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novel squaramides with in vitro liver stage antiplasmodial activity.a structure-activity relationship study was performed with ten 8-aminoquinoline-squaramides compounds active against liver stage malaria parasites, using human hepatoma cells (huh7) infected by plasmodium berghei parasites. in addition, their blood-schizontocidal activity was assessed against chloroquine-resistant w2 strain plasmodium falciparum. compound 3 was 7.3-fold more potent than the positive control primaquine against liver-stage parasites, illustrating the importance of the squarate moi ...201626968650
diarylheptanoids rich fraction of alnus nepalensis attenuates malaria pathogenesis: in-vitro and in-vivo study.diarylheptanoids from alnus nepalensis leaves have been reported for promising activity against filariasis, a mosquito-borne disease, and this has prompted us to investigate its anti-malarial and safety profile using in-vitro and in-vivo bioassays. a. nepalensis leaf extracts were tested in-vitro against chloroquine-sensitive plasmodium falciparum nf54 by measuring the parasite specific lactate dehydrogenase activity. among all, the chloroform extract (anc) has shown promising anti-plasmodial ac ...201626969854
detailed methodology for high resolution scanning electron microscopy (sem) of murine malaria parasitized-erythrocytes.scanning electron microscopy (sem) is a powerful tool used to investigate object surfaces and has been widely applied in both material science and biology. with respect to the study of malaria, sem revealed that erythrocytes infected with plasmodium falciparum, a human parasite, display 'knob-like' structures on their surface comprising parasitized proteins. however, detailed methodology for sem studies of malaria parasites is lacking in the literature making such studies challenging. here, we p ...201626987676
experimental systems for studying plasmodium/hiv coinfection.coinfections with human immunodeficiency virus (hiv) and plasmodium, the causative agents of aids and malaria, respectively, are frequent and their comorbidity especially in sub-saharan africa is high. while clinical studies suggest an influence of the two pathogens on the outcome of the respective infections, experimental studies on the molecular and immunological impact of coinfections are rare. this reflects the limited availability of suitable model systems that reproduce key properties of b ...201627009943
co-infection with plasmodium berghei and trypanosoma brucei increases severity of malaria and trypanosomiasis in mice.individuals in natural populations may be infected with multiple different parasites at a time. these parasites may interact with each other or act independently in the host, and this may result to varying outcomes on host health and survival. this study therefore aimed at investigating the health impact of co-infection of mice with plasmodium berghei and trypanosoma brucei. forty swiss albino mice (14-17g) were divided into four groups of ten. mice in groups a and b received 10(6)p. berghei and ...201627021269
enhanced methylation analysis by recovery of unsequenceable fragments.bisulfite sequencing is a valuable tool for mapping the position of 5-methylcytosine in the genome at single base resolution. however, the associated chemical treatment causes strand scission, which depletes the number of sequenceable dna fragments in a library and thus necessitates pcr amplification. the at-rich nature of the library generated from bisulfite treatment adversely affects this amplification, resulting in the introduction of major biases that can confound methylation analysis. here ...201627031619
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.201627038925
murine model for preclinical studies of var2csa-mediated pathology associated with malaria in pregnancy.plasmodium falciparum infection during pregnancy leads to abortions, stillbirth, low birth weight, and maternal mortality. infected erythrocytes (ies) accumulate in the placenta by adhering to chondroitin sulfate a (csa) via var2csa protein exposed on the p. falciparum ie membrane. plasmodium berghei ie infection in pregnant balb/c mice is a model for severe placental malaria (pm). here, we describe a transgenic p. berghei parasite expressing the full-length var2csa extracellular region (domains ...201627045035
substrate and inhibitor specificity of the plasmodium berghei equilibrative nucleoside transporter type 1.malaria is a critical public health issue in the tropical world, causing extensive morbidity and mortality. infection by unicellular, obligate intracellular plasmodium parasites causes malaria. the emergence of resistance to current antimalarial drugs necessitates the development of novel therapeutics. a potential novel drug target is the purine import transporter. because plasmodium parasites are purine auxotrophic, they must import purines from their host to fulfill metabolic requirements. the ...201627048953
