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plasmodium berghei histamine-releasing factor favours liver-stage development via inhibition of il-6 production and associates with a severe outcome of disease.plasmodium spp., which causes malaria, produces a histamine-releasing factor (hrf), an orthologue of mammalian hrf. histamine-releasing factor produced by erythrocytic stages of the parasite is thought to play a role in the pathogenesis of severe malaria. here, we show in a rodent model that hrf is not important during the erythrocytic but pre-erythrocytic phase of infection, which mainly consists in the transformation in the liver of the mosquito-injected parasite form into the erythrocyte-infe ...201525329441
exacerbation of autoimmune neuro-inflammation in mice cured from blood-stage plasmodium berghei infection.the thymus plays an important role shaping the t cell repertoire in the periphery, partly, through the elimination of inflammatory auto-reactive cells. it has been shown that, during plasmodium berghei infection, the thymus is rendered atrophic by the premature egress of cd4+cd8+ double-positive (dp) t cells to the periphery. to investigate whether autoimmune diseases are affected after plasmodium berghei nk65 infection, we immunized c57bl/6 mice, which was previously infected with p. berghei nk ...201425329161
anti-relapse activity of mirincamycin in the plasmodium cynomolgi sporozoite-infected rhesus monkey model.mirincamycin is a close analog of the drug clindamycin used to treat plasmodium falciparum blood stages. the clinical need to treat plasmodium vivax dormant liver stages and prevent relapse with a drug other than primaquine led to the evaluation of mirinicamycin against liver stages in animals.201425326032
spatiotemporal requirements for irf7 in mediating type i ifn-dependent susceptibility to blood-stage plasmodium infection.type i ifn signaling suppresses splenic t helper 1 (th1) responses during blood-stage plasmodium berghei anka (pba) infection in mice, and is crucial for mediating tissue accumulation of parasites and fatal cerebral symptoms via mechanisms that remain to be fully characterized. interferon regulatory factor 7 (irf7) is considered to be a master regulator of type i ifn responses. here, we assessed irf7 for its roles during lethal pba infection and nonlethal plasmodium chabaudi chabaudi as (pcas) i ...201525319247
enantiomerically pure amino-alcohol quinolines: in vitro anti-malarial activity in combination with dihydroartemisinin, cytotoxicity and in vivo efficacy in a plasmodium berghei mouse model.as resistance to marketed anti-malarial drugs continues to spread, the need for new molecules active on plasmodium falciparum-resistant strains grows. pure (s) enantiomers of amino-alcohol quinolines previously displayed a good in vitro anti-malarial activity. therefore, a more thorough assessment of their potential clinical use through a rodent model and an in vitro evaluation of their combination with artemisinin was undertaken.201425319003
medicinal chemistry optimization of antiplasmodial imidazopyridazine hits from high throughput screening of a softfocus kinase library: part 2.on the basis of our recent results on a novel series of imidazopyridazine-based antimalarials, we focused on identifying compounds with improved aqueous solubility and herg profile while maintaining metabolic stability and in vitro potency. toward this objective, 41 compounds were synthesized and evaluated for antiplasmodial activity against nf54 (sensitive) and k1 (multidrug resistant) strains of the malaria parasite plasmodium falciparum and evaluated for both aqueous solubility and metabolic ...201425313449
in vitro activity of waladin benzimidazoles against different life cycle stages of plasmodium parasites.waladin1 benzimidazoles are specific inhibitors of δ-aminolevulinic acid dehydratase from wolbachia endobacteria of filarial nematodes. we report that waladin1 and two derivatives killed blood stage plasmodium falciparum in vitro (50% inhibitory concentrations, 39, 7.7, and 12.8 μm, respectively). one of these derivatives inhibited gliding motility of plasmodium berghei anka infectious sporozoites with nanomolar affinity and blocked invasion into hepatocytes but did not affect intrahepatocytic r ...201425313210
design, synthesis and evaluation of antimalarial potential of polyphosphazene linked combination therapy of primaquine and dihydroartemisinin.various polymer drug conjugates (13-16) such as primaquine and dihydroartemisinin conjugated 2-propoxy substituted polyphosphazenes (13), primaquine and dihydroartemisinin conjugated 4-acetamidophenoxy substituted polyphosphazenes (14), primaquine and dihydroartemisinin conjugated 4-formyl substituted polyphosphazenes (15) and primaquine and dihydroartemisinin conjugated 4-aminoethylbenzoate substituted polyphosphazenes (16) were synthesized using substituted polyphosphazenes as polymer and prim ...201525312346
evaluation of the antimalarial potential of icacina senegalensis juss (icacinaceae).to evaluate in vivo antimalarial activity of methanol leaf extract of icacina senegalensis.201425312169
effect of thioredoxin peroxidase-1 gene disruption on the liver stages of the rodent malaria parasite plasmodium berghei.phenotypic observation of thioredoxin peroxidase-1 (tpx-1) gene-disrupted plasmodium berghei (tpx-1 ko) in the liver-stage was performed with an in vitro infection system in order to investigate defective liver-stage development in a mouse infection model. indirect immunofluorescence microscopy assay with anti-circumsporozoite protein antibody revealed that in the liver schizont stage, tpx-1 ko parasite cells were significantly smaller than cells of the wild-type parent strain (wt). indirect imm ...201525284813
antimalarial activity of malaysian plectranthus amboinicus against plasmodium berghei.malaria is a mosquito-borne disease caused by parasitic protozoa from the genus of plasmodium. the protozoans have developed resistance against many of current drugs. it is urgent to find an alternative source of new antimalarial agent. in the effort to discover new antimalarial agents, this research has been conducted on plectranthus amboinicus.201425276063
predictive criteria to study the pathogenesis of malaria-associated ali/ards in mice.malaria-associated acute lung injury/acute respiratory distress syndrome (ali/ards) often results in morbidity and mortality. murine models to study malaria-associated ali/ards have been described; we still lack a method of distinguishing which mice will develop ali/ards before death. this work aimed to characterize malaria-associated ali/ards in a murine model and to demonstrate the first method to predict whether mice are suffering from ali/ards before death. dba/2 mice infected with plasmodiu ...201425276057
modulatory effect of crude aqueous extract of lingzhi or reishi medicinal mushroom, ganoderma lucidum (higher basidiomycetes), on hematological and antioxidant indices in plasmodium berghei-infected mice.hematological and antioxidant effects of the aqueous extract of fruiting bodies of ganoderma lucidum were evaluated in plasmodium berghei-infected mice. extract was administered at doses of 100, 250, and 500 mg/kg body weight by an intragastric tube once daily for 14 d starting from the fourth day after parasite inoculation. at the end of treatment period, mice in each group were sacrificed and blood was collected for hematological and biochemical analyses. a significant (p<0.05) decrease was ob ...201425271985
