse prescription.

The background to the legalization of nurse prescribing is reviewed and a small questionnaire survey of health visitors and district nurses described. Significantly more district nurses than health visitors wanted to become nurse prescribers. Health visitor knowledge of some parasiticidal lotions and antifungal agents was found to be variable and the recommended dose of paracetamol for post-immunization pyrexia was recognized by less than two-thirds of the sample. District nurse knowledge of lactulose was limited in comparison to their knowledge of alginate and hydrocolloid dressings; however, their knowledge of factors other than dressing type which enhance or delay healing was variable. The mean knowledge scores of both the health visitors and district nurses were unacceptably low for prescribing purposes. The majority of the total sample stated that they would like further training, with a preference for such provision in the form of study days.

Clinical Competence↗
PubMed2001

Subcellular localization and characterization of chorismate synthase in the apicomplexan Plasmodium falciparum.

The resurgence of drug-resistant apicomplexa, in particular Plasmodium falciparum, the most fatal human malarial parasite, has focused attention on the recent discovery of the shikimate pathway in these organisms, as it may provide the urgently required, novel drug targets resulting from the absence of this pathway in mammals. The direction of a parasiticidal drug design programme obviously requires knowledge of the subcellular localization and indeed full characterization of the possible enzyme targets. Here, we report the cloning and characterization of chorismate synthase from P. falciparum and present the first biochemical and immunological studies of an enzyme of the shikimate pathway from an apicomplexan parasite. We show that this chorismate synthase does not possess an intrinsic flavin reductase activity and is therefore monofunctional like the plant and bacterial chorismate synthases. Highest immunological cross-reactivity was found with a plant chorismate synthase. However, in contrast to the plant enzyme, which is located to the plastid, P. falciparum chorismate synthase is found in the parasite cytosol, akin to the fungal enzymes that possess an intrinsic flavin reductase activity (i.e. are bifunctional). Thus, P. falciparum chorismate synthase has a combination of properties that distinguishes it from other described chorismate synthases.

Amino Acid Sequence↗
PubMed1998

Discrepancy in plasma melarsoprol concentrations between HPLC and bioassay methods in patients with T. gambiense sleeping sickness indicates that melarsoprol is metabolized.

OBJECTIVE: With the use of a specific high-performance liquid chromatography (HPLC) method and a bioassay which determines trypanocidal activity, concentrations of melarsoprol were assessed in plasma, urine and cerebrospinal fluid (CSF) from 8 patients with late-stage Trypanosoma gambiense sleeping sickness. The aim was to unravel to what extent the bioassay codetermines biologically active metabolites of melarsoprol. METHODS: Subjects were given one dose of melarsoprol i.v. per day for 4 days (1.2, 2.4, 3.0-3.6, 3.0-3.6 mg per kg b.w., respectively). Plasma samples were obtained before the first melarsoprol injection, immediately after and at 1 h, 24 h and 5 days after the 4th injection. Urine was collected before melarsoprol therapy and at 24 h after the 4th injection. CSF samples were taken once before treatment and at 24 h after the 4th injection. RESULTS: HPLC analyses showed that plasma concentrations immediately after the 4th injection varied from 2200 to 15,900 nmol/l; dropping to 0-1800 nmol/l at 1 h; and to undetectable levels at 24 h. In urine small amounts of melarsoprol were recovered. Melarsoprol could not be detected in CSF by HPLC. Immediately after injection, bioassay analyses showed plasma concentrations of the same magnitude as HPLC assays but at 1 h they were 4-65-fold higher than the levels assessed by HPLC. Even 24 h and 5 days after the 4th injection there was significant but decreasing activity. Urine levels were 40-260-fold higher than the measured HPLC concentrations, whereas there was low but detectable activity in CSF. CONCLUSION: Results indicate that melarsoprol is rapidly eliminated from plasma. The significant trypanocidal activity determined by bioassay and simultaneous low or undetectable levels of melarsoprol assayed by HPLC indicate that the compound is transformed into metabolites with parasiticidal activity.

Adolescent↗
PubMed2001

The Akt/PKB pathway is constitutively activated in Theileria-transformed leucocytes, but does not directly control constitutive NF-kappaB activation.

