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fret peptides reveal differential proteolytic activation in intraerythrocytic stages of the malaria parasites plasmodium berghei and plasmodium yoelii.malaria is still a major health problem in developing countries. it is caused by the protist parasite plasmodium, in which proteases are activated during the cell cycle. ca(2+) is a ubiquitous signalling ion that appears to regulate protease activity through changes in its intracellular concentration. proteases are crucial to plasmodium development, but the role of ca(2+) in their activity is not fully understood. here we investigated the role of ca(2+) in protease modulation among rodent plasmo ...201021168413
a constitutive pan-hexose permease for the plasmodium life cycle and transgenic models for screening of antimalarial sugar analogs.glucose is considered essential for erythrocytic stages of the malaria parasite, plasmodium falciparum. importance of sugar and its permease for hepatic and sexual stages of plasmodium, however, remains elusive. moreover, increasing global resistance to current antimalarials necessitates the search for novel drugs. here, we reveal that hexose transporter 1 (ht1) of plasmodium berghei can transport glucose (k(m)~87 μm), mannose (k(i)~93 μm), fructose (k(i)~0.54 mm), and galactose (k(i)~5 mm) in l ...201021169382
cd4+ natural regulatory t cells prevent experimental cerebral malaria via ctla-4 when expanded in vivo.studies in malaria patients indicate that higher frequencies of peripheral blood cd4(+) foxp3(+) cd25(+) regulatory t (treg) cells correlate with increased blood parasitemia. this observation implies that treg cells impair pathogen clearance and thus may be detrimental to the host during infection. in c57bl/6 mice infected with plasmodium berghei anka, depletion of foxp3(+) cells did not improve parasite control or disease outcome. in contrast, elevating frequencies of natural treg cells in vivo ...201021170302
engineering the chloroplast targeted malarial vaccine antigens in chlamydomonas starch granules.malaria, an anopheles-borne parasitic disease, remains a major global health problem causing illness and death that disproportionately affects developing countries. despite the incidence of malaria, which remains one of the most severe infections of human populations, there is no licensed vaccine against this life-threatening disease. in this context, we decided to explore the expression of plasmodium vaccine antigens fused to the granule bound starch synthase (gbss), the major protein associate ...201021179538
genetic susceptibility to systemic lupus erythematosus protects against cerebral malaria in mice.plasmodium falciparum has exerted tremendous selective pressure on genes that improve survival in severe malarial infections. systemic lupus erythematosus (sle) is an autoimmune disease that is six to eight times more prevalent in women of african descent than in women of european descent. here we provide evidence that a genetic susceptibility to sle protects against cerebral malaria. mice that are prone to sle because of a deficiency in fcγriib or overexpression of toll-like receptor 7 are prot ...201021187399
antimalarial activity of methanolic leaf extract of piper betle l.the need for new compounds active against malaria parasites is made more urgent by the rapid spread of drug-resistance to available antimalarial drugs. the crude methanol extract of piper betle leaves (50-400 mg/kg) was investigated for its antimalarial activity against plasmodium berghei (nk65) during early and established infections. the phytochemical and antioxidant potentials of the crude extract were evaluated to elucidate the possibilities of its antimalarial effects. the safety of the ext ...201021189459
molecular genetics evidence for the in vivo roles of the two major nadph-dependent disulfide reductases in the malaria parasite.malaria-associated pathology is caused by the continuous expansion of plasmodium parasites inside host erythrocytes. to maintain a reducing intracellular milieu in an oxygen-rich environment, malaria parasites have evolved a complex antioxidative network based on two central electron donors, glutathione and thioredoxin. here, we dissected the in vivo roles of both redox pathways by gene targeting of the respective nadph-dependent disulfide reductases. we show that plasmodium berghei glutathione ...201020852334
functional significance of the intermediate conductance ca2+-activated k+ channel for the short-term survival of injured erythrocytes.increased cytosolic ca(2+) concentrations activate gardos k(+) channels in human erythrocytes with membrane hyperpolarization, efflux of k(+), cl⁻, and osmotically obliged h₂o resulting in cell shrinkage, a phenomenon referred to as gardos effect. we tested whether the gardos effect delays colloid osmotic hemolysis of injured erythrocytes from mice lacking the ca(2+)-activated k(+) channel k(ca)3.1. to this end, we applied patch clamp and flow cytometry and determined in vitro as well as in vivo ...201020857305
plasmodium berghei k173: selection of resistance to naphthoquine in a mouse model.naphthoquine (nq), as a component of arco® which composed of nq and artemisinin, is a new 4-aminoquinoline antimalarial synthesized by our institute. here, a naphthoquine-resistant line of rodent malaria parasite was selected through exposing plasmodium berghei keyberg 173 strain to progressively increased drug pressure. the selected strain showed a more than 200-fold decreased susceptibility to nq with a stable resistance phenotype after 10 serial passages without drug pressure or when cryopres ...201020868687
simultaneous administration of vitamin a and dtp vaccine modulates the immune response in a murine cerebral malaria model.the world health organisation recommends vitamin a supplementation (vas) to children aged 6 months to 5 years in low-income countries, and for logistic reasons, this has been linked to routine childhood immunizations. observational studies suggest that vas given with diphtheria-tetanus-pertussis (dtp) vaccine may increase mortality from non-targeted diseases. we investigated the non-targeted effect of pretreatment with vas and dtp vaccine in a murine model of experimental cerebral malaria. our a ...201020883315
the armadillo repeat protein pf16 is essential for flagellar structure and function in plasmodium male gametes.malaria, caused by the apicomplexan parasite plasmodium, threatens 40% of the world's population. transmission between vertebrate and insect hosts depends on the sexual stages of the life-cycle. the male gamete of plasmodium parasite is the only developmental stage that possesses a flagellum. very little is known about the identity or function of proteins in the parasite's flagellar biology. here, we characterise a plasmodium pf16 homologue using reverse genetics in the mouse malaria parasite pl ...201020886115