direct evidence for the atovaquone action on the plasmodium cytochrome bc1 complex.atovaquone, a coenzyme q analogue has been indicated to specifically target the cytochrome bc1 complex of the mitochondrial respiratory chain in the malarial parasite and other protozoan. various mutations in the quinone binding site of the cytochrome b gene of plasmodium spp. such as m133i, l144s, l271v, k272r, y268c, y268s, y268n, and v284f are suggesting to associate with resistance to atovaquone. there is no direct evidence of relation between the mutations and resistance to atovaquone in pl ...201525264100
distinct properties of the egress-related osmiophilic bodies in male and female gametocytes of the rodent malaria parasite plasmodium berghei.gametogenesis is the earliest event after uptake of malaria parasites by the mosquito vector, with a decisive impact on colonization of the mosquito midgut. this process is triggered by a drop in temperature and contact with mosquito molecules. in a few minutes, male and female gametocytes escape from the host erythrocyte by rupturing the parasitophorous vacuole and the erythrocyte membranes. electron-dense, oval-shaped organelles, the osmiophilic bodies (ob), have been implicated in the egress ...201525262869
zipco, a putative metal ion transporter, is crucial for plasmodium liver-stage development.the malaria parasite, plasmodium, requires iron for growth, but how it imports iron remains unknown. we characterize here a protein that belongs to the zip (zrt-, irt-like protein) family of metal ion transport proteins and have named zip domain-containing protein (zipco). inactivation of the zipco-encoding gene in plasmodium berghei, while not affecting the parasite's ability to multiply in mouse blood and to infect mosquitoes, greatly impairs its capacity to develop inside hepatocytes. iron/zi ...201425257508
anopheles gambiae blood feeding initiates an anticipatory defense response to plasmodium berghei.mosquitoes have potent innate defense mechanisms that protect them from infection by diverse pathogens. much remains unknown about how different pathogens are sensed and specific responses triggered. leucine-rich repeat immune proteins (lrims) are a mosquito-specific family of putative innate receptors. although some lrims have been implicated in mosquito immune responses, the function of most family members is largely unknown. we screened anopheles gambiae lrims by rnai for effects on mosquito ...201425247883
trpv1 antagonism by capsazepine modulates innate immune response in mice infected with plasmodium berghei anka.thousands of people suffer from severe malaria every year. the innate immune response plays a determinant role in host's defence to malaria. transient receptor potential vanilloid 1 (trpv1) modulates macrophage-mediated responses in sepsis, but its role in other pathogenic diseases has never been addressed. we investigated the effects of capsazepine, a trpv1 antagonist, in malaria. c57bl/6 mice received 10(5) red blood cells infected with plasmodium berghei anka intraperitoneally. noninfected mi ...201425242870
characterization of plasmodium developmental transcriptomes in anopheles gambiae midgut reveals novel regulators of malaria transmission.the passage through the mosquito is a major bottleneck for malaria parasite populations and a target of interventions aiming to block disease transmission. here, we used dna microarrays to profile the developmental transcriptomes of the rodent malaria parasite plasmodium berghei in vivo, in the midgut of anopheles gambiae mosquitoes, from parasite stages in the midgut blood bolus to sporulating oocysts on the basal gut wall. data analysis identified several distinct transcriptional programmes en ...201425225164
a novel plasmodium-specific prodomain fold regulates the malaria drug target sub1 subtilase.the plasmodium subtilase sub1 plays a pivotal role during the egress of malaria parasites from host hepatocytes and erythrocytes. here we report the crystal structure of full-length sub1 from the human-infecting parasite plasmodium vivax, revealing a bacterial-like catalytic domain in complex with a plasmodium-specific prodomain. the latter displays a novel architecture with an amino-terminal insertion that functions as a 'belt', embracing the catalytic domain to further stabilize the quaternary ...201425204226
plasma micrornas are promising novel biomarkers for the early detection of toxoplasma gondii infection.micrornas (mirnas) have been shown to be present in plasma, which are remarkably stable, and have been suggested as disease biomarkers. toxoplasma gondii (t. gondii) is a protozoan parasite that is infective to a wide range of animals and human beings. previous studies have found that the parasite generated a large number of mirnas during proliferation and it is known that the spectrum of mirna expression in the infected hosts is pathogen-specific. to date, there are no reports regarding the app ...201425199527
loss of toll-like receptor 7 alters cytokine production and protects against experimental cerebral malaria.malaria, caused by plasmodium sp. parasites, is a leading cause of global morbidity and mortality. cerebral malaria, characterized by neurological symptoms, is a life-threatening complication of malaria affecting over 500,000 young children in africa every year. because of the prevalence and severity of cerebral malaria, a better understanding of the underlying molecular mechanisms of its pathology is desirable and could inform future development of therapeutics. this study sought to clarify the ...201425192715
vascular dysfunction as a target for adjuvant therapy in cerebral malaria.cerebral malaria (cm) is a life-threatening complication of plasmodium falciparum malaria that continues to be a major global health problem. brain vascular dysfunction is a main factor underlying the pathogenesis of cm and can be a target for the development of adjuvant therapies for the disease. vascular occlusion by parasitised red blood cells and vasoconstriction/vascular dysfunction results in impaired cerebral blood flow, ischaemia, hypoxia, acidosis and death. in this review, we discuss t ...201425185000
micromagnetic resonance relaxometry for rapid label-free malaria diagnosis.we report a new technique for sensitive, quantitative and rapid detection of plasmodium spp.-infected red blood cells (rbcs) by means of magnetic resonance relaxometry (mrr). during the intraerythrocytic cycle, malaria parasites metabolize large amounts of cellular hemoglobin and convert it into hemozoin crystallites. we exploit the relatively large paramagnetic susceptibility of these hemozoin particles, which induce substantial changes in the transverse relaxation rate of proton nuclear magnet ...201425173428
a cysteine protease inhibitor of plasmodium berghei is essential for exo-erythrocytic development.plasmodium parasites express a potent inhibitor of cysteine proteases (icp) throughout their life cycle. to analyze the role of icp in different life cycle stages, we generated a stage-specific knockout of the plasmodium berghei icp (pbicp). excision of the pbicb gene occurred in infective sporozoites and resulted in impaired sporozoite invasion of hepatocytes, despite residual pbicp protein being detectable in sporozoites. the vast majority of these parasites invading a cultured hepatocyte cell ...201425166051