a small mitochondrial protein present in myzozoans is essential for malaria transmission.myzozoans (which include dinoflagellates, chromerids and apicomplexans) display notable divergence from their ciliate sister group, including a reduced mitochondrial genome and divergent metabolic processes. the factors contributing to these divergent processes are still poorly understood and could serve as potential drug targets in disease-causing protists. here, we report the identification and characterization of a small mitochondrial protein from the rodent-infecting apicomplexan parasite pl ...201627053680
evaluation of herbal antimalarial mama decoction-amodiaquine combination in murine malaria model.co-administration of amodiaquine with mama decoction (md), an herbal antimalarial drug comprising the leaves of mangifera indica l. (anacardiaceae), alstonia boonei de wild (apocynaceae), morinda lucida benth (rubiaceae) and azadirachta indica a. juss (meliaceae) was investigated. the practice of concurrent administration of herbal medicines with orthodox drugs is currently on the increase globally.201627057621
j-dot targeting of an exported hsp40 in plasmodium falciparum-infected erythrocytes.plasmodium falciparum exports a large number of proteins to its host cell, the mature human erythrocyte, where they are involved in host cell modification. amongst the proteins trafficked to the host cell, many are heat shock protein (hsp)40 homologues. we previously demonstrated that at least two exported pfhsp40s (referred to as pfe55 and pfa660) localise to mobile structures in the p. falciparum-infected erythrocyte (kulzer et al., 2010), termed j-dots. the complete molecular content of these ...201627063072
antimalarial properties of crude extracts of seeds of brucea antidysenterica and leaves of ocimum lamiifolium.the search for new antimalarial drugs has become increasingly urgent due to plasmodial resistance to existing drugs. as part of this global effort, the present study aimed at evaluating the antimalarial activity of two traditionally used medicinal plants against the disease.201627075995
identification of three ookinete-specific genes and evaluation of their transmission-blocking potentials in plasmodium berghei.with a renewed hope for malaria elimination, interventions that prevent transmission of parasites from humans to mosquitoes have received elevated attention. transmission-blocking vaccines (tbvs) targeting the sexual stages are well suited for this task. here, through bioinformatic analysis, we selected two putative plasmodium berghei ookinete-stage proteins (pbanka_111920, and pbanka_145770) and a previously characterized ookinete protein pbanka_135340 (psop7) for evaluation of their transmissi ...201627083421
discriminating protective from nonprotective plasmodium-specific cd8+ t cell responses.despite decades of research, malaria remains a global health crisis. current subunit vaccine approaches do not provide efficient long-term, sterilizing immunity against plasmodium infections in humans. conversely, whole parasite vaccinations with their larger array of target ags have conferred long-lasting sterilizing protection to humans. similar studies in rodent models of malaria reveal that cd8(+) t cells play a critical role in liver-stage immunity after whole parasite vaccination. however, ...201627084099
cd47-sirpα interactions regulate macrophage uptake of plasmodium falciparum-infected erythrocytes and clearance of malaria in vivo.cd47 engagement by the macrophage signal regulatory protein alpha (sirpα) inhibits phagocytic activity and protects red blood cells (rbcs) from erythrophagocytosis. the role of cd47-sirpα in the innate immune response to plasmodium falciparum infection is unknown. we hypothesized that disruption of sirpα signaling may enhance macrophage uptake of malaria parasite-infected rbcs. to test this hypothesis, we examined in vivo clearance in cd47-deficient mice infected with plasmodium berghei anka and ...201627091932
in vivo antimalarial activity of annona muricata leaf extract in mice infected with plasmodium berghei.malaria is one of the most important infectious diseases in the world. the choice for the treatment is highly limited due to drug resistance. hence, finding the new compounds to treat malaria is urgently needed. the present study was attempted to evaluate the antimalarial activity of the annona muricata aqueous leaf extract in plasmodium berghei infected mice. aqueous leaf extract of a. muricata was prepared and tested for acute toxicity in mice. for efficacy test in vivo, standard 4-day suppres ...201627092277
pre-infection administration of asiatic acid retards parasitaemia induction in plasmodium berghei murine malaria infected sprague-dawley rats.malaria prevention has remained a critical area in the absence of efficacious vaccines against malaria. drugs currently used as chemotherapeutics are also used in chemoprophylaxis increasing possible drug resistance. asiatic acid is a natural phytochemical with oxidant, antioxidant and anti-inflammatory properties with emerging anti-malarial potential. the influence of asiatic acid administration prior to plasmodium berghei infection of sprague-dawley rats on parasitaemia induction is here repor ...201627098750
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 ...201627102766
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 ...201627102897
