| assessment of the prophylactic activity and pharmacokinetic profile of oral tafenoquine compared to primaquine for inhibition of liver stage malaria infections. | as anti-malarial drug resistance escalates, new safe and effective medications are necessary to prevent and treat malaria infections. the us army is developing tafenoquine (tq), an analogue of primaquine (pq), which is expected to be more effective in preventing malaria in deployed military personnel. | 2014 | 24731238 |
| cd8+ t cells eliminate liver-stage plasmodium berghei parasites without detectable bystander effect. | immunization with attenuated plasmodium sporozoites or viral vectored vaccines can induce protective cd8(+) t cells that can find and eliminate liver-stage malaria parasites. a key question is whether cd8(+) t cells must recognize and eliminate each parasite in the liver or whether bystander killing can occur. to test this, we transferred antigen-specific effector cd8(+) t cells to mice that were then coinfected with two plasmodium berghei strains, only one of which could be recognized directly ... | 2014 | 24421043 |
| phenotypic characterization of plasmodium berghei responsive cd8+ t cells after immunization with live sporozoites under chloroquine cover. | an effective malaria vaccine remains elusive. the most effective experimental vaccines confer only limited and short-lived protection despite production of protective antibodies. however, immunization with irradiated sporozoites, or with live sporozoites under chloroquine cover, has resulted in long-term protection apparently due to the generation of protective cd8+ t cells. the nature and function of these protective cd8+ t cells has not been elucidated. in the current study, the phenotype of c ... | 2014 | 24620841 |
| phosphoinositide metabolism links cgmp-dependent protein kinase g to essential ca²⁺ signals at key decision points in the life cycle of malaria parasites. | many critical events in the plasmodium life cycle rely on the controlled release of ca²⁺ from intracellular stores to activate stage-specific ca²⁺-dependent protein kinases. using the motility of plasmodium berghei ookinetes as a signalling paradigm, we show that the cyclic guanosine monophosphate (cgmp)-dependent protein kinase, pkg, maintains the elevated level of cytosolic ca²⁺ required for gliding motility. we find that the same pkg-dependent pathway operates upstream of the ca²⁺ signals tha ... | 2014 | 24594931 |
| efficacy of a plasmodium vivax malaria vaccine using chad63 and modified vaccinia ankara expressing thrombospondin-related anonymous protein as assessed with transgenic plasmodium berghei parasites. | plasmodium vivax is the world's most widely distributed malaria parasite and a potential cause of morbidity and mortality for approximately 2.85 billion people living mainly in southeast asia and latin america. despite this dramatic burden, very few vaccines have been assessed in humans. the clinically relevant vectors modified vaccinia virus ankara (mva) and the chimpanzee adenovirus chad63 are promising delivery systems for malaria vaccines due to their safety profiles and proven ability to in ... | 2013 | 24379295 |
| dihydroquinazolinone inhibitors of proliferation of blood and liver stage malaria parasites. | drugs that target both the liver and blood stages of malaria will be needed to reduce the disease's substantial worldwide morbidity and mortality. evaluation of a 259-member library of compounds that block proliferation of the blood stage of malaria revealed several scaffolds--dihydroquinazolinones, phenyldiazenylpyridines, piperazinyl methyl quinolones, and bis-benzimidazoles--with promising activity against the liver stage. focused structure-activity studies on the dihydroquinazolinone scaffol ... | 2013 | 24366746 |
| a cascade of dna-binding proteins for sexual commitment and development in plasmodium. | commitment to and completion of sexual development are essential for malaria parasites (protists of the genus plasmodium) to be transmitted through mosquitoes. the molecular mechanism(s) responsible for commitment have been hitherto unknown. here we show that pbap2-g, a conserved member of the apicomplexan ap2 (apiap2) family of dna-binding proteins, is essential for the commitment of asexually replicating forms to sexual development in plasmodium berghei, a malaria parasite of rodents. pbap2-g ... | 2014 | 24572359 |
| whole pichia pastoris yeast expressing measles virus nucleoprotein as a production and delivery system to multimerize plasmodium antigens. | yeasts are largely used as bioreactors for vaccine production. usually, antigens are produced in yeast then purified and mixed with adjuvants before immunization. however, the purification costs and the safety concerns recently raised by the use of new adjuvants argue for alternative strategies. to this end, the use of whole yeast as both production and delivery system appears attractive. here, we evaluated pichia pastoris yeast as an alternative vaccine production and delivery system for the ci ... | 2014 | 24475165 |
| simple, sensitive and quantitative bioluminescence assay for determination of malaria pre-patent period. | the first phase of malaria infection occurs in the liver and is clinically silent. inside hepatocytes each plasmodium sporozoite replicate into thousands of erythrocyte-infectious merozoites that when released into the blood stream result in clinical symptoms of the disease. the time between sporozoite inoculation and the appearance of parasites in the blood is defined as the pre-patent period, which is classically analysed by time-consuming and labor-intensive techniques, such as microscopy and ... | 2014 | 24400642 |
| tafenoquine and npc-1161b require cyp 2d metabolism for anti-malarial activity: implications for the 8-aminoquinoline class of anti-malarial compounds. | tafenoquine (tq) is an 8-aminoquinoline (8aq) that has been tested in several phase ii and phase iii clinical studies and is currently in late stage development as an anti-malarial prophylactic agent. npc-1161b is a promising 8aq in late preclinical development. it has recently been reported that the 8aq drug primaquine requires metabolic activation by cyp 2d6 for efficacy in humans and in mice, highlighting the importance of pharmacogenomics in the target population when administering primaquin ... | 2014 | 24386891 |
| stress granules and plasmodium liver stage infection. | organisms have evolved numerous strategies to control infection by an array of intracellular pathogens. one cell autonomous pathogen control strategy is global inhibition of protein synthesis via stress granule (sg) formation. sgs are induced by stressful stimuli such as oxidative stress and nutrient deprivation, and are known to counteract both viral and bacterial infections. pathogens, in turn, may actively block an infected cell's ability to form sgs. in vitro and in vivo, many liver stage ma ... | 2014 | 24357231 |
| copper-transporting atpase is important for malaria parasite fertility. | homeostasis of the trace element copper is essential to all eukaryotic life. copper serves as a cofactor in metalloenzymes and catalyses electron transfer reactions as well as the generation of potentially toxic reactive oxygen species. here, we describe the functional characterization of an evolutionarily highly conserved, predicted copper-transporting p-type atpase (cutp) in the murine malaria model parasite plasmodium berghei. live imaging of a parasite line expressing a fluorescently tagged ... | 2013 | 24237419 |