in vivo antiplasmodial potentials of the combinations of four nigerian antimalarial plants.various combinations of nauclea latifolia root, artocarpus altilis stem bark, murraya koenigii leaf and enantia chlorantha stem bark used in african ethnomedicine as decoctions for malaria and fevers, and combinations with standard drugs, were investigated for antiplasmodial activities using plasmodium berghei berghei-infected mice. the respective prophylactic and curative ed50 values of 189.4 and 174.5 mg/kg for n. latifolia and chemosuppressive ed50 value of 227.2 mg/kg for a. altilis showed t ...201425162955
damage to the blood-brain barrier during experimental cerebral malaria results from synergistic effects of cd8+ t cells with different specificities.cd8(+) t cells play a pathogenic role in the development of murine experimental cerebral malaria (ecm) induced by plasmodium berghei anka (pba) infection in c57bl/6 mice. only a limited number of cd8(+) epitopes have been described. here, we report the identification of a new epitope from the bergheilysin protein recognized by pba-specific cd8(+) t cells. induction and functionality of these specific cd8(+) t cells were investigated in parallel with previously reported epitopes, using new tools ...201425156726
the subcellular location of ovalbumin in plasmodium berghei blood stages influences the magnitude of t-cell responses.model antigens are frequently introduced into pathogens to study determinants that influence t-cell responses to infections. to address whether an antigen's subcellular location influences the nature and magnitude of antigen-specific t-cell responses, we generated plasmodium berghei parasites expressing the model antigen ovalbumin (ova) either in the parasite cytoplasm or on the parasitophorous vacuole membrane (pvm). for cytosolic expression, ova alone or conjugated to mcherry was expressed fro ...201425156724
evaluation of antimalarial activity of leaves of acokanthera schimperi and croton macrostachyus against plasmodium berghei in swiss albino mice.malaria is one of the most important tropical diseases and the greatest cause of hospitalization and death. recurring problems of drug resistance are reinforcing the need for finding new antimalarial drugs. in this respect, natural plant products are the main sources of biologically active compounds and have potential for the development of novel antimalarial drugs. a study was conducted to evaluate extracts of the leaves of croton macrostachyus and acokanthera schimperi for their in vivo antima ...201425155821
an essential role of the basal body protein sas-6 in plasmodium male gamete development and malaria transmission.gametocytes are the sole plasmodium parasite stages that infect mosquitoes; therefore development of functional gametes is required for malaria transmission. flagellum assembly of the plasmodium male gamete differs from that of most other eukaryotes in that it is intracytoplasmic but retains a key conserved feature: axonemes assemble from basal bodies. the centriole/basal body protein sas-6 normally regulates assembly and duplication of these organelles and its depletion causes severe flagellar/ ...201425154861
molecular characterization of calreticulin from anopheles stephensi midgut cells and functional assay of the recombinant calreticulin with plasmodium berghei ookinetes.transmission blocking vaccines (tbvs) that target the antigens on the midgut epithelium of anopheles mosquitoes are among the promising tools for the elimination of the malaria parasite. characterization and analysis of effective antigens is the first step to design tbvs. calreticulin (crt), a lectin-like protein, from anopheles albimanus midgut, has shown antigenic features, suggesting a promising and novel tbv target. crt is a highly conserved protein with similar features in vertebrates and i ...201425150160
evaluation of the adjuvant activity of propranolol, a beta-adrenergic receptor antagonist, on efficacy of a malaria vaccine model in balb/c mice.we have previously shown the adjuvant activity of propranolol (prp) (a beta-adrenergic receptor antagonist) using a vaccine model for salmonella typhimurium. in this study prp was used as an adjuvant in combination with plasmodium berghei (p. berghei) whole blood stage (pwbs) antigens. balb/c mice were immunized three times with a 2-week interval, either pwbs vaccine alone or in combination with the adjuvant alum or propranolol. the control group received phosphate buffered saline. evaluation of ...201425150071
orally bioavailable 6-chloro-7-methoxy-4(1h)-quinolones efficacious against multiple stages of plasmodium.the continued proliferation of malaria throughout temperate and tropical regions of the world has promoted a push for more efficacious treatments to combat the disease. unfortunately, more recent remedies such as artemisinin combination therapies have been rendered less effective due to developing parasite resistance, and new drugs are required that target the parasite in the liver to support the disease elimination efforts. research was initiated to revisit antimalarials developed in the 1940s ...201425148516
dominant negative mutant of plasmodium rad51 causes reduced parasite burden in host by abrogating dna double-strand break repair.malaria parasites survive through repairing a plethora of dna double-stranded breaks (dsbs) experienced during their asexual growth. in plasmodium rad51 mediated homologous recombination (hr) mechanism and homology-independent alternative end-joining mechanism have been identified. here we address whether loss of hr activity can be compensated by other dsb repair mechanisms. creating a transgenic plasmodium line defective in hr function, we demonstrate that hr is the most important dsb repair pa ...201425145341
preparation, characterization, and optimization of primaquine-loaded solid lipid nanoparticles.primaquine (pq) is one of the most widely used antimalarial drugs and is the only available drug that combats the relapsing form of malaria. pq use in higher doses is limited by severe tissue toxicity including hematological- and gastrointestinal-related side effects. nanoformulation of drugs in an appropriate drug carrier system has been extensively studied and shown to have the potential to improve bioavailability, thereby enhancing activity, reducing dose frequency, and subsequently reducing ...201425143734
43 kda and 66 kda, two blood stage antigens induce immune response in plasmodium berghei malaria.the hunt for an effective vaccine against malaria still continues. several new target antigens as candidates for vaccine design are being explored and tested for their efficacy. in the present study the sera from mice immunized with 24,000 x g fraction of plasmodium berghei has been used to identify highly immunogenic blood stage antigens. the protective antibodies present in immune sera were covalently immobilized on cnbr activated sepharose 4b and used for affinity chromatography purification ...201425141540
anopheles gambiae eicosanoids modulate plasmodium berghei survival from oocyst to salivary gland invasion.eicosanoids affect the immunity of several pathogen/insect models, but their role on the anopheles gambiae response to plasmodium is still unknown. plasmodium berghei-infected mosquitoes were injected with an eicosanoid biosynthesis inhibitor, indomethacin (in), or a substrate, arachidonic acid (aa), at day 7 or day 12 post-infection (p.i.). salivary gland invasion was evaluated by sporozoite counts at day 21 p.i. in promoted infection upon sporozoite release from oocysts, but inhibited infectio ...201425141285