development of the malaria parasite in the skin of the mammalian host.the first step of plasmodium development in vertebrates is the transformation of the sporozoite, the parasite stage injected by the mosquito in the skin, into merozoites, the stage that invades erythrocytes and initiates the disease. the current view is that, in mammals, this stage conversion occurs only inside hepatocytes. here, we document the transformation of sporozoites of rodent-infecting plasmodium into merozoites in the skin of mice. after mosquito bite, ∼50% of the parasites remain in t ...201020921402
transgenic plasmodium that expresses hiv-1 gag elicits immunity and protects mice against vaccinia virus-gag and malarial parasites.malaria and human immunodeficiency virus type 1 (hiv-1) infection overlap in many regions of the world. our goal was to determine the feasibility of developing transgenic plasmodium berghei that expresses hiv-1 gag, pbgag, as a conceptual bivalent vaccine against both hiv-1 infection and malaria. immunization of mice with pbgag induced specific responses to the hiv-1 gag. importantly, mice vaccinated with pbgag were significantly protected from challenge with vaccinia virus-gag (vv-gag) with an ...201020933565
sequestration and tissue accumulation of human malaria parasites: can we learn anything from rodent models of malaria?the sequestration of plasmodium falciparum-infected red blood cells (irbcs) in the microvasculature of organs is associated with severe disease; correspondingly, the molecular basis of irbc adherence is an active area of study. in contrast to p. falciparum, much less is known about sequestration in other plasmodium parasites, including those species that are used as models to study severe malaria. here, we review the cytoadherence properties of irbcs of the rodent parasite plasmodium berghei ank ...201020941396
the systematic functional analysis of plasmodium protein kinases identifies essential regulators of mosquito transmission.although eukaryotic protein kinases (epks) contribute to many cellular processes, only three plasmodium falciparum epks have thus far been identified as essential for parasite asexual blood stage development. to identify pathways essential for parasite transmission between their mammalian host and mosquito vector, we undertook a systematic functional analysis of epks in the genetically tractable rodent parasite plasmodium berghei. modeling domain signatures of conventional epks identified 66 put ...201020951971
a single, low, oral dose of a 5-carbon-linked trioxane dimer orthoester plus mefloquine cures malaria-infected mice.four 5-carbon-linked trioxane dimer orthoesters (6a-6d) have been prepared in 4 or 5 chemical steps from the natural trioxane artemisinin (1). when administered orally to malaria-infected mice using a single dose of only 6mg/kg body weight along with 18mg/kg of mefloquine hydrochloride, trioxane dimer orthoester sulfone 6d completely and safely cured the mice; after 30days, the cured mice showed no detectable parasitemia, gained at least as much weight as the control mice (no infection), and beh ...201020952197
a rapid murine coma and behavior scale for quantitative assessment of murine cerebral malaria.cerebral malaria (cm) is a neurological syndrome that includes coma and seizures following malaria parasite infection. the pathophysiology is not fully understood and cannot be accounted for by infection alone: patients still succumb to cm, even if the underlying parasite infection has resolved. to that effect, there is no known adjuvant therapy for cm. current murine cm (mcm) models do not allow for rapid clinical identification of affected animals following infection. an animal model that more ...201020957049
selective accumulation of a novel antimalarial rhodacyanine derivative, ssj-127, in an organelle of plasmodium berghei.ssj-127, a novel antimalarial rhodacyanine derivative, has shown potent antimalarial activity against chloroquine-resistant plasmodium strains in vitro and subcutaneous administration of ssj-127 results in a complete cure of a mouse malaria model. ssj-127 was detected by fluorescence microscopy in the mouse malaria parasites plasmodium berghei after exposure of infected red blood cells to the compound in vitro and in vivo. selective accumulation of ssj-127 in an organelle is observed in all bloo ...201020970347
histopathological studies in two strains of semi-immune mice infected with plasmodium berghei anka after chronic exposure.to mimic a human malaria infection in the endemic condition, two strains of mice (balb/c and cba) were infected and treated several times to generate so-called semi-immune status. as previously reported, neither mice (balb/c and cba) strain showed cerebral malaria, even in the susceptible c57bl/6 (b6). the significant difference between the mice strains in our previous study was the rate of destruction of uninfected red blood cells (urbcs) at infection. after the established repeated cycles of i ...201020978790
development of experimental cerebral malaria is independent of il-23 and il-17.cerebral malaria (cm) is the most severe complication of plasmodium infection. although inappropriate immune responses to plasmodium falciparum are reported as the major causes of cm, the precise mechanisms for development remain unclear. il-23 and il-17 have critical roles in the onset of autoimmunity and inflammatory diseases triggered by microbial infections. thus, we investigated the influence of il-23 and il-17 on experimental cm (ecm) using plasmodium berghei anka infection of c57bl/6 mice ...201021036146
cutting edge: adaptive versus innate receptor signals selectively control the pool sizes of murine ifn-γ- or il-17-producing γδ t cells upon infection.γδ t lymphocytes are commonly viewed as embracing properties of both adaptive and innate immunity. contributing to this is their responsiveness to pathogen products, either with or without the involvement of the tcr and its coreceptors. this study clarifies this paradoxical behavior by showing that these two modes of responsiveness are the properties of two discrete sets of murine lymphoid γδ t cells. thus, myd88 deficiency severely impaired the response to malaria infection of cd27((-)), il-17a ...201021037088
plasmodium berghei anka: erythropoietin activates neural stem cells in an experimental cerebral malaria model.cerebral malaria (cm) causes substantial mortality and neurological sequelae in survivors, and no neuroprotective regimens are currently available for this condition. erythropoietin (epo) reduces neuropathology and improves survival in murine cm. using the plasmodium berghei model of cm, we investigated if epo's neuroprotective effects include activation of endogenous neural stem cells (nsc). by using immunohistochemical markers of different nsc maturation stages, we show that epo increased the ...201021044627
identification and characterization of a liver stage-specific promoter region of the malaria parasite plasmodium.during the blood meal of a plasmodium-infected mosquito, 10 to 100 parasites are inoculated into the skin and a proportion of these migrate via the bloodstream to the liver where they infect hepatocytes. the plasmodium liver stage, despite its clinical silence, represents a highly promising target for antimalarial drug and vaccine approaches. successfully invaded parasites undergo a massive proliferation in hepatocytes, producing thousands of merozoites that are transported into a blood vessel t ...201021048918