The intracellular protozoan parasites Theileria parva and Theileria annulata transform leucocytes by interfering with host cell signal transduction pathways. They differ from tumour cells, however, in that the transformation process can be entirely reversed by elimination of the parasite from the host cell cytoplasm using a specific parasiticidal drug. We investigated the state of activation of Akt/PKB, a downstream target of PI3-K-generated phosphoinositides, in Theileria-transformed leucocytes. Akt/PKB is constitutively activated in a PI3-K- and parasite-dependent manner, as judged by the specific phosphorylation of key residues, in vitro kinase assays and its cellular distribution. In previous work, we demonstrated that the parasite induces constitutive activation of the transcription factor NF-kappaB, providing protection against spontaneous apoptosis that accompanies transformation. In a number of other systems, a link has been established between the PI3-K-Akt/PKB pathway and NF-kappaB activation, resulting in protection against apoptosis. In Theileria-transformed leucocytes, activation of the NF-kappaB and the PI3-K-Akt/PKB pathways are not directly linked. The PI3-K-Akt/PKB pathway does not contribute to the persistent induction of IkappaBalpha phosphorylation, NF-kappaB DNA-binding or transcriptional activity. We show that the two pathways are downregulated with different kinetics when the parasite is eliminated from the host cell cytoplasm and that NF-kappaB-dependent protection against apoptosis is not dependent on a functional PI3-K-Akt/PKB pathway. We also demonstrate that Akt/PKB contributes, at least in part, to the proliferation of Theileria-transformed T cells.

Animals↗
PubMed2003

Ivermectin and filariasis.

Ivermectin, a parasiticide that long ago proved its worth in veterinary medicine, became one of the most effective tools for control programs against human filarial diseases in the 1980s. It is provided at no cost, is effective against microfilariae (blocking their transmission) and can be administered annually as a single oral dose with virtually no side-effects: these considerations led the WHO to officially declare eradicable two endemic filarial diseases (among the major endemic diseases worldwide), onchocerciasis and lymphatic filariasis.

Child↗
PubMed2000

Drug-resistant Drosophila indicate glutamate-gated chloride channels are targets for the antiparasitics nodulisporic acid and ivermectin.

The fruit fly Drosophila melanogaster was used to examine the mode of action of the novel insecticide and acaricide nodulisporic acid. Flies resistant to nodulisporic acid were selected by stepwise increasing the dose of drug in the culture media. The resistant strain, glc(1), is at least 20-fold resistant to nodulisporic acid and 3-fold cross-resistant to the parasiticide ivermectin, and exhibited decreased brood size, decreased locomotion, and bang sensitivity. Binding assays using glc(1) head membranes showed a marked decrease in the affinity for nodulisporic acid and ivermectin. A combination of genetics and sequencing identified a proline to serine mutation (P299S) in the gene coding for the glutamate-gated chloride channel subunit DmGluClalpha. To examine the effect of this mutation on the biophysical properties of DmGluClalpha channels, it was introduced into a recombinant DmGluClalpha, and RNA encoding wild-type and mutant subunits was injected into Xenopus oocytes. Nodulisporic acid directly activated wild-type and mutant DmGluClalpha channels. However, mutant channels were approximately 10-fold less sensitive to activation by nodulisporic acid, as well as ivermectin and the endogenous ligand glutamate, providing direct evidence that nodulisporic acid and ivermectin act on DmGluClalpha channels.

Animals↗
PubMed1977

The resistance of intracellular Leishmania parasites to digestion by lysosomal enzymes.

Infections of Leishmania mexicana in cultured normal mouse peritoneal macrophages show different morphological features depending on whether the parasites invade as promastigote or amastigote forms. Infections derived from promastigote invasion are characterized by parasitophorous vacuoles which develop slowly, and acquire only modest proportions. In contrast, the organisms in amastigote-derived infections lie within parasitophorous vacuoles which develop more rapidly, and attain a much greater size. From observation of promastigotes of different species of Leishmania, it appeared that survival subsequent to endocytosis by normal macrophages depends on the parasites' rapid transformation to the amastigote form. Activation of the macrophage population produced an enhanced parasiticidal effect only against incompletely transformed Leishmania promastigotes. Electron microscope investigations, involving enzyme histochemistry and lysosome labelling techniques, indicate that intracellular Leishmania avoid digestion by interfering with the activity of lysosomal enzymes that are freely delivered to the parasitophorous vacuole. It is proposed that this ability is acquired on transformation to the amastigote, and incidentally induces fluid distension of the parasitophorous vacuole through phenomena recently described by other workers.

Acid Phosphatase↗
PubMed1998

Why is it that antimalarial drug treatments do not always work?

The objective of antimalarial drug treatment in severe malaria is to save the patient's life. In uncomplicated malaria it is to reduce the parasite biomass to zero, or down to a level where host defences can deal with the remainder. Treatment regimens with rapidly eliminated drugs must generally cover four asexual life-cycles (i.e. > 6 days for Plasmodium falciparum and P. vivax) to eradicate all the parasites in the blood. For slowly eliminated drugs, blood concentrations must exceed the parasites' minimum inhibitory concentration (and preferably the minimum parasiticidal concentration) until all parasites have been eradicated. Resistance means that there is a right shift in the concentration-effect relationship. This may be large and abrupt, as with the point mutations that confer pyrimethamine, sulphonamide or atovaquone resistance, or slow and gradual, as with the processes that determine resistance to chloroquine, quinine or mefloquine. Although treatment failure in malaria usually results from poor compliance, inadequate dosing, pharmacokinetic factors or resistance, some infections will recrudesce when none of these factors operates. How parasites persist despite apparently adequate antimalarial treatment remains unresolved.