| the malarial serine protease sub1 plays an essential role in parasite liver stage development. | transmission of the malaria parasite to its vertebrate host involves an obligatory exoerythrocytic stage in which extensive asexual replication of the parasite takes place in infected hepatocytes. the resulting liver schizont undergoes segmentation to produce thousands of daughter merozoites. these are released to initiate the blood stage life cycle, which causes all the pathology associated with the disease. whilst elements of liver stage merozoite biology are similar to those in the much bette ... | 2013 | 24348254 |
| hypoxia promotes liver-stage malaria infection in primary human hepatocytes in vitro. | homeostasis of mammalian cell function strictly depends on balancing oxygen exposure to maintain energy metabolism without producing excessive reactive oxygen species. in vivo, cells in different tissues are exposed to a wide range of oxygen concentrations, and yet in vitro models almost exclusively expose cultured cells to higher, atmospheric oxygen levels. existing models of liver-stage malaria that utilize primary human hepatocytes typically exhibit low in vitro infection efficiencies, possib ... | 2013 | 24291761 |
| inhibitor of cysteine proteases is critical for motility and infectivity of plasmodium sporozoites. | malaria is transmitted when motile sporozoites are injected into the dermis by an infected female anopheles mosquito. inside the mosquito vector, sporozoites egress from midgut-associated oocysts and eventually penetrate the acinar cells of salivary glands. parasite-encoded factors with exclusive vital roles in the insect vector can be studied by classical reverse genetics. here, we characterized the in vivo roles of plasmodium berghei falstatin/icp (inhibitor of cysteine proteases). this protei ... | 2013 | 24281719 |
| a small molecule glycosaminoglycan mimetic blocks plasmodium invasion of the mosquito midgut. | malaria transmission-blocking (t-b) interventions are essential for malaria elimination. small molecules that inhibit the plasmodium ookinete-to-oocyst transition in the midgut of anopheles mosquitoes, thereby blocking sporogony, represent one approach to achieving this goal. chondroitin sulfate glycosaminoglycans (cs-gags) on the anopheles gambiae midgut surface are putative ligands for plasmodium falciparum ookinetes. we hypothesized that our synthetic polysulfonated polymer, vs1, acting as a ... | 2013 | 24278017 |
| plasmodium berghei calcium dependent protein kinase 1 is not required for host cell invasion. | plasmodium calcium dependent protein kinase (cdpk1) is required for the development of sexual stages in the mosquito. in addition, it is proposed to play an essential role in the parasite's invasive stages possibly through the regulation of the actinomyosin motor and micronemal secretion. we demonstrate that plasmodium berghei cdpk1 is dispensable in the parasite's erythrocytic and pre-erythrocytic stages. we successfully disrupted p. berghei cdpk1 (pbcdpk1) by homologous recombination. the reco ... | 2013 | 24265753 |
| trem2 governs kupffer cell activation and explains belr1 genetic resistance to malaria liver stage infection. | plasmodium liver stage infection is a target of interest for the treatment of and vaccination against malaria. here we used forward genetics to search for mechanisms underlying natural host resistance to infection and identified triggering receptor expressed on myeloid cells 2 (trem2) and mhc class ii molecules as determinants of plasmodium berghei liver stage infection in mice. locus belr1 confers resistance to malaria liver stage infection. the use of newly derived subcongenic mouse lines allo ... | 2013 | 24218563 |
| cd8+ t cells specific for a malaria cytoplasmic antigen form clusters around infected hepatocytes and are protective at the liver stage of infection. | following anopheles mosquito-mediated introduction into a human host, plasmodium parasites infect hepatocytes and undergo intensive replication. accumulating evidence indicates that cd8(+) t cells induced by immunization with attenuated plasmodium sporozoites can confer sterile immunity at the liver stage of infection; however, the mechanisms underlying this protection are not clearly understood. to address this, we generated recombinant plasmodium berghei anka expressing a fusion protein of an ... | 2013 | 23897612 |
| comparative susceptibility of different biological forms of anopheles stephensi to plasmodium berghei anka strain. | there are varying degrees of compatibility between malaria parasite-mosquito species, and understanding this compatibility may be crucial for developing effective transmission-blocking vaccines. this study investigates the compatibility of different biological forms of a malaria vector, anopheles stephensi, to plasmodium berghei anka strain. | 2013 | 24086525 |
| expression profiling of plasmodium berghei hsp70 genes for generation of bright red fluorescent parasites. | live cell imaging of recombinant malarial parasites encoding fluorescent probes provides critical insights into parasite-host interactions and life cycle progression. in this study, we generated a red fluorescent line of the murine malarial parasite plasmodium berghei. to allow constitutive and abundant expression of the mcherry protein we profiled expression of all members of the p. berghei heat shock protein 70 (hsp70) family. we identified pbhsp70/1, an invariant ortholog of plasmodium falcip ... | 2013 | 24013507 |
| development of a chimeric plasmodium berghei strain expressing the repeat region of the p. vivax circumsporozoite protein for in vivo evaluation of vaccine efficacy. | the development of vaccine candidates against plasmodium vivax-the most geographically widespread human malaria species-is challenged by technical difficulties, such as the lack of in vitro culture systems and availability of animal models. chimeric rodent plasmodium parasites are safe and useful tools for the preclinical evaluation of new vaccine formulations. we report the successful development and characterization of chimeric plasmodium berghei parasites bearing the type i repeat region of p ... | 2013 | 23716612 |
| immunisation against a serine protease inhibitor reduces intensity of plasmodium berghei infection in mosquitoes. | the mosquito innate immune response is able to clear the majority of plasmodium parasites. this immune clearance is controlled by a number of regulatory molecules including serine protease inhibitors (serpins). to determine whether such molecules could represent a novel target for a malaria transmission-blocking vaccine, we vaccinated mice with anopheles gambiae serpin-2. antibodies against anopheles gambiae serpin-2 significantly reduced the infection of a heterologous anopheles species (anophe ... | 2013 | 23872520 |
| morphogenesis of plasmodium zoites is uncoupled from tensile strength. | a shared feature of the motile stages (zoites) of malaria parasites is a cortical cytoskeletal structure termed subpellicular network (spn), thought to define and maintain cell shape. plasmodium alveolins comprise structural components of the spn, and alveolin gene knockout causes morphological abnormalities that coincide with markedly reduced tensile strength of the affected zoites, indicating the alveolins are prime cell shape determinants. here, we characterize a novel spn protein of plasmodi ... | 2013 | 23773015 |
| the etramp family member sep2 is expressed throughout plasmodium berghei life cycle and is released during sporozoite gliding motility. | the early transcribed membrane proteins etramps belong to a family of small, transmembrane molecules unique to plasmodium parasite, which share a signal peptide followed by a short lysine-rich stretch, a transmembrane domain and a variable, highly charged c-terminal region. etramps are usually expressed in a stage-specific manner. in the blood stages they localize to the parasitophorous vacuole membrane and, in described cases, to vesicle-like structures exported to the host erythrocyte cytosol. ... | 2013 | 23840634 |