in vitro and in vivo anti-malarial activity of limonoids isolated from the residual seed biomass from carapa guianensis (andiroba) oil production.carapa guianensis is a cultivable tree used by traditional health practitioners in the amazon region to treat several diseases and particularly symptoms related to malaria. abundant residual pressed seed material (rpsm) results as a by-product of carapa or andiroba oil production. the objective of this study was to evaluate the in vitro and in vivo anti-malarial activity and cytotoxicity of limonoids isolated from c. guaianensis rpsm.201425124944
proteomic analysis of the plasmodium male gamete reveals the key role for glycolysis in flagellar motility.gametogenesis and fertilization play crucial roles in malaria transmission. while male gametes are thought to be amongst the simplest eukaryotic cells and are proven targets of transmission blocking immunity, little is known about their molecular organization. for example, the pathway of energy metabolism that power motility, a feature that facilitates gamete encounter and fertilization, is unknown.201425124718
depletion of regulatory t cells augments a vaccine-induced t effector cell response against the liver-stage of malaria but fails to increase memory.regulatory t cells (t(reg)) have been shown to restrict vaccine-induced t cell responses in different experimental models. in these studies cd4(+)cd25(+) t(reg) were depleted using monoclonal antibodies against cd25, which might also interfere with cd25 on non-regulatory t cell populations and would have no effect on foxp3(+)cd25(-) t(reg). to obtain more insights in the specific function of t(reg) during vaccination we used mice that are transgenic for a bacterial artificial chromosome expressi ...201425115805
immunization against a merozoite sheddase promotes multiple invasion of red blood cells and attenuates plasmodium infection in mice.subtilisin-like protease 2 (sub2) is a conserved serine protease utilized by plasmodium parasites as a surface sheddase required for successful merozoite invasion of host red blood cells and has been implicated in ookinete invasion of the mosquito midgut. to determine if sub2 is a suitable vaccine target to interfere with malaria parasite development, the effects of sub2-immunization on the plasmodium life cycle were examined in its vertebrate and invertebrate hosts.201425115675
vectored antibody gene delivery protects against plasmodium falciparum sporozoite challenge in mice.malaria caused by plasmodium falciparum kills nearly one million children each year and imposes crippling economic burdens on families and nations worldwide. no licensed vaccine exists, but infection can be prevented by antibodies against the circumsporozoite protein (csp), the major surface protein of sporozoites, the form of the parasite injected by mosquitoes. we have used vectored immunoprophylaxis (vip), an adeno-associated virus-based technology, to introduce preformed antibody genes encod ...201425114213
antimalarial activity of the myxobacterial macrolide chlorotonil a.myxobacteria are gram-negative soil-dwelling bacteria belonging to the phylum proteobacteria. they are a rich source of promising compounds for clinical application, such as epothilones for cancer therapy and several new antibiotics. in the course of a bioactivity screening program of secondary metabolites produced by sorangium cellulosum strains, the macrolide chlorotonil a was found to exhibit promising antimalarial activity. subsequently, we evaluated chlorotonil a against plasmodium falcipar ...201425114138
2-octadecynoic acid as a dual life stage inhibitor of plasmodium infections and plasmodial fas-ii enzymes.the malaria parasite plasmodium goes through two life stages in the human host, a non-symptomatic liver stage (ls) followed by a blood stage with all clinical manifestation of the disease. in this study, we investigated a series of 2-alkynoic fatty acids (2-afas) with chain lengths between 14 and 18 carbon atoms for dual in vitro activity against both life stages. 2-octadecynoic acid (2-oda) was identified as the best inhibitor of plasmodium berghei parasites with ten times higher potency (ic50= ...201425103602
expression and localization of rhoptry neck protein 5 in merozoites and sporozoites of plasmodium yoelii.host cell invasion by apicomplexan parasites marks a crucial step in disease establishment and pathogenesis. the moving junction (mj) is a conserved and essential feature among parasites of this phylum during host cell invasion, thus proteins that associate at this mj are potential targets of drug and vaccine development. in both toxoplasma gondii and plasmodium falciparum, a micronemal protein, apical membrane antigen 1 (ama1), and rhoptry neck proteins (rons; ron2 and ron4) form an essential c ...201425102354
genetic ablation of plasmodj1, a multi-activity enzyme, attenuates parasite virulence and reduces oocyst production.malaria parasites must respond to stresses and environmental signals to perpetuate efficiently during their multistage development in diverse environments. to gain insights into the parasite's stress response mechanisms, we investigated a conserved plasmodium protein, which we have named plasmodj1 on the basis of the presence of a putative cysteine protease motif of the dj-1/pfpi superfamily, for its activities, potential to respond to stresses and role in parasite development. plasmodj1 is expr ...201425097910
interaction between rifampicin, amodiaquine and artemether in mice infected with chloroquine resistant plasmodium berghei.artemisinin-based combination therapy (act) remains the most effective chemotherapeutic strategy in the management of malaria. however, reports of reduced susceptibility of plasmodium falciparum to the act justify the need for continued search for alternative anti-malarial drugs. the use of antibiotics with anti-malarial properties represents a potentially valuable chemotherapeutic option for the management of drug resistant infections. thus, the intrinsic anti-malarial activity of the combinati ...201425091936
genetic ablation of plasmodj1, a multi-activity enzyme, attenuates parasite virulence and reduces oocyst production.malaria parasites must respond to stresses and environmental signals to perpetuate efficiently during their multistage development in diverse environments. to gain insights into the parasite's stress response mechanisms, we investigated a conserved plasmodium protein, which we have named plasmodj1 on the basis of the presence of a putative cysteine protease motif of the dj-1/pfpi superfamily, for its activities, potential to respond to stresses and role in parasite development. plasmodj1 is expr ...201425091419
potent antimalarial activity of acriflavine in vitro and in vivo.malaria continues to be a major health problem globally. there is an urgent need to find new antimalarials. acriflavine (acf) is known as an antibacterial agent and more recently as an anticancer agent. here, we report that acf inhibits the growth of asexual stages of both chloroquine (cq) sensitive and resistant strains of human malarial parasite, plasmodium falciparum in vitro at nanomolar concentration. acf clears the malaria infection in vivo from the bloodstreams of mice infected with plasm ...201425089658