population biology of malaria within the mosquito: density-dependent processes and potential implications for transmission-blocking interventions.the combined effects of multiple density-dependent, regulatory processes may have an important impact on the growth and stability of a population. in a malaria model system, it has been shown that the progression of plasmodium berghei through anopheles stephensi and the survival of the mosquito both depend non-linearly on parasite density. these processes regulating the development of the malaria parasite within the mosquito may influence the success of transmission-blocking interventions (tbis) ...201021050427
production of ifn-γ by cd4(+) t cells in response to malaria antigens is il-2 dependent.t-cell immune responses are critical for protection of the host and for disease pathogenesis during infection with plasmodium species. we examined the regulation of cd4(+) t-cell cytokine responses during infection with plasmodium berghei anka (pba). cd4(+) t cells from pba-infected mice produced ifn-γ, il-4 and il-10 in response to tcr stimulation at levels higher than those from uninfected mice. this altered cytokine response was dependent on parasitemia. to examine the specificity of the resp ...201021059770
plasmodium berghei circumvents immune responses induced by merozoite surface protein 1- and apical membrane antigen 1-based vaccines.two current leading malaria blood-stage vaccine candidate antigens for plasmodium falciparum, the c-terminal region of merozoite surface protein 1 (msp1(19)) and apical membrane antigen 1 (ama1), have been prioritized because of outstanding protective efficacies achieved in a rodent malaria plasmodium yoelii model. however, p. falciparum vaccines based on these antigens have had disappointing outcomes in clinical trials. discrepancies in the vaccine efficacies observed between the p. yoelii mode ...201021060850
in vitro and in vivo antimalarial activity of puberulic acid and its new analogs, viticolins a-c, produced by penicillium sp. fki-4410.in the course of screening for antimalarial agents, five tropolone compounds were isolated from the culture broth of penicillium sp. fki-4410. two were known compounds, puberulic acid and stipitatic acid. three were new analogs of puberulic acid, designated viticolins a-c. among them, puberulic acid exhibited potent antimalarial inhibition, with ic(50) values of 0.01 μg ml(-1) against chloroquine-sensitive and -resistant plasmodium falciparum strains in vitro. furthermore, puberulic acid showed ...201021063422
apolipophorin-iii mediates antiplasmodial epithelial responses in anopheles gambiae (g3) mosquitoes.apolipophorin-iii (apolp-iii) is known to play an important role in lipid transport and innate immunity in lepidopteran insects. however, there is no evidence of involvement of apolp-iiis in the immune responses of dipteran insects such as drosophila and mosquitoes.201021072214
c-jun n terminal kinases (jnk) are activated in the brain during the pathology of experimental cerebral malaria.experimental cerebral malaria (ecm) resulting from plasmodium berghei anka (pba) infection in c57bl/6j mice manifests cell death in the brain. however, the precise molecular and biochemical mechanisms regulating cell death during ecm remains unknown. in this study we have examined, the role of a stress activated protein kinase called c-jun n terminal kinase during the pathology of ecm. we report in this study, for the first time the activation of all key elements in the jnk pathway like p-mkk4, ...201021073918
median lethal dose, antimalarial activity, phytochemical screening and radical scavenging of methanolic languas galanga rhizome extract.the methanolic extract of languas galanga rhizomes was investigated for antimalarial activity against plasmodium berghei (nk65) infections in mice. the median lethal dose was determined to ascertain the safety of the extract in icr mice of both sexes. the antimalarial activities during early and established infections, as well as the prophylactic activity were evaluated. phytochemical screening and radical scavenging activity of the extract were also investigated to elucidate the possible mechan ...201021081857
dematin, a component of the erythrocyte membrane skeleton, is internalized by the malaria parasite and associates with plasmodium 14-3-3.the malaria parasite invades the terminally differentiated erythrocytes, where it grows and multiplies surrounded by a parasitophorous vacuole. plasmodium blood stages translocate newly synthesized proteins outside the parasitophorous vacuole and direct them to various erythrocyte compartments, including the cytoskeleton and the plasma membrane. here, we show that the remodeling of the host cell directed by the parasite also includes the recruitment of dematin, an actin-binding protein of the er ...201021084299
increased levels of glutamate in the central nervous system are associated with behavioral symptoms in experimental malaria.cerebral malaria (cm) is a severe complication resulting from plasmodium falciparum infection. this condition has been associated with cognitive, behavioral and motor dysfunctions, seizures and coma. the underlying mechanisms of cm are incompletely understood. glutamate and other metabolites such as lactate have been implicated in its pathogenesis. in the present study, we investigated the involvement of glutamate in the behavioral symptoms of cm. seventeen female c57bl/6 mice (20-25 g) aged 6-8 ...201021085889
functional immunogenicity of baculovirus expressing pfs25, a human malaria transmission-blocking vaccine candidate antigen.we have focused on development of a novel vaccine vector based on "baculophage", a baculovirus display system for expression of proteins on the surface of the viral envelope, as a non-pathogenic and non-vertebrate insect virus. in the present study, recombinant baculovirus (acnpv-pfs25surf) were generated, which displayed pfs25, a potent plasmodium falciparum transmission-blocking vaccine candidate. both intranasal and intramuscular immunizations of mice with acnpv-pfs25surf induced high levels ...201020709008
dialkylaminoalkyl derivatives of bicyclic compounds with antiplasmodial activity.dialkylaminoalkyl derivatives of 2-azabicyclo[3.2.2]nonanes and of bicyclo[2.2.2]octanes were prepared and their activities determined in vitro against the multiresistant k1 strain of plasmodium falciparum. several of the new compounds exhibited very promising antiplasmodial activity and selectivity. the results were compared to those of formerly synthesized analogues and of drugs in use. structure-activity relationships were detected. some of the more potent compounds were tested in vivo agains ...201020709557
phosphatidylinositol 3-phosphate, an essential lipid in plasmodium, localizes to the food vacuole membrane and the apicoplast.phosphoinositides are important regulators of diverse cellular functions, and phosphatidylinositol 3-monophosphate (pi3p) is a key element in vesicular trafficking processes. during its intraerythrocytic development, the malaria parasite plasmodium falciparum establishes a sophisticated but poorly characterized protein and lipid trafficking system. here we established the detailed phosphoinositide profile of p. falciparum-infected erythrocytes and found abundant amounts of pi3p, while phosphatid ...201020709789