| the metabolism of primaquine to its active metabolite is dependent on cyp 2d6. | the efficacy of the 8-aminoquinoline (8aq) drug primaquine (pq) has been historically linked to cyp-mediated metabolism. although to date no clear evidence exists in the literature that unambiguously assigns the metabolic pathway or specific metabolites necessary for activity, recent literature suggests a role for cyp 2d6 in the generation of redox active metabolites. | 2013 | 23782898 |
| transgenic parasites stably expressing full-length plasmodium falciparum circumsporozoite protein as a model for vaccine down-selection in mice using sterile protection as an endpoint. | circumsporozoite protein (csp) of plasmodium falciparum is a protective human malaria vaccine candidate. there is an urgent need for models that can rapidly down-select novel csp-based vaccine candidates. in the present study, the mouse-mosquito transmission cycle of a transgenic plasmodium berghei malaria parasite stably expressing a functional full-length p. falciparum csp was optimized to consistently produce infective sporozoites for protection studies. a minimal sporozoite challenge dose wa ... | 2013 | 23536694 |
| identification of targets of cd8⁺ t cell responses to malaria liver stages by genome-wide epitope profiling. | cd8⁺ t cells mediate immunity against plasmodium liver stages. however, the paucity of parasite-specific epitopes of cd8⁺ t cells has limited our current understanding of the mechanisms influencing the generation, maintenance and efficiency of these responses. to identify antigenic epitopes in a stringent murine malaria immunisation model, we performed a systematic profiling of h(2b)-restricted peptides predicted from genome-wide analysis. we describe the identification of plasmodium berghei (pb ... | 2013 | 23675294 |
| transmission-blocking interventions eliminate malaria from laboratory populations. | transmission-blocking interventions aim to reduce the prevalence of infection in endemic communities by targeting plasmodium within the insect host. although many studies have reported the successful reduction of infection in the mosquito vector, direct evidence that there is an onward reduction in infection in the vertebrate host is lacking. here we report the first experiments using a population, transmission-based study of plasmodium berghei in anopheles stephensi to assess the impact of a tr ... | 0 | 23652000 |
| translational repression controls temporal expression of the plasmodium berghei lccl protein complex. | plasmodium lccl proteins comprise a family of six proteins that function as a protein complex and have essential roles in sporozoite transmission. in plasmodium berghei, family members pblap1, pblap2 and pblap3 have been shown to be expressed in gametocytes and, following gametogenesis and fertilization, to be targeted to distinctive multivesicular organelles termed crystalloids that form in the ookinete. here, we show by gfp-tagging that pblap4, pblap5 and pblap6, like their family members, are ... | 2013 | 23684590 |
| mechanisms of protective immune responses induced by the plasmodium falciparum circumsporozoite protein-based, self-assembling protein nanoparticle vaccine. | a lack of defined correlates of immunity for malaria, combined with the inability to induce long-lived sterile immune responses in a human host, demonstrate a need for improved understanding of potentially protective immune mechanisms for enhanced vaccine efficacy. protective sterile immunity (>90%) against the plasmodium falciparum circumsporozoite protein (csp) has been achieved using a transgenically modified plasmodium berghei sporozoite (tg-pb/pfcsp) and a self-assembling protein nanopartic ... | 2013 | 23607541 |
| the survival of memory cd8 t cells that is mediated by il-15 correlates with sustained protection against malaria. | ag-specific memory t cell responses elicited by infections or vaccinations are inextricably linked to long-lasting protective immunity. studies of protective immunity among residents of malaria endemic areas indicate that memory responses to plasmodium ags are not adequately developed or maintained, as people who survive episodes of childhood malaria are still vulnerable to either persistent or intermittent malaria infections. in contrast, multiple exposures to radiation-attenuated plasmodium be ... | 2013 | 23589611 |
| quantitative bioluminescent imaging of pre-erythrocytic malaria parasite infection using luciferase-expressing plasmodium yoelii. | the liver stages of plasmodium parasites are important targets for the development of anti-malarial vaccine candidates and chemoprophylaxis approaches that aim to prevent clinical infection. analyzing the impact of interventions on liver stages in the murine malaria model system plasmodium yoelii has been cumbersome and requires terminal procedures. in vivo imaging of bioluminescent parasites has previously been shown to be an effective and non-invasive alternative to monitoring liver stage burd ... | 2013 | 23593316 |
| a key role for lipoic acid synthesis during plasmodium liver stage development. | the successful navigation of malaria parasites through their life cycle, which alternates between vertebrate hosts and mosquito vectors, requires a complex interplay of metabolite synthesis and salvage pathways. using the rodent parasite plasmodium berghei, we have explored the synthesis and scavenging pathways for lipoic acid, a short-chain fatty acid derivative that regulates the activity of α-ketoacid dehydrogenases including pyruvate dehydrogenase. in plasmodium, lipoic acid is either synthe ... | 2013 | 23490300 |
| functional characterization of plasmodium berghei psop25 during ookinete development and as a malaria transmission-blocking vaccine candidate. | plasmodium ookinete surface proteins as post-fertilization target antigens are potential malaria transmission-blocking vaccine (tbv) candidates. putative secreted ookinete protein 25 (psop25) is a highly conserved ookinete surface protein, and has been shown to be a promising novel tbv target. here, we further investigated the tbv activities of the full-length recombinant psop25 (rpsop25) protein in plasmodium berghei, and characterized the potential functions of psop25 during the p. berghei lif ... | 2017 | 28057055 |
| the plasmodium alveolin imc1a is stabilised by its terminal cysteine motifs and facilitates sporozoite morphogenesis and infectivity in a dose-dependent manner. | apicomplexan parasites possess a unique cortical cytoskeleton structure composed of intermediate filaments. its building blocks are provided by a conserved family of proteins named alveolins. the core alveolin structure is made up of tandem repeat sequences, thought to be responsible for the filamentous properties of these proteins. a subset of alveolins also possess conserved motifs composed of three closely spaced cysteine residues situated near the ends of the polypeptides. the roles of these ... | 2016 | 27693349 |
| cytochrome p450 2d-mediated metabolism is not necessary for tafenoquine and primaquine to eradicate the erythrocytic stages of plasmodium berghei. | due to the ability of the 8-aminoquinolines (8aqs) to kill different stages of the malaria parasite, primaquine (pq) and tafenoquine (tq) are vital for causal prophylaxis and the eradication of erythrocytic plasmodium sp. parasites. recognizing the potential role of cytochrome (cyp) 450 2d6 in the metabolism and subsequent hepatic efficacy of 8-aminoquinolines, studies were designed to explore whether cyp2d-mediated metabolism was related to the ability of single-dose pq and tq to eliminate the ... | 2016 | 27923405 |