maladjusted host immune responses induce experimental cerebral malaria-like pathology in a murine borrelia and plasmodium co-infection model.in the plasmodium infected host, a balance between pro- and anti-inflammatory responses is required to clear the parasites without inducing major host pathology. clinical reports suggest that bacterial infection in conjunction with malaria aggravates disease and raises both mortality and morbidity in these patients. in this study, we investigated the immune responses in balb/c mice, co-infected with plasmodium berghei nk65 parasites and the relapsing fever bacterium borrelia duttonii. in contras ...201425075973
in depth annotation of the anopheles gambiae mosquito midgut transcriptome.genome sequencing of anopheles gambiae was completed more than ten years ago and has accelerated research on malaria transmission. however, annotation needs to be refined and verified experimentally, as most predicted transcripts have been identified by comparative analysis with genomes from other species. the mosquito midgut-the first organ to interact with plasmodium parasites-mounts effective antiplasmodial responses that limit parasite survival and disease transmission. high-throughput illum ...201425073905
antigen export during liver infection of the malaria parasite augments protective immunity.protective immunity against preerythrocytic malaria parasite infection is difficult to achieve. intracellular plasmodium parasites likely minimize antigen presentation by surface-expressed major histocompatibility complex class i (mhc-i) molecules on infected cells, yet they actively remodel their host cells by export of parasite factors. whether exported liver-stage proteins constitute better candidates for mhc-i antigen presentation to cd8(+) t lymphocytes remains unknown. here, we systematica ...201425073641
iron overload in plasmodium berghei-infected placenta as a pathogenesis mechanism of fetal death.plasmodium infection during gestation may lead to severe clinical manifestations including abortion, stillbirth, intrauterine growth retardation, and low birth weight. mechanisms underlying such poor pregnancy outcomes are still unclear. in the animal model of severe placental malaria (pm), in utero fetal death frequently occurs and mothers often succumb to infection before or immediately after delivery. plasmodium berghei-infected erythrocytes (ies) continuously accumulate in the placenta, wher ...201425071574
biochemical and antiparasitic properties of inhibitors of the plasmodium falciparum calcium-dependent protein kinase pfcdpk1.pfcdpk1 is a plasmodium falciparum calcium-dependent protein kinase, which has been identified as a potential target for novel antimalarial chemotherapeutics. in order to further investigate the role of pfcdpk1, we established a high-throughput in vitro biochemical assay and used it to screen a library of over 35,000 small molecules. five chemical series of inhibitors were initially identified from the screen, from which series 1 and 2 were selected for chemical optimization. indicative of their ...201425070106
chitinase 3-like 1 is induced by plasmodium falciparum malaria and predicts outcome of cerebral malaria and severe malarial anaemia in a case-control study of african children.severe and fatal malaria are associated with dysregulated host inflammatory responses to infection. chitinase 3-like 1 (chi3l1) is a secreted glycoprotein implicated in regulating immune responses. expression and function of chi3l1 in malaria infection were investigated.201425047113
antiplasmodial potential of homeopathic drugs chelidonium and nosode against plasmodium berghei infection.malaria remains a major global health concern in developing regions of the world. homeopathy, a holistic system of medicine, has a lot to offer in protecting against malaria.201425046315
innexin agap001476 is critical for mediating anti-plasmodium responses in anopheles mosquitoes.the toll and imd pathways are known to be induced upon plasmodium berghei and plasmodium falciparum infection, respectively. it is unclear how plasmodium or other pathogens in the blood meal and their invasion of the midgut epithelium would trigger the innate immune responses in immune cells, in particular hemocytes. gap junctions, which can mediate both cell-to-cell and cell-to-extracellular communication, may participate in this signal transduction. this study examined whether innexins, gap ju ...201425035430
real-time imaging reveals the dynamics of leukocyte behaviour during experimental cerebral malaria pathogenesis.during experimental cerebral malaria (ecm) mice develop a lethal neuropathological syndrome associated with microcirculatory dysfunction and intravascular leukocyte sequestration. the precise spatio-temporal context in which the intravascular immune response unfolds is incompletely understood. we developed a 2-photon intravital microscopy (2p-ivm)-based brain-imaging model to monitor the real-time behaviour of leukocytes directly within the brain vasculature during ecm. ly6c(hi) monocytes, but n ...201425033406
bckdh: the missing link in apicomplexan mitochondrial metabolism is required for full virulence of toxoplasma gondii and plasmodium berghei.while the apicomplexan parasites plasmodium falciparum and toxoplasma gondii are thought to primarily depend on glycolysis for atp synthesis, recent studies have shown that they can fully catabolize glucose in a canonical tca cycle. however, these parasites lack a mitochondrial isoform of pyruvate dehydrogenase and the identity of the enzyme that catalyses the conversion of pyruvate to acetyl-coa remains enigmatic. here we demonstrate that the mitochondrial branched chain ketoacid dehydrogenase ...201425032958
a novel adjuvant, the mixture of alum and naltrexone, augments vaccine-induced immunity against plasmodium berghei.we previously showed that the mixture of naltrexone (nlt), a general opioid antagonist, and alum, acts as an effective adjuvant in enhancing vaccine-induced t helper 1 (th1) humoral immune responses against toxoplasma gondii. here, we tested the efficacy of the mixture of nlt and alum in the induction of immunity in response to blood stages of plasmodium berghei (bspb) as a model vaccine. balb/c mice were divided into five vaccination groups. mice in the experimental groups received the bspb vac ...201425020077
a serine protease homolog negatively regulates tep1 consumption in systemic infections of the malaria vector anopheles gambiae.clip domain serine protease homologs are widely distributed in insect genomes and play important roles in regulating insect immune responses, yet their exact functions remain poorly understood. here, we show that clipa2, a clip domain serine protease homolog of anopheles gambiae, regulates the consumption of the mosquito complement-like protein tep1 during systemic bacterial infections. we provide evidence that clipa2 localizes to microbial surfaces in a tep1-dependent manner whereby it negative ...201425012124