immune-mediated mechanisms of parasite tissue sequestration during experimental cerebral malaria.cerebral malaria is a severe complication of malaria. sequestration of parasitized rbcs in brain microvasculature is associated with disease pathogenesis, but our understanding of this process is incomplete. in this study, we examined parasite tissue sequestration in an experimental model of cerebral malaria (ecm). we show that a rapid increase in parasite biomass is strongly associated with the induction of ecm, mediated by ifn-gamma and lymphotoxin alpha, whereas tnf and il-10 limit this proce ...201020720206
key factors regulating plasmodium berghei sporozoite survival and transformation revealed by an automated visual assay.malaria is transmitted to the host when plasmodium sporozoites are injected by a mosquito vector. sporozoites eventually enter hepatocytes, where they differentiate into liver-stage parasites. during the first hours after hepatocyte invasion, the crescent-shaped sporozoites transform into spherical intracellular exoerythrocytic parasites. this process, which precedes genome replication, can be mimicked in vitro in the absence of host cells. here, we developed an automated method to follow transf ...201020798246
effect of amphotericin b on parasitemia and survival of plasmodium berghei-infected mice.premature death of plasmodium-infected erythrocytes is considered to favourably influence the clinical course of malaria. amphotericin b has previously been shown to trigger suicidal erythrocyte death or eryptosis, which is characterized by cell membrane scrambling leading to phosphatidylserine exposure at the cell surface. phosphatidylserine-exposing cells are rapidly cleared from circulating blood. the present study thus tested whether amphotericin b exerts a direct effect on plasmodium falcip ...201020798519
effect of anandamide in plasmodium berghei-infected mice.eryptosis, the suicidal death of erythrocytes, is characterized by exposure of phosphatidylserine at the erythrocyte surface and cell shrinkage. triggers of eryptosis include anandamide. enhanced eryptosis of infected human erythrocytes is expected to delay the development of parasitaemia during infection with plasmodium, the parasite causing malaria. the present experiments aimed to test, whether anandamide influences eryptosis, parasite growth and/or host survival during in vitro or in vivo in ...201020798520
persistent cognitive and motor deficits after successful antimalarial treatment in murine cerebral malaria.human cerebral malaria causes neurological and behavioral deficits which persist long after resolution of infection and clearance of parasites with antimalarial drugs. previously, we demonstrated that during active infection, mice with cerebral malaria demonstrated negative behavioral outcomes. here we used a chloroquine treatment model of cerebral malaria to determine whether these abnormal outcomes would be persistent in the mouse model. c57bl/6 mice were infected with plasmodium berghei anka, ...201020800692
immunization with pre-erythrocytic antigen celtos from plasmodium falciparum elicits cross-species protection against heterologous challenge with plasmodium berghei.the plasmodium protein cell-traversal protein for ookinetes and sporozoites (celtos) plays an important role in cell traversal of host cells in both, mosquito and vertebrates, and is required for successful malaria infections. celtos is highly conserved among the plasmodium species, suggesting an important functional role across all species. therefore, targeting the immune response to this highly conserved protein and thus potentially interfering with its biological function may result in protec ...201020808868
spiroindolones, a potent compound class for the treatment of malaria.recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. the spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of plasmodium falciparum and plasmodium vivax clinical isolates at low nanomolar concentration. spiroindolones rapidly inhibit protein synthesis in p. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the ge ...201020813948
alpha-tocopherol transfer protein inhibition is effective in the prevention of cerebral malaria in mice.nutritional status likely plays an important role in determining the outcome of protozoan infections. despite the evidence of plasmodium sensitivity to oxidative stress, the potential role of vitamin e, a free radical scavenger, on the outcome of cerebral malaria (cm) has yet to be elucidated.201019923370
synthesis and evaluation of phenylequine for antimalarial activity in vitro and in vivo.synthesis of the potent antiplasmodial 4-aminoquinoline, phenylequine (pq), is reported for the first time. pq and the two analogues show increased efficacy in moving from the chloroquine sensitive d10 to the chloroquine resistant k1 strain in vitro. the in vivo efficacy of pq, and salts thereof, have been determined in plasmodium berghei anka and plasmodium yoelii. phenylequine hydrochloride has shown an ed(50) of 0.81 in p. yoelii (cf chloroquine ed(50)=1.31).201020034790
the plasmodium serine-type sera proteases display distinct expression patterns and non-essential in vivo roles during life cycle progression of the malaria parasite.parasite proteases play key roles in several fundamental steps of the plasmodium life cycle, including haemoglobin degradation, host cell invasion and parasite egress. plasmodium exit from infected host cells appears to be mediated by a class of papain-like cysteine proteases called 'serine repeat antigens' (seras). a sera subfamily, represented by plasmodium falciparum sera5, contains an atypical active site serine residue instead of a catalytic cysteine. members of this seraser subfamily are a ...201020039882
assessment of in vivo antimalarial activity of rifampicin, isoniazide, and ethambutol combination therapy.the existing armament of drugs for the treatment and prevention of malaria is inadequate due to development of resistance. in addition to this due to lack of economic enticement the rate of new drug development and new drug discovery in the segment of parasitic diseases is very low as compared to the other segments. this has necessitated the better deployment and usage of existing antimalarial drugs as well as discovery of antimalarial activity of drugs which are well characterized for other dis ...201020165870
universal features of post-transcriptional gene regulation are critical for plasmodium zygote development.a universal feature of metazoan sexual development is the generation of oocyte p granules that withhold certain mrna species from translation to provide coding potential for proteins during early post-fertilization development. stabilisation of translationally quiescent mrna pools in female plasmodium gametocytes depends on the rna helicase dozi, but the molecular machinery involved in the silencing of transcripts in these protozoans is unknown. using affinity purification coupled with mass-spec ...201020169188