| plasmodium yoelii nigeriensis (n67) is a robust animal model to study malaria transmission by south american anopheline mosquitoes. | malaria is endemic in the american continent and the amazonian rainforest is the region with the highest risk of transmission. however, the lack of suitable experimental models to infect malaria vectors from the americas has limited the progress to understand the biology of transmission in this region. anopheles aquasalis, a major vector in coastal areas of south america, was found to be highly refractory to infection with two strains of plasmodium falciparum (nf54 and 7g8) and with plasmodium b ... | 2016 | 27911924 |
| angiotensin ii type-1 receptor (at1r) regulates expansion, differentiation, and functional capacity of antigen-specific cd8(+) t cells. | angiotensin ii (ang ii) and its receptor at1 (at1r), an important effector axis of renin-angiotensin system (ras), have been demonstrated to regulate t-cell responses. however, these studies characterized ang ii and at1r effects using pharmacological tools, which do not target only ang ii/at1r axis. the specific role of at1r expressed by antigen-specific cd8(+) t cells is unknown. then we immunized transgenic mice expressing a t-cell receptor specific for siinfekl epitope (ot-i mice) with sporoz ... | 2016 | 27782175 |
| characterization of novel antimalarial compound act-451840: preclinical assessment of activity and dose-efficacy modeling. | artemisinin resistance observed in southeast asia threatens the continued use of artemisinin-based combination therapy in endemic countries. additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. herein, the preclinical characterization of one of these com ... | 2016 | 27701420 |
| human cd8+ t cells mediate protective immunity induced by a human malaria vaccine in human immune system mice. | a number of studies have shown that cd8+ t cells mediate protective anti-malaria immunity in a mouse model. however, whether human cd8+ t cells play a role in protection against malaria remains unknown. we recently established human immune system (his) mice harboring functional human cd8+ t cells (his-cd8 mice) by transduction with hla-a∗0201 and certain human cytokines using recombinant adeno-associated virus-based gene transfer technologies. these his-cd8 mice mount a potent, antigen-specific ... | 2016 | 27502569 |
| characterization of the plasmodium falciparum and p. berghei glycerol 3-phosphate acyltransferase involved in fasii fatty acid utilization in the malaria parasite apicoplast. | malaria parasites can synthesize fatty acids via a type ii fatty acid synthesis (fasii) pathway located in their apicoplast. the fasii pathway has been pursued as an anti-malarial drug target, but surprisingly little is known about its role in lipid metabolism. here we characterize the apicoplast glycerol 3-phosphate acyltransferase that acts immediately downstream of fasii in human (plasmodium falciparum) and rodent (plasmodium berghei) malaria parasites and investigate how this enzyme contribu ... | 2016 | 27324409 |
| protection against malaria in mice is induced by blood stage-arresting histamine-releasing factor (hrf)-deficient parasites. | although most vaccines against blood stage malaria in development today use subunit preparations, live attenuated parasites confer significantly broader and more lasting protection. in recent years, plasmodium genetically attenuated parasites (gaps) have been generated in rodent models that cause self-resolving blood stage infections and induce strong protection. all such gaps generated so far bear mutations in housekeeping genes important for parasite development in red blood cells. in this stu ... | 2016 | 27432939 |
| a putative small solute transporter is responsible for the secretion of g377 and trap-containing secretory vesicles during plasmodium gamete egress and sporozoite motility. | regulated protein secretion is required for malaria parasite life cycle progression and transmission between the mammalian host and mosquito vector. during transmission from the host to the vector, exocytosis of highly specialised secretory vesicles, such as osmiophilic bodies, is key to the dissolution of the red blood cell and parasitophorous vacuole membranes enabling gamete egress. the positioning of adhesins from the trap family, from micronemes to the sporozoite surface, is essential for g ... | 2016 | 27427910 |
| comparative plasmodium gene overexpression reveals distinct perturbation of sporozoite transmission by profilin. | plasmodium relies on actin-based motility to migrate from the site of infection and invade target cells. using a substrate-dependent gliding locomotion, sporozoites are able to move at fast speed (1-3 μm/s). this motility relies on a minimal set of actin regulatory proteins and occurs in the absence of detectable filamentous actin (f-actin). here we report an overexpression strategy to investigate whether perturbations of f-actin steady-state levels affect gliding locomotion and host invasion. w ... | 2016 | 27226484 |
| the actin filament-binding protein coronin regulates motility in plasmodium sporozoites. | parasites causing malaria need to migrate in order to penetrate tissue barriers and enter host cells. here we show that the actin filament-binding protein coronin regulates gliding motility in plasmodium berghei sporozoites, the highly motile forms of a rodent malaria-causing parasite transmitted by mosquitoes. parasites lacking coronin show motility defects that impair colonization of the mosquito salivary glands but not migration in the skin, yet result in decreased transmission efficiency. in ... | 2016 | 27409081 |
| overexpression of plasmodium berghei atg8 by liver forms leads to cumulative defects in organelle dynamics and to generation of noninfectious merozoites. | plasmodium parasites undergo continuous cellular renovation to adapt to various environments in the vertebrate host and insect vector. in hepatocytes, plasmodium berghei discards unneeded organelles for replication, such as micronemes involved in invasion. concomitantly, intrahepatic parasites expand organelles such as the apicoplast that produce essential metabolites. we previously showed that the atg8 conjugation system is upregulated in p. berghei liver forms and that p. berghei atg8 (pbatg8) ... | 2016 | 27353755 |
| systematic tracking of altered haematopoiesis during sporozoite-mediated malaria development reveals multiple response points. | haematopoiesis is the complex developmental process that maintains the turnover of all blood cell lineages. it critically depends on the correct functioning of rare, quiescent haematopoietic stem cells (hscs) and more numerous, hsc-derived, highly proliferative and differentiating haematopoietic progenitor cells (hpcs). infection is known to affect hscs, with severe and chronic inflammatory stimuli leading to stem cell pool depletion, while acute, non-lethal infections exert transient and even p ... | 0 | 27335321 |
| il-22 dampens the t cell response in experimental malaria. | a tight regulation between the pro- and anti-inflammatory immune responses during plasmodial infection is of crucial importance, since a disruption leads to severe malaria pathology. il-22 is a member of the il-10 cytokine family, which is known to be highly important in immune regulation. we could detect high plasma levels of il-22 in plasmodium falciparum malaria as well as in plasmodium berghei anka (pba)-infected c57bl/6j mice. the deficiency of il-22 in mice during pba infection led to an e ... | 2016 | 27311945 |
| maternally supplied s-acyl-transferase is required for crystalloid organelle formation and transmission of the malaria parasite. | transmission of the malaria parasite from the mammalian host to the mosquito vector requires the formation of adequately adapted parasite forms and stage-specific organelles. here we show that formation of the crystalloid-a unique and short-lived organelle of the plasmodium ookinete and oocyst stage required for sporogony-is dependent on the precisely timed expression of the s-acyl-transferase dhhc10. dhhc10, translationally repressed in female plasmodium berghei gametocytes, is activated transl ... | 2016 | 27303037 |