genome-wide functional analysis of plasmodium protein phosphatases reveals key regulators of parasite development and differentiation.reversible protein phosphorylation regulated by kinases and phosphatases controls many cellular processes. although essential functions for the malaria parasite kinome have been reported, the roles of most protein phosphatases (pps) during plasmodium development are unknown. we report a functional analysis of the plasmodium berghei protein phosphatome, which exhibits high conservation with the p. falciparum phosphatome and comprises 30 predicted pps with differential and distinct expression patt ...025011111
deletion of c-reactive protein ameliorates experimental cerebral malaria?c-reactive protein (crp) level correlates with parasitemia and severity of malaria, but whether this reflects causality remains unknown.201425002461
dual-stage triterpenoids from an african medicinal plant targeting the malaria parasite.sixteen triterpenoids (1-16), previously isolated from the aerial parts of the african medicinal plant momordica balsamina or obtained by derivatization, were evaluated for their activity against liver stages of plasmodium berghei, measuring the luminescence intensity in huh-7 cells infected with a firefly luciferase-expressing p. berghei line, pbgfp-luccon. toxicity of compounds (1-16) was assessed on the same cell line through the fluorescence measurement of cell confluency. the highest activi ...201425002232
transcriptome-wide analysis of microrna expression in the malaria mosquito anopheles gambiae.micrornas (mirnas) are a highly abundant class of small noncoding regulatory rnas that post-transcriptionally regulate gene expression in multicellular organisms. mirnas are involved in a wide range of biological and physiological processes, including the regulation of host immune responses to microbial infections. small-scale studies of mirna expression in the malaria mosquito anopheles gambiae have been reported, however no comprehensive analysis of mirnas has been performed so far.201424997592
evaluating experimental cerebral malaria using oxidative stress indicator okd48 mice.cerebral malaria is a fatal complication of malaria. conventional methods for evaluating experimental cerebral malaria have several drawbacks. therefore, we aimed to develop an easy-to-use method for evaluating experimental cerebral malaria using okd48 (keap1-dependent oxidative stress detector, no-48-luciferase) mice to evaluate oxidative stress. okd48 mice infected with plasmodium berghei anka strain (pba) suffered from experimental cerebral malaria and oxidative stress was successfully detect ...201424995619
systemic and cerebral vascular endothelial growth factor levels increase in murine cerebral malaria along with increased calpain and caspase activity and can be reduced by erythropoietin treatment.the pathogenesis of cerebral malaria (cm) includes compromised microvascular perfusion, increased inflammation, cytoadhesion, and endothelial activation. these events cause blood-brain barrier disruption and neuropathology and associations with the vascular endothelial growth factor (vegf) signaling pathway have been shown. we studied this pathway in mice infected with plasmodium berghei anka causing murine cm with or without the use of erythropoietin (epo) as adjunct therapy. elisa and western ...201424995009
implementation of minimally invasive and objective humane endpoints in the study of murine plasmodium infections.summary defining appropriate and objective endpoints for animal research can be difficult. previously we evaluated and implemented a body temperature (bt) of <32 °c as an endpoint for experimental cerebral malaria (ecm) and were interested in a similar endpoint for a model of severe malarial anaemia (sma). furthermore, we investigate the potential of a minimally invasive, non-contact infrared thermometer for repeated bt measurement. ecm was induced with plasmodium berghei anka infection in c57bl ...201424993593
host pi(3,5)p2 activity is required for plasmodium berghei growth during liver stage infection.malaria parasites go through an obligatory liver stage before they infect erythrocytes and cause disease symptoms. in the host hepatocytes, the parasite is enclosed by a parasitophorous vacuole membrane (pvm). here, we dissected the interaction between the plasmodium parasite and the host cell late endocytic pathway and show that parasite growth is dependent on the phosphoinositide 5-kinase (pikfyve) that converts phosphatidylinositol 3-phosphate [pi(3)p] into phosphatidylinositol 3,5-bisphospha ...201424992508
dietary supplementation of chloroquine with nigella sativa seed and oil extracts in the treatment of malaria induced in mice with plasmodium berghei.the aim of the study was to investigate the effects of dietary combination of nigella sativa seed and oil extracts with chloroquine (cq), and how these combinations enhance cq efficacy in mice infected with plasmodium berghei and their survival rates.201424991115
enhanced antimalarial activity by a novel artemether-lumefantrine lipid emulsion for parenteral administration.artemether and lumefantrine (also known as benflumetol) are difficult to formulate for parenteral administration because of their low aqueous solubility. cremophor el as an emulsion excipient has been shown to cause serious side effects. this study reports a method of preparation and the therapeutic efficacies of novel lipid emulsion (le) delivery systems with artemether, lumefantrine, or artemether in combination with lumefantrine, for parenteral administration. their physical and chemical stab ...201424982079
local immune response to injection of plasmodium sporozoites into the skin.malarial infection is initiated when the sporozoite form of the plasmodium parasite is inoculated into the skin by a mosquito. sporozoites invade hepatocytes in the liver and develop into the erythrocyte-infecting form of the parasite, the cause of clinical blood infection. protection against parasite development in the liver can be induced by injection of live attenuated parasites that do not develop in the liver and thus do not cause blood infection. radiation-attenuated sporozoites (ras) and ...201424981449
plasmodium berghei infection ameliorates atopic dermatitis-like skin lesions in nc/nga mice.atopic diseases are more prevalent in industrialized countries than in developing countries. in addition, significant differences in the prevalence of allergic diseases are observed between rural and urban areas within the same country. this difference in prevalence has been attributed to what is called the 'hygiene hypothesis'. although parasitic infections are known to protect against allergic reactions, the mechanism is still unknown. the aim of this study was to investigate whether or not ma ...201424976451
electron microscopic features of brain edema in rodent cerebral malaria in relation to glial fibrillary acidic protein expression.the mechanisms leading to cerebral malaria (cm) are not completely understood. brain edema has been suggested as having an important role in experimental cm. in this study, cba/cah mice were infected with plasmodium berghei anka blood-stage and when typical symptoms of cm developed on day 7, brain tissues were processed for electron-microscopic and immunohistochemical studies. the study demonstrated ultrastructural hallmarks of cerebral edema by perivascular edema and astroglial dilatation confi ...201424966914