antimalarial activity of fractions of aqueous extract of acacia nilotica root.the problem of resistance of malarial parasites to available antimalarial drugs makes the development of new drugs imperative, with natural plant products providing an alternative source for discovering new drugs.201727104040
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.201627113469
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 ...201627129682
editorial: cd36: russian roulette of host and parasites during malaria infection. 201627130887
in vivo antimalarial activity of extracts of tanzanian medicinal plants used for the treatment of malaria.plants used in traditional medicine have been the source of a number of currently used antimalarial medicines and continue to be a promising resource for the discovery of new classes of antimalarial compounds. the aim of this study was to evaluate in vivo antimalarial activity of four plants; erythrina schliebenii harms, holarrhena pubescens buch-ham, phyllanthus nummulariifolius poir, and caesalpinia bonducella (l.) flem used for treatment of malaria in tanzania. in vivo antimalarial activity w ...201727144154
identifying antimalarial compounds targeting dihydrofolate reductase-thymidylate synthase (dhfr-ts) by chemogenomic profiling.the mode of action of many antimalarial drugs is unknown. chemogenomic profiling is a powerful method to address this issue. this experimental approach entails disruption of gene function and phenotypic screening for changes in sensitivity to bioactive compounds. here, we describe the application of reverse genetics for chemogenomic profiling in plasmodium. plasmodium falciparum parasites harbouring a transgenic insertion of the glms ribozyme downstream of the dihydrofolate reductase-thymidylate ...201627150044
cysteamine broadly improves the anti-plasmodial activity of artemisinins against murine blood stage and cerebral malaria.the potential emergence and spread of resistance to artemisinins in the plasmodium falciparum malaria parasite constitutes a major global health threat. hence, improving the efficacy of artemisinins and of artemisinin-based combination therapy (act) represents a major short-term goal in the global fight against malaria. mice defective in the enzyme pantetheinase (vnn3) show increased susceptibility to blood-stage malaria (increased parasitaemia, reduced survival), and supplementation of vnn3 mut ...201627150250
synthesis, cytotoxic activity on leukemia cell lines and quantitative structure-activity relationships (qsar) studies of morita-baylis-hillman adducts.the morita-baylis-hillman reaction is an organocatalyzed chemical transformation that allows access to small poly-functionalized molecules and has considerable synthetic potential and promising biological profiles. the morita-baylis-hillman adducts (mbha) are a new class of bioactive compounds and highlight its potentialities to the discovery of new cheaper and efficient drugs, e.g. as anti-leishmania chagasi and leishmania amazonensis, anti- trypanosoma cruzi, anti-plasmodium falciparum and pla ...201627150963
route of administration of attenuated sporozoites is instrumental in rendering immunity against plasmodia infection.whole sporozoite vaccine (wsv) approach has been shown to induce efficient cd8(+) t cell response, critical for developing of long-lasting sterile protection against plasmodium. although wsv was initiated over four decades ago, we still do not fully understand about the absolute requirements for the generation of liver-stage specific cd8(+) t memory cells. for more than a decade intravenous (iv) route of immunization has been shown to be protective in pre-clinical studies. however, the intraderm ...201627160038
an antibody against an anopheles albimanus midgut myosin reduces plasmodium berghei oocyst development.malaria parasites are transmitted by anopheles mosquitoes. although several studies have identified mosquito midgut surface proteins that are putatively important for plasmodium ookinete invasion, only a few have characterized these protein targets and demonstrated transmission-blocking activity. molecular information about these proteins is essential for the development of transmission-blocking vaccines (tbv). the aim of the present study was to test three monoclonal antibodies (mabs), a-140, a ...201627165123
antiplasmodial, antioxidant and immunomodulatory activities of ethanol extract of vernonia amygdalina del. leaf in swiss mice.vernonia amygdalina (v. amygdalina) leaf is locally employed in the southern region of nigeria in the treatment of malaria infection. this study evaluated the in vivo antiplasmodial, antioxidant and immunomodulatory effect of ethanol extract of v. amygdalina leaf.201727222837
expression of the plasmodium berghei actin ii gene is controlled by elements in a long genomic region.plasmodium parasites have two actin isoforms. actin i is ubiquitously expressed, while the second actin isoform is expressed in the sexual stages and ookinetes. reverse genetic analysis revealed two phenotypes in parasites lacking the protein: a block in male gametogenesis (exflagellation) and a second phenotype in oocyst development, dependent upon the expression of the gene in female gametocytes. here, we report that the genetic complementation of two independent mutants lacking actin ii does ...201627225004