| the machinery underlying malaria parasite virulence is conserved between rodent and human malaria parasites. | sequestration of red blood cells infected with the human malaria parasite plasmodium falciparum in organs such as the brain is considered important for pathogenicity. a similar phenomenon has been observed in mouse models of malaria, using the rodent parasite plasmodium berghei, but it is unclear whether the p. falciparum proteins known to be involved in this process are conserved in the rodent parasite. here we identify the p. berghei orthologues of two such key factors of p. falciparum, sbp1 a ... | 2016 | 27225796 |
| development of a plasmodium berghei transgenic parasite expressing the full-length plasmodium vivax circumsporozoite vk247 protein for testing vaccine efficacy in a murine model. | the approach of using transgenic rodent malaria parasites to assess the immune system's response to antigenic targets from a human malaria parasite has been shown to be useful for preclinical evaluation of new vaccine formulations. the transgenic plasmodium berghei parasite line [pvcsp(vk210)/pb] generated previously expresses the full-length circumsporozoite protein (csp) vk210 from plasmodium vivax. the transgenic parasite expresses one of the two most common alleles of csp, defined by nine am ... | 2016 | 27129682 |
| defining rules of cd8(+) t cell expansion against pre-erythrocytic plasmodium antigens in sporozoite-immunized mice. | whole plasmodium sporozoites serve as both experimental tools and potentially as deployable vaccines in the fight against malaria infection. live sporozoites infect hepatocytes and induce a diverse repertoire of cd8(+) t cell responses, some of which are capable of killing plasmodium-infected hepatocytes. previous studies in plasmodium yoelii-immunized balb/c mice showed that some cd8(+) t cell responses expanded with repeated parasite exposure, whereas other responses did not. | 2016 | 27113469 |
| an ultrasensitive nanoluc-based luminescence system for monitoring plasmodium berghei throughout its life cycle. | bioluminescence imaging is widely used for cell-based assays and animal imaging studies, both in biomedical research and drug development. its main advantages include its high-throughput applicability, affordability, high sensitivity, operational simplicity, and quantitative outputs. in malaria research, bioluminescence has been used for drug discovery in vivo and in vitro, exploring host-pathogen interactions, and studying multiple aspects of plasmodium biology. while the number of fluorescent ... | 2016 | 27102897 |
| enhanced transmission of malaria parasites to mosquitoes in a murine model of type 2 diabetes. | more than half of the world's population is at risk of malaria and simultaneously, many malaria-endemic regions are facing dramatic increases in the prevalence of type 2 diabetes. studies in murine malaria models have examined the impact of malaria infection on type 2 diabetes pathology, it remains unclear how this chronic metabolic disorder impacts the transmission of malaria. in this report, the ability type 2 diabetic rodents infected with malaria to transmit parasites to anopheles stephensi ... | 2016 | 27102766 |
| characterization of a plasmodium berghei sexual stage antigen pbph as a new candidate for malaria transmission-blocking vaccine. | transmission-blocking vaccines (tbvs) are a promising strategy for malaria control and elimination. however, candidate tbv antigens are currently limited, highlighting the urgency of identifying new antigens for tbv development. | 2016 | 27038925 |
| experimental cerebral malaria spreads along the rostral migratory stream. | it is poorly understood how progressive brain swelling in experimental cerebral malaria (ecm) evolves in space and over time, and whether mechanisms of inflammation or microvascular sequestration/obstruction dominate the underlying pathophysiology. we therefore monitored in the plasmodium berghei anka-c57bl/6 murine ecm model, disease manifestation and progression clinically, assessed by the rapid-murine-coma-and-behavioral-scale (rmcbs), and by high-resolution in vivo mri, including sensitive a ... | 2016 | 26964100 |
| high-throughput luciferase-based assay for the discovery of therapeutics that prevent malaria. | in order to identify the most attractive starting points for drugs that can be used to prevent malaria, a diverse chemical space comprising tens of thousands to millions of small molecules may need to be examined. achieving this throughput necessitates the development of efficient ultra-high-throughput screening methods. here, we report the development and evaluation of a luciferase-based phenotypic screen of malaria exoerythrocytic-stage parasites optimized for a 1536-well format. this assay us ... | 2016 | 27275010 |
| mycobacterium tuberculosis coinfection has no impact on plasmodium berghei anka-induced experimental cerebral malaria in c57bl/6 mice. | cerebral malaria (cm) is the most severe complication of human infection with plasmodium falciparum. the mechanisms predisposing to cm are still not fully understood. proinflammatory immune responses are required for the control of blood-stage malaria infection but are also implicated in the pathogenesis of cm. a fine balance between pro- and anti-inflammatory immune responses is required for parasite clearance without the induction of host pathology. the most accepted experimental model to stud ... | 2015 | 26644378 |
| translational control of uis4 protein of the host-parasite interface is mediated by the rna binding protein puf2 in plasmodium berghei sporozoites. | uis4 is a key protein component of the host-parasite interface in the liver stage of the rodent malaria parasite plasmodium berghei and required for parasite survival after invasion. in the infectious sporozoite, uis4 protein has variably been shown to be translated but also been reported to be translationally repressed. here we show that uis4 mrna translation is regulated by the p. berghei rna binding protein pumilio-2 (pbpuf2 or puf2 from here on forward) in infectious salivary gland sporozoit ... | 2016 | 26808677 |
| functional profiles of orphan membrane transporters in the life cycle of the malaria parasite. | assigning function to orphan membrane transport proteins and prioritizing candidates for detailed biochemical characterization remain fundamental challenges and are particularly important for medically relevant pathogens, such as malaria parasites. here we present a comprehensive genetic analysis of 35 orphan transport proteins of plasmodium berghei during its life cycle in mice and anopheles mosquitoes. six genes, including four candidate aminophospholipid transporters, are refractory to gene d ... | 2016 | 26796412 |
| a vacuolar iron-transporter homologue acts as a detoxifier in plasmodium. | iron is an essential micronutrient but is also highly toxic. in yeast and plant cells, a key detoxifying mechanism involves iron sequestration into intracellular storage compartments, mediated by members of the vacuolar iron-transporter (vit) family of proteins. here we study the vit homologue from the malaria parasites plasmodium falciparum (pfvit) and plasmodium berghei (pbvit). pfvit-mediated iron transport in a yeast heterologous expression system is saturable (km ∼ 14.7 μm), and selective f ... | 2016 | 26786069 |