kynurenine is an endothelium-derived relaxing factor produced during inflammation.control of blood vessel tone is central to vascular homeostasis. here we show that metabolism of tryptophan to kynurenine by indoleamine 2,3-dioxygenase (ido) expressed in endothelial cells contributes to arterial vessel relaxation and the control of blood pressure. infection of mice with malarial parasites (plasmodium berghei) or induction of endotoxemia in mice led to endothelial expression of ido, decreased plasma tryptophan concentration, increased kynurenine concentration and hypotension. p ...201020190767
minimal role for the circumsporozoite protein in the induction of sterile immunity by vaccination with live rodent malaria sporozoites.immunization with live plasmodium sporozoites under chloroquine prophylaxis (spz plus cq) induces sterile immunity against sporozoite challenge in rodents and, more importantly, in humans. full protection is obtained with substantially fewer parasites than with the classic immunization with radiation-attenuated sporozoites. the sterile protection observed comprised a massive reduction in the hepatic parasite load and an additional effect at the blood stage level. differences in the immune respon ...201020194600
transmission blocking activity of a standardized neem (azadirachta indica) seed extract on the rodent malaria parasite plasmodium berghei in its vector anopheles stephensi.the wide use of gametocytocidal artemisinin-based combination therapy (act) lead to a reduction of plasmodium falciparum transmission in several african endemic settings. an increased impact on malaria burden may be achieved through the development of improved transmission-blocking formulations, including molecules complementing the gametocytocidal effects of artemisinin derivatives and/or acting on plasmodium stages developing in the vector. azadirachtin, a limonoid (tetranortriterpenoid) abund ...201020196858
dysregulation of angiopoietins is associated with placental malaria and low birth weight.placental malaria (pm) is associated with adverse pregnancy outcomes including low birth weight (lbw). however, the precise mechanisms by which pm induces lbw are poorly defined. based on the essential role of angiopoietin (ang)-1 and -2 in normal placental vascular development, we hypothesized that pm may result in the dysregulation of angiopoietins and thereby contribute to lbw outcomes.201020208992
suppressive effect of azithromycin on plasmodium berghei mosquito stage development and apicoplast replication.azithromycin (azm) is a macrolide antibiotic that displays an excellent safety profile even in children and pregnant women and has been shown to have anti-malarial activity against blood stage plasmodium falciparum. this study evaluated the transmission-blocking effect of azm using a rodent malaria model.201020219090
natural regulatory t cells mediate the development of cerebral malaria by modifying the pro-inflammatory response.cerebral malaria (cm) is a severe neurologic complication that arises predominantly in children and non-immune adults infected with plasmodium falciparum. in the current study, the dynamics of cd4(+)cd25(+)foxp3(+) regulatory t cells (tregs) and pro- and anti-inflammatory cytokines were analyzed in p. berghei anka (p.banka)-infected c57bl/6, balb/c, and dba/2 mice. we showed that c57bl/6 mice were susceptible to cm, while balb/c and dba/2 mice were resistant to cm and succumbed to hyperparasitem ...201020219695
artemisinin directly targets malarial mitochondria through its specific mitochondrial activation.the biological mode of action of artemisinin, a potent antimalarial, has long been controversial. previously we established a yeast model addressing its mechanism of action and found mitochondria the key in executing artemisinin's action. here we present data showing that artemisinin directly acts on mitochondria and it inhibits malaria in a similar way as yeast. specifically, artemisinin and its homologues exhibit correlated activities against malaria and yeast, with the peroxide bridge playing ...201020221395
a peroxidase/dual oxidase system modulates midgut epithelial immunity in anopheles gambiae.extracellular matrices in diverse biological systems are cross-linked by dityrosine covalent bonds catalyzed by the peroxidase/oxidase system. we show that a peroxidase, secreted by the anopheles gambiae midgut, and dual oxidase form a dityrosine network that decreases gut permeability to immune elicitors. this network protects the microbiota by preventing activation of epithelial immunity. it also provides a suitable environment for malaria parasites to develop within the midgut lumen without i ...201020223948
a putative kinase-related protein (pkrp) from plasmodium berghei mediates infection in the midgut and salivary glands of the mosquito.the completion of the plasmodium (malaria) life cycle in the mosquito requires the parasite to traverse first the midgut and later the salivary gland epithelium. we have identified a putative kinase-related protein (pkrp) that is predicted to be an atypical protein kinase, which is conserved across many species of plasmodium. the pkrp gene encodes a rna of about 5300 nucleotides that is expressed as a 90kda protein in sporozoites. targeted disruption of the pkrp gene in plasmodium berghei, a rod ...201020227415
functional identification of the plasmodium centromere and generation of a plasmodium artificial chromosome.the artificial chromosome represents a useful tool for gene transfer, both as cloning vectors and in chromosome biology research. to generate a plasmodium artificial chromosome (pac), we had to first functionally identify and characterize the parasite's centromere. a putative centromere (pbcen5) was cloned from chromosome 5 of the rodent parasite p. berghei based on a plasmodium gene-synteny map. plasmids containing pbcen5 were stably maintained in parasites during a blood-stage infection with h ...201020227667
pretreatment with cry1ac protoxin modulates the immune response, and increases the survival of plasmodium-infected cba/ca mice.malaria is a major global health problem that kills 1-2 million people each year. despite exhaustive research, naturally acquired immunity is poorly understood. cry1a proteins are potent immunogens with adjuvant properties and are able to induce strong cellular and humoral responses. in fact, it has been shown that administration of cry1ac protoxin alone or with amoebic lysates induces protection against the lethal infection caused by the protozoa naegleria fowleri. in this work, we studied whet ...201020300584
tomatine adjuvantation of protective immunity to a major pre-erythrocytic vaccine candidate of malaria is mediated via cd8+ t cell release of ifn-gamma.the glycoalkaloid tomatine, derived from the wild tomato, can act as a powerful adjuvant to elicit an antigen-specific cell-mediated immune response to the circumsporozoite (cs) protein, a major pre-erythrocytic stage malaria vaccine candidate antigen. using a defined mhc-class-i-restricted cs epitope in a plasmodium berghei rodent model, antigen-specific cytotoxic t lymphocyte activity and ifn-gamma secretion ex vivo were both significantly enhanced compared to responses detected from similarly ...201020300588