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 ...201627225796
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 ...201627226484
in vivo and in vitro effectiveness of azadirachta indica-synthesized silver nanocrystals against plasmodium berghei and plasmodium falciparum, and their potential against malaria mosquitoes.malaria transmission is a serious emergence in urban and semiurban areas worldwide, becoming a major international public health concern. malaria is transmitted through the bites of anopheles mosquitoes. the extensive employ of synthetic pesticides leads to negative effects on human health and the environment. recently, plant-synthesized nanoparticles have been proposed as highly effective mosquitocides. in this research, we synthesized silver nanoparticles (agnp) using the azadirachta indica se ...201627234530
increased susceptibility to pentylenetetrazol following survival of cerebral malaria in mice.malaria is considered a neglected disease and public health problem, affecting >200 million people worldwide. in the present study we used the plasmodium berghei anka (pba) model of experimental cerebral malaria (cm) in c57bl/6 mice. after rescue from cm and parasite clearance, animals were submitted to a seizure susceptibility test (45 days after infection) using a low dose of pentylenetetrazol (ptz, 30 mg/kg) and monitored with use of behavioral and electroencephalography (eeg) methods. mice r ...201627247141
antimalarial benzoxaboroles target plasmodium falciparum leucyl-trna synthetase.there is a need for new antimalarials, ideally with novel mechanisms of action. benzoxaboroles have been shown to be active against bacteria, fungi, and trypanosomes. therefore, we investigated the antimalarial activity and mechanism of action of 3-aminomethyl benzoxaboroles against plasmodium falciparum two 3-aminomethyl compounds, an6426 and an8432, demonstrated good potency against cultured multidrug-resistant (w2 strain) p. falciparum (50% inhibitory concentration [ic50] of 310 nm and 490 nm ...201627270277
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 ...201627275010
ici 56,780 optimization: structure-activity relationship studies of 7-(2-phenoxyethoxy)-4(1h)-quinolones with antimalarial activity.though malaria mortality rates are down 48% globally since 2000, reported occurrences of resistance against current therapeutics threaten to reverse that progress. recently, antimalarials that were once considered unsuitable therapeutic agents have been revisited to improve physicochemical properties and efficacy required for selection as a drug candidate. one such compound is 4(1h)-quinolone ici 56,780, which is known to be a causal prophylactic that also displays blood schizonticidal activity ...201627291102
phyto suppression of plasmodium berghei multiplication by nauclea latifolia improves the indices of pancreatic beta cell function and anaemia in experimental mice.malaria remains one of the major causes of childhood mortality in many parts of the world, especially in the sub-saharan africa, including nigeria. increasing chemotherapeutic failure and side effects of available antimalarial drugs have promoted the use of natural herbs for the treatment of malaria in nigerian communities.201627295805
protective efficacy induced by genetically attenuated mid-to-late liver-stage arresting plasmodium berghei δmrp2 parasites.whole parasite immunization strategies employing genetically attenuated parasites (gap), which arrest during liver-stage development, have been applied successfully for induction of sterile malaria protection in rodents. recently, we generated a plasmodium berghei gap-lacking expression of multidrug resistance-associated protein (mrp2) (pbδmrp2) that was capable of partial schizogony in hepatocytes but showed complete growth arrest. here, we investigated the protective efficacy after intravenous ...201627296385
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 ...201627303037
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 ...201627311945
translational repression of the cpw-wpc gene family in the malaria parasite plasmodium.the technical challenges of working with the sexual stages of the malaria parasite plasmodium have hindered the characterization of sexual stage antigens in the quest for a successful malaria transmission-blocking vaccine. one such predicted and largely uncharacterized group of sexual stage candidate antigens is the cpw-wpc family of proteins. cpw-wpc proteins are named for a characteristic domain that contains two conserved motifs, cpxxw and wpc. conserved across apicomplexa, this family is als ...201627312996
plasmodium rab5b is secreted to the cytoplasmic face of the tubovesicular network in infected red blood cells together with n-acylated adenylate kinase 2.rab5 gtpase regulates membrane trafficking between the plasma membrane and endosomes and harbours a conserved c-terminal isoprenyl modification that is necessary for membrane recruitment. plasmodium falciparum encodes three rab5 isotypes, and one of these, rab5b (pfrab5b), lacks the c-terminal modification but possesses the n-terminal myristoylation motif. pfrab5b was reported to localize to the parasite periphery. however, the trafficking pathway regulated by pfrab5b is unknown.201627316546