| plasmodium p-type cyclin cyc3 modulates endomitotic growth during oocyst development in mosquitoes. | cell-cycle progression and cell division in eukaryotes are governed in part by the cyclin family and their regulation of cyclin-dependent kinases (cdks). cyclins are very well characterised in model systems such as yeast and human cells, but surprisingly little is known about their number and role in plasmodium, the unicellular protozoan parasite that causes malaria. malaria parasite cell division and proliferation differs from that of many eukaryotes. during its life cycle it undergoes two type ... | 2015 | 26565797 |
| asparagine requirement in plasmodium berghei as a target to prevent malaria transmission and liver infections. | the proteins of plasmodium, the malaria parasite, are strikingly rich in asparagine. plasmodium depends primarily on host haemoglobin degradation for amino acids and has a rudimentary pathway for amino acid biosynthesis, but retains a gene encoding asparagine synthetase (as). here we show that deletion of as in plasmodium berghei (pb) delays the asexual- and liver-stage development with substantial reduction in the formation of ookinetes, oocysts and sporozoites in mosquitoes. in the absence of ... | 2015 | 26531182 |
| evaluation of antiplasmodial activity of extracts and constituents from ampelozizyphus amazonicus. | ampelozizyphus amazonicus ducke, a plant that is widely used by the population of the amazonian region to prevent and treat malaria, was investigated in this work, which describes, for the first time, the antiplasmodial activity of its extracts and associates this activity with its isolated constituents. | 0 | 26664012 |
| global transcriptional repression: an initial and essential step for plasmodium sexual development. | gametocytes are nonreplicative sexual forms that mediate malaria transmission to a mosquito vector. they are generated from asexual blood-stage parasites that proliferate in the circulation. however, little is known about how this transition is genetically regulated. here, we report that an apetala2 (ap2) family transcription factor, ap2-g2, regulates this transition as a transcriptional repressor. disruption of ap2-g2 in the rodent malaria parasite plasmodium berghei did not prevent commitment ... | 2015 | 26417110 |
| plasmodium berghei mapk1 displays differential and dynamic subcellular localizations during liver stage development. | mitogen-activated protein kinases (mapks) regulate key signaling events in eukaryotic cells. in the genomes of protozoan plasmodium parasites, the causative agents of malaria, two genes encoding kinases with significant homology to other eukaryotic mapks have been identified (mapk1, mapk2). in this work, we show that both genes are transcribed during plasmodium berghei liver stage development, and analyze expression and subcellular localization of the pbmapk1 protein in liver stage parasites. li ... | 2013 | 23544094 |
| plasmodium yoelii inhibitor of cysteine proteases is exported to exomembrane structures and interacts with yoelipain-2 during asexual blood-stage development. | plasmodium falciparum (pf) blood stages express falstatin, an inhibitor of cysteine proteases (icp), which is implicated in regulating proteolysis during red blood cell infection. recent data using the plasmodium berghei rodent malaria model suggested an additional role for icp in the infection of hepatocytes by sporozoites and during liver-stage development. here we further characterize the role of icp in vivo during infection with plasmodium yoelii (py) and pf. we found that py-icp was refract ... | 2013 | 23421981 |
| the plasmodium berghei ca(2+)/h(+) exchanger, pbcax, is essential for tolerance to environmental ca(2+) during sexual development. | ca(2+) contributes to a myriad of important cellular processes in all organisms, including the apicomplexans, plasmodium and toxoplasma. due to its varied and essential roles, free ca(2+) is tightly regulated by complex mechanisms. these mechanisms are therefore of interest as putative drug targets. one pathway in ca(2+) homeostatic control in apicomplexans uses a ca(2+)/h(+) exchanger (a member of the cation exchanger family, cax). the p. falciparum cax (pfcax) has recently been characterised i ... | 2013 | 23468629 |
| perturbations of plasmodium puf2 expression and rna-seq of puf2-deficient sporozoites reveal a critical role in maintaining rna homeostasis and parasite transmissibility. | malaria's cycle of infection requires parasite transmission between a mosquito vector and a mammalian host. we here demonstrate that the plasmodium yoelii pumilio-fbf family member puf2 allows the sporozoite to remain infectious in the mosquito salivary glands while awaiting transmission. puf2 mediates this solely through its rna-binding domain (rbd) likely by stabilizing or hastening the degradation of specific mrnas. puf2 traffics to sporozoite cytosolic granules, which are negative for severa ... | 2013 | 23356439 |
| costs of crowding for the transmission of malaria parasites. | the utility of using evolutionary and ecological frameworks to understand the dynamics of infectious diseases is gaining increasing recognition. however, integrating evolutionary ecology and infectious disease epidemiology is challenging because within-host dynamics can have counterintuitive consequences for between-host transmission, especially for vector-borne parasites. a major obstacle to linking within- and between-host processes is that the drivers of the relationships between the density, ... | 2013 | 23789029 |
| features of autophagic cell death in plasmodium liver-stage parasites. | analyzing molecular determinants of plasmodium parasite cell death is a promising approach for exploring new avenues in the fight against malaria. three major forms of cell death (apoptosis, necrosis and autophagic cell death) have been described in multicellular organisms but which cell death processes exist in protozoa is still a matter of debate. here we suggest that all three types of cell death occur in plasmodium liver-stage parasites. whereas typical molecular markers for apoptosis and ne ... | 2013 | 23388496 |
| expression of cytosolic peroxiredoxins in plasmodium berghei ookinetes is regulated by environmental factors in the mosquito bloodmeal. | the plasmodium ookinete develops over several hours in the bloodmeal of its mosquito vector where it is exposed to exogenous stresses, including cytotoxic reactive oxygen species (ros). how the parasite adapts to these challenging conditions is not well understood. we have systematically investigated the expression of three cytosolic antioxidant proteins, thioredoxin-1 (trx-1), peroxiredoxin-1 (tpx-1), and 1-cys peroxiredoxin (1-cys prx), in developing ookinetes of the rodent parasite plasmodium ... | 2013 | 23382676 |
| novel type ii fatty acid biosynthesis (fas ii) inhibitors as multistage antimalarial agents. | malaria is a potentially fatal disease caused by plasmodium parasites and poses a major medical risk in large parts of the world. the development of new, affordable antimalarial drugs is of vital importance as there are increasing reports of resistance to the currently available therapeutics. in addition, most of the current drugs used for chemoprophylaxis merely act on parasites already replicating in the blood. at this point, a patient might already be suffering from the symptoms associated wi ... | 2013 | 23341167 |
| quantification of sporozoite invasion, migration, and development by microscopy and flow cytometry. | there is an important role for in vitro assays to better understand the initial steps of malaria infection. in this section, we describe both microscopy-based and flow cytometry-based sporozoite invasion, migration and development assays with the rodent malaria parasites, plasmodium berghei and plasmodium yoelii, and the human malaria parasite, plasmodium falciparum. | 0 | 22990793 |