vitamin d inhibits the occurrence of experimental cerebral malaria in mice by suppressing the host inflammatory response.in animal models of experimental cerebral malaria (ecm), neuropathology is associated with an overwhelming inflammatory response and sequestration of leukocytes and parasite-infected rbcs in the brain. in this study, we explored the effect of vitamin d (vd; cholecalciferol) treatment on host immunity and outcome of ecm in c57bl/6 mice during plasmodium berghei anka (pba) infection. we observed that oral administration of vd both before and after pba infection completely protected mice from ecm. ...201424965778
comparing systemic metabolic responses in mice to single or dual infection with plasmodium berghei and heligmosomoides bakeri.concomitant infections with plasmodium and gastrointestinal nematodes are frequently observed in humans. at the metabolic level, the cross-talk between the host and multiple coexisting pathogens is poorly characterized. the purpose of this study was to give a comprehensive insight into the systemic metabolic phenotype of mice with a single or dual infection with plasmodium berghei and heligmosomoides bakeri. four groups of eight nmri female mice were infected with p. berghei or h. bakeri, or wit ...201424960299
engineered single nucleotide polymorphisms in the mosquito mek docking site alter plasmodium berghei development in anopheles gambiae.susceptibility to plasmodium infection in anopheles gambiae has been proposed to result from naturally occurring polymorphisms that alter the strength of endogenous innate defenses. despite the fact that some of these mutations are known to introduce non-synonymous substitutions in coding sequences, these mutations have largely been used to rationalize knockdown of associated target proteins to query the effects on parasite development in the mosquito host. here, we assay the effects of engineer ...201424957684
synergistic effect of aqueous extract of telfaria occidentalis on the biological activities of artesunate in plasmodium berghei infected mice.resistance to most antimalarial drugs has encouraged the use of herbal preparations along with prescribed orthodox drugs.201324940320
ultrastructure of the lung in a murine model of malaria-associated acute lung injury/acute respiratory distress syndrome.the mechanisms through which infection with plasmodium spp. result in lung disease are largely unknown. recently a number of mouse models have been developed to research malaria-associated lung injury but no detailed ultrastructure studies of the disease in its terminal stages in a murine model have yet been published. the goal was to perform an ultrastructural analysis of the lungs of mice that died with malaria-associated acute lung injury/acute respiratory distress syndrome to better determin ...201424927627
scalable preparation and differential pharmacologic and toxicologic profiles of primaquine enantiomers.hematotoxicity in individuals genetically deficient in glucose-6-phosphate dehydrogenase (g6pd) activity is the major limitation of primaquine (pq), the only antimalarial drug in clinical use for treatment of relapsing plasmodium vivax malaria. pq is currently clinically used in its racemic form. a scalable procedure was developed to resolve racemic pq, thus providing pure enantiomers for the first time for detailed preclinical evaluation and potentially for clinical use. these enantiomers were ...201424913163
treatment of murine cerebral malaria by artemisone in combination with conventional antimalarial drugs: antiplasmodial effects and immune responses.the decreasing effectiveness of antimalarial therapy due to drug resistance necessitates constant efforts to develop new drugs. artemisinin derivatives are the most recent drugs that have been introduced and are considered the first line of treatment, but there are already indications of plasmodium falciparum resistance to artemisinins. consequently, drug combinations are recommended for prevention of the induction of resistance. the research here demonstrates the effects of novel combinations o ...201424913162
discovery of hdac inhibitors with potent activity against multiple malaria parasite life cycle stages.in this work we investigated the antiplasmodial activity of a series of hdac inhibitors containing an alkoxyamide connecting-unit linker region. hdac inhibitor 1a (lmk235), previously shown to be a novel and specific inhibitor of human hdac4 and 5, was used as a starting point to rapidly construct a mini-library of hdac inhibitors using a straightforward solid-phase supported synthesis. several of these novel hdac inhibitors were found to have potent in vitro activity against asexual stage plasm ...201424904967
antiplasmodial effect of anthocleista vogelii on albino mice experimentally infected with plasmodium berghei berghei (nk 65).the objective of the present study was to investigate the antiplasmodial effect of the ethanolic stem bark extract of anthocleista vogelii at different doses in albino mice infected with plasmodium berghei berghei (nk 65). thirty-six mice were divided into six groups of six mice each. five groups (b1-b3, d, and g) were infected with plasmodium berghei berghei parasitized red blood cells. groups d, h, and g served as the controls. six days after infection, mice in groups b1, b2, and b3 were treat ...201424900913
identification and optimization of an aminoalcohol-carbazole series with antimalarial properties.recent observations on the emergence of artemisinin resistant parasites have highlighted the need for new antimalarial treatments. an hts campaign led to the identification of the 1-(1-aminopropan-2-ol)carbazole analogues as potent hits against plasmodium falciparum k1 strain. the sar study and optimization of early adme and physicochemical properties direct us to the selection of a late lead compound that shows good efficacy when orally administrated in the in vivo p. berghei mouse model.201324900603
identification and in-vitro adme assessment of a series of novel anti-malarial agents suitable for hit-to-lead chemistry.triage of a set of antimalaria hit compounds, identified through high throughput screening against the chloroquine sensitive (3d7) and resistant (dd2) parasite plasmodium falciparum strains identified several novel chemotypes suitable for hit-to-lead chemistry investigation. the set was further refined through investigation of their in vitro adme properties, which identified templates with good potential to be developed further as antimalarial agents. one example was profiled in an in vivo murin ...201224900512
novel 4-aminoquinoline-pyrimidine based hybrids with improved in vitro and in vivo antimalarial activity.a class of hybrid molecules consisting of 4-aminoquinoline and pyrimidine were synthesized and tested for antimalarial activity against both chloroquine (cq)-sensitive (d6) and chloroquine (cq)-resistant (w2) strains of plasmodium falciparum through an in vitro assay. eleven hybrids showed better antimalarial activity against both cq-sensitive and cq-resistant strains of p. falciparum in comparison to standard drug cq. four molecules were more potent (7-8-fold) than cq in d6 strain, and eight mo ...201224900509
discovery of novel benzo[a]phenoxazine ssj-183 as a drug candidate for malaria.malaria is a serious infectious disease caused by protozoan parasites in tropical and subtropical regions. even inhabitants of temperate zones are exposed to the danger of malaria infection because of travel and global warming. novel, effective, safe, and inexpensive drugs are required to treat malaria and contribute to the global goal of eradication. a search for new antimalarial agents has been performed by the synthesis of new benzo[a]phenoxazines, followed by biological evaluations. the deri ...201024900219