up- and down-modulation of liver cytochrome p450 activities and associated events in two murine malaria models.the mechanisms by which malaria up and down-regulates cyp activities are not understood yet. it is also unclear whether cyp activities are modulated during non-lethal malaria infections. this study was undertaken to evaluate the time course of cyp alterations in lethal (plasmodium berghei anka) and non-lethal (plasmodium chabaudi chabaudi) murine malaria. additionally, hypotheses on the association of cyp depression with enhanced nitric oxide (no) production, and of cyp2a5 induction with endopla ...201020307316
algorithms to predict cerebral malaria in murine models using the shirpa protocol.plasmodium berghei anka infection in c57bl/6 mice induces cerebral malaria (cm), which reproduces, to a large extent, the pathological features of human cm. however, experimental cm incidence is variable (50-100%) and the period of incidence may present a range as wide as 6-12 days post-infection. the poor predictability of which and when infected mice will develop cm can make it difficult to determine the causal relationship of early pathological changes and outcome. with the purpose of contrib ...201020334682
murine cerebral malaria: how far from human cerebral malaria? 201020335068
membrane fusion triggers rapid degradation of two gamete-specific, fusion-essential proteins in a membrane block to polygamy in chlamydomonas.the plasma membranes of gametes are specialized for fusion, yet, once fusion occurs, in many organisms the new zygote becomes incapable of further membrane fusion reactions. the molecular mechanisms that underlie this loss of fusion capacity (block to polygamy) remain unknown. during fertilization in the green alga chlamydomonas, the plus gamete-specific membrane protein fus1 is required for adhesion between the apically localized sites on the plasma membranes of plus and minus gametes that are ...201020335357
ancient chinese methods are remarkably effective for the preparation of artemisinin-rich extracts of qing hao with potent antimalarial activity.ancient chinese herbal texts as far back as the 4th century zhou hou bei ji fang describe methods for the use of qing hao (artemisia annua) for the treatment of intermittent fevers. today, the a. annua constituent artemisinin is an important antimalarial drug and the herb itself is being grown and used locally for malaria treatment although this practice is controversial. here we show that the ancient chinese methods that involved either soaking, (followed by wringing) or pounding, (followed by ...201020335947
anti-infective discorhabdins from a deep-water alaskan sponge of the genus latrunculia.bioassay- and lc-ms-guided fractionation of a methanol extract from a new deep-water alaskan sponge species of the genus latrunculia resulted in the isolation of two new brominated pyrroloiminoquinones, dihydrodiscorhabdin b and discorhabdin y (2), along with six known pyrroloiminoquinone alkaloids, discorhabdins a (3), c (4), e (5), and l (6), dihydrodiscorhabdin c (7), and the benzene derivative 8. compounds 3, 4, and 7 exhibited anti-hcv activity, antimalarial activity, and selective antimicr ...201020337497
mosquito cell line glycoproteins: an unsuitable model system for the plasmodium ookinete-mosquito midgut interaction?abstract:201020338056
neuropathogenesis of human and murine malaria. 201020338809
preclinical evaluation of the antifolate qn254, 5-chloro- n'6'-(2,5-dimethoxy-benzyl)-quinazoline-2,4,6-triamine, as an antimalarial drug candidate.drug resistance against dihydrofolate reductase (dhfr) inhibitors-such as pyrimethamine (pm)-has now spread to almost all regions where malaria is endemic, rendering antifolate-based malaria treatments highly ineffective. we have previously shown that the di-amino quinazoline qn254 [5-chloro-n'6'-(2,5-dimethoxy-benzyl)-quinazoline-2,4,6-triamine] is active against the highly pm-resistant plasmodium falciparum v1s strain, suggesting that qn254 could be used to treat malaria in regions with a high ...201020350951
small variant surface antigens and plasmodium evasion of immunity.antigenic variation at the plasmodium-infected erythrocyte surface plays a critical role in malaria disease severity and host immune evasion. our current understanding of the role of plasmodium variant surface antigens in antigenic variation and immune evasion is largely limited to the extensive work carried out on the plasmodium falciparum var gene family. although homologues of var genes are not present in other malaria species, small variant gene families comprising the rif and stevor genes i ...201020353305
exoerythrocytic plasmodium parasites secrete a cysteine protease inhibitor involved in sporozoite invasion and capable of blocking cell death of host hepatocytes.plasmodium parasites must control cysteine protease activity that is critical for hepatocyte invasion by sporozoites, liver stage development, host cell survival and merozoite liberation. here we show that exoerythrocytic p. berghei parasites express a potent cysteine protease inhibitor (pbicp, p. berghei inhibitor of cysteine proteases). we provide evidence that it has an important function in sporozoite invasion and is capable of blocking hepatocyte cell death. pre-incubation with specific ant ...201020361051
cerebral malaria: in praise of epistemes. 201020363672
cerebral malaria: human versus mouse studies. 201020382077
murine cerebral malaria: the whole story. 201020382078
rapid quantification of the effects of blotting for correlation of light and cryo-light microscopy images.recent technical developments allowed the accurate correlation of fluorescently labelled organelles in living cells to cryo-electron micrographs. we aimed at expanding this approach to plasmodium berghei sporozoites, the motile forms of a rodent malaria parasite, which can be imaged by cryo-electron tomography in toto without the need for sectioning. sporozoites are crescent shaped eukaryotic cells that move on flat supports including em grids in a circular, unidirectional manner. while sporozoi ...201020384834
three members of the 6-cys protein family of plasmodium play a role in gamete fertility.the process of fertilization is critically dependent on the mutual recognition of gametes and in plasmodium, the male gamete surface protein p48/45 is vital to this process. this protein belongs to a family of 10 structurally related proteins, the so called 6-cys family. to identify the role of additional members of this family in plasmodium fertilisation, we performed genetic and functional analysis on the five members of the 6-cys family that are transcribed during the gametocyte stage of p. b ...201020386715
a role for cd4+ and cd8+ cells and not for cd25+ cells in the control of plasmodium berghei anka blood stage parasites in rats.in previous studies of the infection of rats by p. berghei anka, we have shown that primary blood stage infection induced the expansion of cd4+ t cells and cd8+ t cells in adult resistant rats while the number of cd4+cd25+ cells was found to be higher in young susceptible rats. in this work, the respective contribution of each cell population was determined in young and adult rats treated with monoclonal antibodies. down-regulation of surface cd25 molecules, including those expressed by cd4+ cel ...201020387739