| 4(1h)-quinolones with liver stage activity against plasmodium berghei. | with the exception of primaquine, tafenoquine, and atovaquone, there are very few antimalarials that target liver stage parasites. in this study, a transgenic plasmodium berghei parasite (1052cl1; pbgfp-luc(con)) that expresses luciferase was used to assess the anti-liver stage parasite activity of ici 56,780, a 7-(2-phenoxyethoxy)-4(1h)-quinolone (peq), as well as two 3-phenyl-4(1h)-quinolones (p4q), p4q-146 and p4q-158, by using bioluminescent imaging (bli). results showed that all of the comp ... | 2012 | 23129047 |
| a tetracycline-repressible transactivator system to study essential genes in malaria parasites. | a major obstacle in analyzing gene function in apicomplexan parasites is the absence of a practical regulatable expression system. here, we identified functional transcriptional activation domains within apicomplexan ap2 (apiap2) family transcription factors. these apiap2 transactivation domains were validated in blood-, liver-, and mosquito-stage parasites and used to create a robust conditional expression system for stage-specific, tetracycline-dependent gene regulation in toxoplasma gondii, p ... | 0 | 23245327 |
| hiv nonnucleoside reverse transcriptase inhibitors and trimethoprim-sulfamethoxazole inhibit plasmodium liver stages. | although nonnucleoside reverse transcriptase inhibitors (nnrtis) are usually part of first-line treatment regimens for human immunodeficiency virus (hiv), their activity on plasmodium liver stages remains unexplored. additionally, trimethoprim-sulfamethoxazole (tmp-smx), used for opportunistic infection prophylaxis in hiv-exposed infants and hiv-infected patients, reduces clinical episodes of malaria; however, tmp-smx effect on plasmodium liver stages requires further study. | 0 | 23125449 |
| mitochondrial peroxidase tpx-2 is not essential in the blood and insect stages of plasmodium berghei. | malaria parasites actively proliferate in the body of their vertebrate and insect hosts, and are subjected to the toxic effects of reactive oxygen species. the antioxidant defenses of malaria parasites are considered to play essential roles in their survival and are thus considered promising targets for intervention. we sought to identify the cellular function of thioredoxin peroxidase-2 (tpx-2), which is expressed in the mitochondria, by disrupting the tpx-2 gene (pbtpx-2) of the rodent malaria ... | 2012 | 23146411 |
| identification of an ap2-family protein that is critical for malaria liver stage development. | liver-stage malaria parasites are a promising target for drugs and vaccines against malaria infection. however, little is currently known about gene regulation in this stage. in this study, we used the rodent malaria parasite plasmodium berghei and showed that an ap2-family transcription factor, designated ap2-l, plays a critical role in the liver-stage development of the parasite. ap2-l-depleted parasites proliferated normally in blood and in mosquitoes. however, the ability of these parasites ... | 2012 | 23144823 |
| natural transmission of plasmodium berghei exacerbates chronic tuberculosis in an experimental co-infection model. | human populations are rarely exposed to one pathogen alone. particularly in high incidence regions such as sub-saharan africa, concurrent infections with more than one pathogen represent a widely underappreciated public health problem. two of the world's most notorious killers, malaria and tuberculosis, are co-endemic in impoverished populations in the tropics. however, interactions between both infections in a co-infected individual have not been studied in detail. both pathogens have a major i ... | 2012 | 23110184 |
| antibiotic and antimalarial quinones from fungus-growing ant-associated pseudonocardia sp. | three new members of the angucycline class of antibiotics, pseudonocardones a-c (1-3), along with the known antibiotics 6-deoxy-8-o-methylrabelomycin (4) and x-14881 e (5) have been isolated from the culture of a pseudonocardia strain associated with the fungus-growing ant apterostigma dentigerum. compounds 4 and 5 showed antibiotic activity against bacillus subtilis 3610 and liver-stage plasmodium berghei, while 1-3 were inactive or only weakly active in a variety of biological assays. compound ... | 2012 | 23025282 |
| conformational co-dependence between plasmodium berghei lccl proteins promotes complex formation and stability. | malaria parasites express a conserved family of lccl-lectin adhesive-like domain proteins (laps) that have essential functions in sporozoite transmission. in plasmodium falciparum all six family members are expressed in gametocytes and form a multi-protein complex. intriguingly, knockout of p. falciparum lccl proteins adversely affects expression of other family members at protein, but not at mrna level, a phenomenon termed co-dependent expression. here, we investigate this in plasmodium berghei ... | 2012 | 22877575 |
| tricks in plasmodium's molecular repertoire--escaping 3'utr excision-based conditional silencing of the chloroquine resistance transporter gene. | in the human malaria parasite plasmodium falciparum, the major determinant of chloroquine resistance, p. falciparum chloroquine resistance transporter (pfcrt), likely plays an essential role in asexual blood stages, thus precluding conventional gene targeting approaches. we attempted to conditionally silence the expression of its ortholog in plasmodium berghei (pbcrt) through flp recombinase-mediated excision of the 3'untranslated region (utr) during mosquito passage. however, parasites maintain ... | 2012 | 23023047 |
| a unique protein phosphatase with kelch-like domains (ppkl) in plasmodium modulates ookinete differentiation, motility and invasion. | protein phosphorylation and dephosphorylation (catalysed by kinases and phosphatases, respectively) are post-translational modifications that play key roles in many eukaryotic signalling pathways, and are often deregulated in a number of pathological conditions in humans. in the malaria parasite plasmodium, functional insights into its kinome have only recently been achieved, with over half being essential for blood stage development and another 14 kinases being essential for sexual development ... | 2012 | 23028336 |
| variation in apoptosis mechanisms employed by malaria parasites: the roles of inducers, dose dependence and parasite stages. | plasmodium berghei ookinetes exhibit an apoptotic phenotype when developing within the mosquito midgut lumen or when cultured in vitro. markers of apoptosis increase when they are exposed to nitric oxide or reactive oxygen species but high concentrations of hydrogen peroxide cause death without observable signs of apoptosis. chloroquine and other drugs have been used to induce apoptosis in erythrocytic stages of plasmodium falciparum and to formulate a putative pathway involving cysteine proteas ... | 2012 | 22929459 |
| a plasmodium calcium-dependent protein kinase controls zygote development and transmission by translationally activating repressed mrnas. | calcium-dependent protein kinases (cdpks) play key regulatory roles in the life cycle of the malaria parasite, but in many cases their precise molecular functions are unknown. using the rodent malaria parasite plasmodium berghei, we show that cdpk1, which is known to be essential in the asexual blood stage of the parasite, is expressed in all life stages and is indispensable during the sexual mosquito life-cycle stages. knockdown of cdpk1 in sexual stages resulted in developmentally arrested par ... | 0 | 22817984 |
| extrahepatic exoerythrocytic forms of rodent malaria parasites at the site of inoculation: clearance after immunization, susceptibility to primaquine, and contribution to blood-stage infection. | plasmodium sporozoites are inoculated into the skin of the mammalian host as infected mosquitoes probe for blood. a proportion of the inoculum enters the bloodstream and goes to the liver, where the sporozoites invade hepatocytes and develop into the next life cycle stage, the exoerythrocytic, or liver, stage. here, we show that a small fraction of the inoculum remains in the skin and begins to develop into exoerythrocytic forms that can persist for days. skin exoerythrocytic forms were observed ... | 2012 | 22431651 |