deorphaning pyrrolopyrazines as potent multi-target antimalarial agents.the discovery of pyrrolopyrazines as potent antimalarial agents is presented, with the most effective compounds exhibiting ec50 values in the low nanomolar range against asexual blood stages of plasmodium falciparum in human red blood cells, and plasmodium berghei liver schizonts, with negligible hepg2 cytotoxicity. their potential mode of action is uncovered by predicting macromolecular targets through avant-garde computer modeling. the consensus prediction method suggested a functional resembl ...201424895172
gene disruption reveals a dispensable role for plasmepsin vii in the plasmodium berghei life cycle.plasmepsins (pm), aspartic proteases of plasmodium, comprises a family of ten proteins that perform critical functions in plasmodium life cycle. except vii and viii, functions of the remaining plasmepsin members have been well characterized. here, we have generated a mutant parasite lacking pm vii in plasmodium berghei using reverse genetics approach. systematic comparison of growth kinetics and infection in both mosquito and vertebrate host revealed that pm vii depleted mutants exhibited no def ...201424893340
hplc-based activity profiling for antiplasmodial compounds in the traditional indonesian medicinal plant carica papaya l.leaf decoctions of carica papaya have been traditionally used in some parts of indonesia to treat and prevent malaria. leaf extracts and fraction have been previously shown to possess antiplasmodial activity in vitro and in vivo.201424892830
effects of the vascular endothelial growth factor receptor-2 (vegfr-2) inhibitor su5416 on in vitro cultures of plasmodium falciparum.vascular endothelial growth factor (vegf) is taken up by parasitized red blood cells during malaria and stimulates intra-erythrocytic growth of plasmodium falciparum in vitro. the cause and consequence of this uptake is not understood.201424885283
investigation of indolglyoxamide and indolacetamide analogues of polyamines as antimalarial and antitrypanosomal agents.pure compound screening has previously identified the indolglyoxy lamidospermidine ascidian metabolites didemnidine a and b (2 and 3) to be weak growth inhibitors of trypanosoma brucei rhodesiense (ic50 59 and 44 μm, respectively) and plasmodium falciparum (k1 dual drug resistant strain) (ic50 41 and 15 μm, respectively), but lacking in selectivity (l6 rat myoblast, ic50 24 μm and 25 μm, respectively). to expand the structure-activity relationship of this compound class towards both parasites, w ...201424879541
vascular dysfunction as a target for adjuvant therapy in cerebral malaria.cerebral malaria (cm) is a life-threatening complication of plasmodium falciparum malaria that continues to be a major global health problem. brain vascular dysfunction is a main factor underlying the pathogenesis of cm and can be a target for the development of adjuvant therapies for the disease. vascular occlusion by parasitised red blood cells and vasoconstriction/vascular dysfunction results in impaired cerebral blood flow, ischaemia, hypoxia, acidosis and death. in this review, we discuss t ...201424863978
antibodies to pfsea-1 block parasite egress from rbcs and protect against malaria infection.novel vaccines are urgently needed to reduce the burden of severe malaria. using a differential whole-proteome screening method, we identified plasmodium falciparum schizont egress antigen-1 (pfsea-1), a 244-kilodalton parasite antigen expressed in schizont-infected red blood cells (rbcs). antibodies to pfsea-1 decreased parasite replication by arresting schizont rupture, and conditional disruption of pfsea-1 resulted in a profound parasite replication defect. vaccination of mice with recombinan ...201424855263
cd8+ t cells from a novel t cell receptor transgenic mouse induce liver-stage immunity that can be boosted by blood-stage infection in rodent malaria.to follow the fate of cd8+ t cells responsive to plasmodium berghei anka (pba) infection, we generated an mhc i-restricted tcr transgenic mouse line against this pathogen. t cells from this line, termed pbt-i t cells, were able to respond to blood-stage infection by pba and two other rodent malaria species, p. yoelii xnl and p. chabaudi as. these pbt-i t cells were also able to respond to sporozoites and to protect mice from liver-stage infection. examination of the requirements for priming afte ...201424854165
a prospective strategy to restore the tissue damage in malaria infection: approach with chitosan-trypolyphosphate conjugated nanochloroquine in swiss mice.accumulating evidence indicates that wide range of polymer based nanoconjugated drug have the ability to overcome the microbial infection. the present study was to evaluate the effects of nanoconjugated chloroquine (nch) against plasmodium berghei nk65 (p. berghei) infection on selective makers of oxidative damage, antioxidant status, pro-inflammatory and anti-inflammatory cytokines in liver and spleen. p. berghei infected swiss mice were treated with nch (250mg/kg bw for 15 days) compared with ...201424836985
tetraoxane-pyrimidine nitrile hybrids as dual stage antimalarials.the use of artemisinin or other endoperoxides in combination with other drugs is a strategy to prevent development of resistant strains of plasmodium parasites. our previous work demonstrated that hybrid compounds, comprising endoperoxides and vinyl sulfones, were capable of high activity profiles comparable to artemisinin and chloroquine while acting through two distinct mechanisms of action: oxidative stress and falcipain inhibition. in this study, we adapted this approach to a novel class of ...201424824551
[study on ficolin-a against infection of plasmodium berghei in mouse model].to evaluate the effect of ficolin-a, a lectin complement against plasmodium berghei in mice model.201424822364
role of the aryl hydrocarbon receptor in the immune response profile and development of pathology during plasmodium berghei anka infection.infection with plasmodium falciparum may result in severe disease affecting various organs, including liver, spleen, and brain, resulting in high morbidity and mortality. plasmodium berghei anka infection of mice recapitulates many features of severe human malaria. the aryl hydrocarbon receptor (ahr) is an intracellular receptor activated by ligands important in the modulation of the inflammatory response. we found that ahr-knockout (ko) mice infected with p. berghei anka displayed increased par ...201424818665
the protective effect of cd40 ligand-cd40 signalling is limited during the early phase of plasmodium infection.γδ t cells are essential for eliminating plasmodium berghei xat. because administration of the agonistic anti-cd40 antibody can induce elimination of p. berghei xat parasites in γδ t cell-deficient mice, we considered that γδ t cells might activate dendritic cells via cd40 signalling during infection. here we report that administration of the anti-cd40 antibody to γδ t cell-deficient mice 3-10 days post-p. berghei xat infection could eliminate the parasites. our data suggest that dendritic cell ...201424815981
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