blood-stage plasmodium berghei infection leads to short-lived parasite-associated antigen presentation by dendritic cells.despite extensive evidence that plasmodium species are capable of stimulating the immune system, the association of malaria with a higher incidence of other infectious diseases and reduced responses to vaccination against unrelated pathogens suggests the existence of immune suppression. recently, we provided evidence that blood-stage plasmodium berghei infection leads to suppression of mhc class i-restricted immunity to third party (non-malarial) antigens as a consequence of systemic dc activati ...201020391433
synthesis, in vitro and in vivo antimalarial assessment of sulfide, sulfone and vinyl amide-substituted 1,2,4-trioxanes prepared via thiol-olefin co-oxygenation (toco) of allylic alcohols.thiol-olefin co-oxygenation (toco) methodology has been applied to the synthesis of a small library of weak base and polar 1,2,4-trioxanes. the 1,2,4-trioxane units synthesised exhibit remarkable stability as they survive base catalysed hydrolysis and mixed anhydride/amine coupling reactions. this unique stability feature has enabled a range of novel substitution patterns to be incorporated within the spiro 1,2,4-trioxane unit. selected analogues express potent in vitro nm antimalarial activity, ...201020401383
alpha-tocopherol transfer protein disruption confers resistance to malarial infection in mice.various factors impact the severity of malaria, including the nutritional status of the host. vitamin e, an intra and extracellular anti-oxidant, is one such nutrient whose absence was shown previously to negatively affect plasmodium development. however, mechanisms of this plasmodium inhibition, in addition to means by which to exploit this finding as a therapeutic strategy, remain unclear.201020403155
fertilization is a novel attacking site for the transmission blocking of malaria parasites.malaria parasites perform sexual reproduction in mosquitoes where a pair of gametes fertilizes and differentiates into zygotes, and a single zygote produces several thousands of progeny infectious to next vertebrates. although the parasite fertilization step has been considered as achilles' heel of parasite life cycle and thus a critical target for blocking malaria transmission in the mosquito, its molecular mechanisms are largely unknown. previously, we identified that generative cell specific ...201019665985
initiation of plasmodium sporozoite motility by albumin is associated with induction of intracellular signalling.malaria infection is initiated when a mosquito injects plasmodium sporozoites into a mammalian host. sporozoites exhibit gliding motility both in vitro and in vivo. this motility is associated with the secretion of at least two proteins, circumsporozoite protein (csp) and thrombospondin-related anonymous protein (trap). both derive from micronemes, which are organelles that empty out of the apical end of the sporozoite. sporozoite motility can be initiated in vitro by albumin added to the medium ...201019654011
il-10 plays a crucial role for the protection of experimental cerebral malaria by co-infection with non-lethal malaria parasites.cerebral malaria is an infrequent but serious complication of plasmodium falciparum infection in humans. co-infection with different plasmodium species is common in endemic areas and the existence of benign malaria parasites, such as plasmodium vivax, during p. falciparum infection has been considered to reduce the risk of developing pathogenesis. however, it is still unknown how disease severity is reduced in the host during co-infection. in the present study, we investigated the influence of c ...201019735663
plasmodium berghei ookinetes glide and release pbs25 and circumsporozoite thrombospondin-related protein on solid surface substrata.plasmodium spp. development within mosquito vectors includes invasive ookinete and sporozoites stages, which display gliding movements during invasion of the midgut and salivary glands, respectively. sporozoite gliding has been well documented, and several proteins released during sporozoite's locomotion have been described. however, proteins on the ookinete gliding trails are poorly described. in the present study, we documented that 2 proteins, pbs25 and circumsporozoite thrombospondin-related ...201019747017
changes in cell migration-related molecules expressed by thymic microenvironment during experimental plasmodium berghei infection: consequences on thymocyte development.we previously showed alterations in the thymus during experimental infection with plasmodium berghei. such alterations comprised histological changes, with loss of cortical-medullary limits, and the intrathymic presence of parasites. as the combination of chemokines, adhesion molecules and extracellular matrix (ecm) is critical to appropriate thymocyte development, we analysed the thymic expression of ecm ligands and receptors, as well as chemokines and their respective receptors during the expe ...201019824923
malaria: targeting parasite and host cell kinomes.malaria still remains one of the deadliest infectious diseases, and has a tremendous morbidity and mortality impact in the developing world. the propensity of the parasites to develop drug resistance, and the relative reluctance of the pharmaceutical industry to invest massively in the developments of drugs that would offer only limited marketing prospects, are major issues in antimalarial drug discovery. protein kinases (pks) have become a major family of targets for drug discovery research in ...201019840874
identification of a novel cerebral malaria susceptibility locus (berr5) on mouse chromosome 19.cerebral malaria (cm) is an acute, generally lethal condition characterized by high fever, seizures and coma. the genetic component to cm can be investigated in mouse models that vary in degree of susceptibility to infection with plasmodium berghei anka. using survival time to measure susceptibility in an informative f2 cross (n=257), we identified linkage to chromosome 19 (berr5 (berghei resistance locus 5), lod=4.69) controlling, in part, the differential response between resistant balb/c and ...201019865103
neither mosquito saliva nor immunity to saliva has a detectable effect on the infectivity of plasmodium sporozoites injected into mice.malaria infection is initiated when a female anopheles mosquito probing for blood injects saliva, together with sporozoites, into the skin of its mammalian host. prior studies had suggested that saliva may enhance sporozoite infectivity. using rodent malaria models (plasmodium berghei and p. yoelii), we were unable to show that saliva had any detectable effect on sporozoite infectivity. this is encouraging for plans to immunize humans with washed, attenuated p. falciparum sporozoites because man ...201019884338