| liver-stage malaria parasites vulnerable to diverse chemical scaffolds. | human malaria infection begins with a one-time asymptomatic liver stage followed by a cyclic symptomatic blood stage. all high-throughput malaria drug discovery efforts have focused on the cyclic blood stage, which has limited potential for the prophylaxis, transmission blocking, and eradication efforts that will be needed in the future. to address these unmet needs, a high-throughput phenotypic liver-stage plasmodium parasite screen was developed to systematically identify molecules with liver- ... | 2012 | 22586124 |
| characterization of plasmodium liver stage inhibition by halofuginone. | malaria is a devastating parasitic disease that afflicts one-third of the world's population. antimalarial drugs in common use address few targets, and their efficacy is being undermined by parasite resistance. most therapeutics target blood-stage malaria, whereas only few compounds are active against malaria's liver stage, the first stage of the plasmodium parasite's life cycle within the human host. the identification of inhibitors active against liver-stage malaria would benefit the developme ... | 2012 | 22438279 |
| roles of the amino terminal region and repeat region of the plasmodium berghei circumsporozoite protein in parasite infectivity. | the circumsporozoite protein (csp) plays a key role in malaria sporozoite infection of both mosquito salivary glands and the vertebrate host. the conserved regions i and ii have been well studied but little is known about the immunogenic central repeat region and the n-terminal region of the protein. rodent malaria plasmodium berghei parasites, in which the endogenous cs gene has been replaced with the avian plasmodium gallinaceum cs (pgcs) sequence, develop normally in the a. stephensi mosquito ... | 2012 | 22393411 |
| a putative homologue of cdc20/cdh1 in the malaria parasite is essential for male gamete development. | cell-cycle progression is governed by a series of essential regulatory proteins. two major regulators are cell-division cycle protein 20 (cdc20) and its homologue, cdc20 homologue 1 (cdh1), which activate the anaphase-promoting complex/cyclosome (apc/c) in mitosis, and facilitate degradation of mitotic apc/c substrates. the malaria parasite, plasmodium, is a haploid organism which, during its life-cycle undergoes two stages of mitosis; one associated with asexual multiplication and the other wit ... | 2012 | 22383885 |
| the exported plasmodium berghei protein ibis1 delineates membranous structures in infected red blood cells. | the importance of pathogen-induced host cell remodelling has been well established for red blood cell infection by the human malaria parasite plasmodium falciparum. exported parasite-encoded proteins, which often possess a signature motif, termed plasmodium export element (pexel) or host-targeting (ht) signal, are critical for the extensive red blood cell modifications. to what extent remodelling of erythrocyte membranes also occurs in non-primate hosts and whether it is in fact a hallmark of al ... | 2012 | 22329949 |
| mixed vector immunization with recombinant adenovirus and mva can improve vaccine efficacy while decreasing antivector immunity. | substantial protection can be provided against the pre-erythrocytic stages of malaria by vaccination first with an adenoviral and then with an modified vaccinia virus ankara (mva) poxviral vector encoding the same me.trap transgene. we investigated whether the two vaccine components adenovirus (ad) and mva could be coinjected as a mixture to enhance protection against malaria. a single-shot mixture at specific ratios of ad and mva (ad+mva) enhanced cd8(+) t cell-dependant protection of mice agai ... | 2012 | 22354374 |
| salinomycin and other ionophores as a new class of antimalarial drugs with transmission-blocking activity. | the drug target profile proposed by the medicines for malaria venture for a malaria elimination/eradication policy focuses on molecules active on both asexual and sexual stages of plasmodium, thus with both curative and transmission-blocking activities. the aim of the present work was to investigate whether the class of monovalent ionophores, which includes drugs used in veterinary medicine and that were recently proposed as human anticancer agents, meets these requirements. the activity of sali ... | 2015 | 26055362 |
| the plasmodium berghei translocon of exported proteins reveals spatiotemporal dynamics of tubular extensions. | the erythrocyte is an extraordinary host cell for intracellular pathogens and requires extensive remodelling to become permissive for infection. malaria parasites modify their host red blood cells through protein export to acquire nutrients and evade immune responses. endogenous fluorescent tagging of three signature proteins of the plasmodium berghei translocon of exported proteins (ptex), heat shock protein 101, exported protein 2 (exp2), and ptex88, revealed motile, tubular extensions of the ... | 2015 | 26219962 |
| long-term live imaging reveals cytosolic immune responses of host hepatocytes against plasmodium infection and parasite escape mechanisms. | plasmodium parasites are transmitted by anopheles mosquitoes to the mammalian host and actively infect hepatocytes after passive transport in the bloodstream to the liver. in their target host hepatocyte, parasites reside within a parasitophorous vacuole (pv). in the present study it was shown that the parasitophorous vacuole membrane (pvm) can be targeted by autophagy marker proteins lc3, ubiquitin, and sqstm1/p62 as well as by lysosomes in a process resembling selective autophagy. the dynamics ... | 0 | 26208778 |
| biogenesis of the crystalloid organelle in plasmodium involves microtubule-dependent vesicle transport and assembly. | malaria parasites possess unique subcellular structures and organelles. one of these is the crystalloid, a multivesicular organelle that forms during the parasite's development in vector mosquitoes. the formation and function of these organelles remain poorly understood. a family of six conserved and modular proteins named lccl-lectin adhesive-like proteins (laps), which have essential roles in sporozoite transmission, localise to the crystalloids. in this study we analyse crystalloid formation ... | 2015 | 25900212 |
| parasite-induced er stress response in hepatocytes facilitates plasmodium liver stage infection. | upon infection of a mammalian host, plasmodium parasites first replicate inside hepatocytes, generating thousands of new parasites. although plasmodium intra-hepatic development represents a substantial metabolic challenge to the host hepatocyte, how infected cells respond to and integrate this stress remains poorly understood. here, we present proteomic and transcriptomic analyses, revealing that the endoplasmic reticulum (er)-resident unfolded protein response (upr) is activated in host hepato ... | 2015 | 26113366 |
| in vivo and in vitro characterization of a plasmodium liver stage-specific promoter. | little is known about stage-specific gene regulation in plasmodium parasites, in particular the liver stage of development. we have previously described in the plasmodium berghei rodent model, a liver stage-specific (lisp2) gene promoter region, in vitro. using a dual luminescence system, we now confirm the stage specificity of this promoter region also in vivo. furthermore, by substitution and deletion analyses we have extended our in vitro characterization of important elements within the prom ... | 2015 | 25874388 |