Animals↗
PubMed1998

Chloroquine or amodiaquine combined with sulfadoxine-pyrimethamine as a treatment for uncomplicated malaria--a systematic review.

The 4-aminoquinolines, chloroquine or amodiaquine, have long been the drugs of choice for treating uncomplicated, falciparum malaria in Africa, although resistance to them is now common. Sulfadoxine-pyrimethamine (SP) is the usual alternative when 4-aminoquinoline treatment fails. A combination-treatment regimen could combine the rapid symptom relief offered by the 4-aminoquinolines with the prolonged parasiticidal activity of SP, and also slow down development of resistance to the individual drugs. A systematic review of randomized trials was conducted so that the evidence of effectiveness and safety of such combination treatment could be summarized and compared with the results of treatment with either drug given alone. The results of trials were sought by searching through electronic databases and by contact with researchers in the field. Five studies were identified. Although there are few data, there is evidence that control of clinical symptoms is better when a 4-aminoquinoline is used with SP than when SP is used alone, and the cure rate also tends to be higher with the combination regimen. No evidence of serious side-effects was found. Larger scale trials are needed if this combination is to be adopted more widely.

Amodiaquine↗
PubMed1992

An evaluation of an oral formulation of moxidectin against selected anthelmintic-resistant and -susceptible strains of nematodes in lambs.

The efficacy of an oral formulation of the newly developed parasiticide, moxidectin, was tested against benzimidazole-resistant Haemonchus contortus, Trichostrongylus colubriformis, and Nematodirus spathiger, levamisole-resistant Ostertagia circumcincta, and susceptible Cooperia curticei infections in weaned lambs. Thirty-two lambs were experimentally infected with mixed doses of the above strains of nematodes. They were allocated into four treatment groups by stratified randomisation using liveweights and faecal egg counts 28 days later. One group received moxidectin at 0.2 mg/kg liveweight, one group oxfendazole at 4.5 mg/kg liveweight, one group levamisole at 7.5 mg/kg liveweight and the last group remained untreated as the control. Worm burdens in the lambs at slaughter 10 days after oral treatment confirmed the resistance status of the nematode strains used, and showed that moxidectin had a greater than 99.9% efficacy (p<0.01) against all of them. No adverse effects due to treatment with moxidectin were observed in any of the animals.

Journal Article↗
PubMed2005

Do neuroglobin and myoglobin protect Toxoplasma gondii from nitrosative stress?

Toxoplasma gondii is a Apicomplexa obligate intracellular protozoan parasite that infects up to a third of the world's population. In most humans infected with T. gondii, the disease toxoplasmosis is asymptomatic. However, T. gondii causes blindness, severe neurological disorders, hepatitis, and pneumonia in immunocompromised patients, and severe damage to the fetus. Here, we postulate that the colonization of the retina, heart, and skeletal muscle by T. gondii may reflect the role of neuroglobin (Ngb) and myoglobin (Mb) to protect the parasite from the toxoplasmacidal effects of nitric oxide (NO). This is based on the knowledge that Ngb and Mb catalyzes NO oxidation yielding the harmless nitrate. The postulated protective role of Ngb and Mb on the viability of T. gondii is reminiscent of that postulated for hemoglobin (Hb) and Mb in protecting intraerythrocytic Plasmodia and T. cruzi in cardiomyocytes, respectively, from the parasiticidal effect of NO. Therefore, undesirable pathogen protection by pseudo-enzymatic NO scavenging may represent a new unexpected function of members of the Hb superfamily.

Animals↗
PubMed1995

Congenital Chagas' disease: diagnostic and clinical aspects.

The diagnostic and clinical aspects of congenital Chagas' disease were studied in 71 children in Buenos Aires. The children's ages ranged from 2 days to 10 years. In infants < 6 months old, the disease was diagnosed by detection of Trypanosoma cruzi in the blood; the microhematocrit test was positive in 38 (97.4%) of 39 cases. This test was the fastest and most reliable diagnostic method in this group, whereas two conventional serological methods were useful in children > or = 6 months of age. Forty-six (64.8%) of the 71 children had no clinical signs of infection. The clinical sign most frequently documented was hepatomegaly (18.3%). Three children were coinfected with human immunodeficiency virus; the latter infection was severe in two instances. Nifurtimox (10-15 mg/[kg.d] for 2 months) was used for parasiticidal treatment, and use of this drug resulted in mild adverse effects.

Animals↗