analgesic and antimalarial activities of crude leaf extract and fractions of acalypha wilkensiana.antiplasmodial and analgesic activities of leaf extract and fractions of acalypha wilkensiana were evaluated to ascertain the folkloric claim of its antimalarial and analgesic activities.201019892007
phosphothioate oligodeoxynucleotides inhibit plasmodium sporozoite gliding motility.plasmodium sporozoites, transmitted to the mammalian host through a mosquito bite, travel to the liver, where they invade hepatocytes, and develop into a form that is then able to infect red blood cells. in spite of the importance of innate immunity in controlling microbial infections, almost nothing is known about its role during the liver stage of a malaria infection. here, we tested whether synthetic cpg phosphothioate (ps) oligodeoxynucleotides (odns), which bind to toll-like receptor 9 (tlr ...201019912239
synthesis and antimalarial evaluation of 1, 3, 5-trisubstituted pyrazolines.a series of 1,3,5-trisubstituted pyrazolines were synthesized and evaluated for in vitro antimalarial efficacy against chloroquine sensitive (mrc-02) as well as chloroquine resistant (rkl9) strains of plasmodium falciparum. the activity was at nano molar concentration. beta-hematin formation inhibition activity (bhia(50)) of the pyrazolines were determined and correlated with antimalarial activity. a reasonably good correlation (r=0.62) was observed between antimalarial activity (ic(50)) and bhi ...201019926176
the murine cerebral malaria phenomenon.p.berghei anka infection in cba or cb57bl/6 mice is used widely as a murine 'model' of human cerebral malaria (hcm), despite markedly different histopathological features. the pathology of the murine model is characterised by marked inflammation with little or no intracerebral sequestration of parasitised erythrocytes, whereas hcm is associated with intense intracerebral sequestration, often with little inflammatory response. there are now more than ten times as many studies each year of the mur ...201019932638
plasmodium berghei crystalloids contain multiple lccl proteins.malaria crystalloids are unique organelles of unknown function that are present only in the mosquito-specific ookinete and early oocyst stages of the parasite. recently, crystalloid formation in plasmodium berghei was linked to the parasite protein pbsr, a member of the plasmodium lccl protein family composed of six modular multidomain proteins involved in sporozoite development and infectivity. here, we show by fluorescent protein tagging that two other lccl protein family members are targeted ...201019932717
role of plasmodium berghei cgmp-dependent protein kinase in late liver stage development.the liver is the first organ infected by plasmodium sporozoites during malaria infection. in the infected hepatocytes, sporozoites undergo a complex developmental program to eventually generate hepatic merozoites that are released into the bloodstream in membrane-bound vesicles termed merosomes. parasites blocked at an early developmental stage inside hepatocytes elicit a protective host immune response, making them attractive targets in the effort to develop a pre-erythrocytic stage vaccine. he ...201019940133
experimental cerebral malaria progresses independently of the nlrp3 inflammasome.cerebral malaria is the most severe complication of plasmodium falciparum infection in humans and the pathogenesis is still unclear. using the p. berghei anka infection model of mice, we investigated a potential involvement of nlrp3 and the inflammasome in the pathogenesis of cerebral malaria. nlrp3 mrna expression was upregulated in brain endothelial cells after exposure to p. berghei anka. although beta-hematin, a synthetic compound of the parasites heme polymer hemozoin, induced the release o ...201019950187
the comparative antimalarial properties of weak base and neutral synthetic ozonides.thirty-three n-acyl 1,2,4-dispiro trioxolanes (secondary ozonides) were synthesized. for these ozonides, weak base functional groups were not required for high antimalarial potency against plasmodium falciparum in vitro, but were necessary for high antimalarial efficacy in plasmodium berghei-infected mice. a wide range of logp/d(ph)(7.4) values were tolerated, although more lipophilic ozonides tended to be less metabolically stable.201019962893
synthesis and antiplasmodial activity of new indolone n-oxide derivatives.a series of 66 new indolone-n-oxide derivatives was synthesized with three different methods. compounds were evaluated for in vitro activity against cq-sensitive (3d7), cq-resistant (fcb1), and cq and pyrimethamine cross-resistant (k1) strains of plasmodium falciparum (p.f.), as well as for cytotoxic concentration (cc(50)) on mcf7 and kb human tumor cell lines. compound 26 (5-methoxy-indolone-n-oxide analogue) had the most potent antiplasmodial activity in vitro (<3 nm on fcb1 and = 1.7 nm on 3d ...201020014857
plasmepsin 4-deficient plasmodium berghei are virulence attenuated and induce protective immunity against experimental malaria.plasmodium parasites lacking plasmepsin 4 (pm4), an aspartic protease that functions in the lysosomal compartment and contributes to hemoglobin digestion, have only a modest decrease in the asexual blood-stage growth rate; however, pm4 deficiency in the rodent malaria parasite plasmodium berghei results in significantly less virulence than that for the parental parasite. p. berghei deltapm4 parasites failed to induce experimental cerebral malaria (ecm) in ecm-susceptible mice, and ecm-resistant ...201020019192
transcription factor ap2-sp and its target genes in malarial sporozoites.the malarial sporozoite is the stage that infects the liver, and genes expressed in this stage are potential targets for vaccine development. here, we demonstrate that specific gene expression in this stage is regulated by an ap2-related transcription factor, designated ap2-sp (apetala2 in sporozoites), that is expressed from the late oocyst to the salivary gland sporozoite. disruption of the ap2-sp gene did not affect parasite replication in the erythrocyte but resulted in loss of sporozoite fo ...201020025671
mosquito immune defenses against plasmodium infection.the causative agent of malaria, plasmodium, has to undergo complex developmental transitions and survive attacks from the mosquito's innate immune system to achieve transmission from one host to another through the vector. here we discuss recent findings on the role of the mosquito's innate immune signaling pathways in preventing infection by the plasmodium parasite, the identification and mechanistic description of novel anti-parasite molecules, the role that natural bacteria harbored in the mo ...201020026176
a dispensable plasmodium locus for stable transgene expression.the ribosomal small subunit locus has been used for transgene expression in the rodent malaria parasites, plasmodium berghei and plasmodium yoelii, but this strategy utilizes single crossover integration and is thus prone to reversion by plasmid excision. targeting of the ribosomal subunit locus may also have a negative effect on oocyst development in the mosquito. in p. berghei, the p230 paralog locus has been used for transgene expression. here, we show that the p. yoelii s1 locus (sporozoite ...201020045029
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