antimalarial actions of lawsonia inermis, tithonia diversifolia and chromolaena odorata in combination.chromolaena odorata, tithonia diversifolia and lawsonia inermis are medicinal plants used in treating malaria in traditional medicine system. previous studies however showed that their dichloromethane, methanol (1:1) extracts were more active against plasmodium parasite than the aqueous extracts.201627321410
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 ...201627324409
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 ...027335321
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) ...201627353755
a stem cell strategy identifies glycophorin c as a major erythrocyte receptor for the rodent malaria parasite plasmodium berghei.the clinical complications of malaria are caused by the parasite expansion in the blood. invasion of erythrocytes is a complex process that depends on multiple receptor-ligand interactions. identification of host receptors is paramount for fighting the disease as it could reveal new intervention targets, but the enucleated nature of erythrocytes makes genetic approaches impossible and many receptors remain unknown. host-parasite interactions evolve rapidly and are therefore likely to be species- ...201627362409
methylene blue inhibits lumefantrine-resistant plasmodium berghei.chemotherapy still is the most effective way to control malaria, a major public health problem in sub-saharan africa. the large-scale use of the combination therapy artemether-lumefantrine for malaria treatment in africa predisposes lumefantrine to emergence of resistance. there is need to identify drugs that can be used as substitutes to lumefantrine for use in combination therapy. methylene blue, a synthetic anti-methemoglobinemia drug, has been shown to contain antimalarial properties, making ...201627367013
proteomic analysis of the plasmodium berghei gametocyte egressome and vesicular bioid of osmiophilic body proteins identifies merozoite trap-like protein (mtrap) as an essential factor for parasite transmission.malaria transmission from an infected host to the mosquito vector requires the uptake of intraerythrocytic sexual precursor cells into the mosquito midgut. for the release of mature extracellular gametes two membrane barriers-the parasite parasitophorous vacuole membrane and the host red blood cell membrane-need to be dissolved. membrane lysis occurs after the release of proteins from specialized secretory vesicles including osmiophilic bodies. in this study we conducted proteomic analyses of th ...201627371728
π-delocalized lipophilic cations as new candidates for antimalarial, antitrypanosomal and antileishmanial agents: synthesis, evaluation of antiprotozoal potency, and insight into their action mechanisms.the search for new drugs that could treat tropical protozoan diseases, such as malaria or neglected tropical diseases (ntds), motivates many medicinal chemists. new classes of antiprotozoal drugs that act through a novel mechanism of action must be developed. this review presents our efforts toward finding new candidate treatments for malaria, american trypanosomiasis, human african trypanosomiasis and leishmaniasis based on π-delocalized lipophilic cations (dlcs). dlcs, such as rhodacyanines, a ...201627373622
4-aminoquinoline derivatives: synthesis, in vitro and in vivo antiplasmodial activity against chloroquine-resistant parasites.synthetic quinoline derivatives continue to be considered as candidates for new drug discovery if they act against cq-resistant strains of malaria even after the widespread emergence of resistance to cq. in this study, we explored the activities of two series of new 4-aminoquinoline derivatives and found them to be effective against plasmodium falciparum under in vitro conditions. further, we selected four most active derivatives 1m, 1o, 2c and 2j and evaluated their antimalarial potential again ...201627394399
glut1-mediated glucose uptake plays a crucial role during plasmodium hepatic infection.intracellular pathogens have evolved mechanisms to ensure their survival and development inside their host cells. here, we show that glucose is a pivotal modulator of hepatic infection by the rodent malaria parasite plasmodium berghei and that glucose uptake via the glut1 transporter is specifically enhanced in p. berghei-infected cells. we further show that atp levels of cells containing developing parasites are decreased, which is known to enhance membrane glut1 activity. in addition, glut1 mo ...201727404888
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 ...201627409081
evaluation of the combination of uvaria chamae (p. beauv.) and amodiaquine in murine malaria.the leaf and fruit of uvaria chamae p. beauv (annonaceae) are used in antimalarial ethnomedical preparations. therefore, they were investigated for antimalarial activities as well as possible herb-drug interaction with amodiaquine (aq).201627416806
artemether-lumefantrine nanostructured lipid carriers for oral malaria therapy: enhanced efficacy at reduced dose and dosing frequency.artemether-lumefantrine (arm-lfn) is a world health organization (who) approved fixed-dose combination having low solubility and poor oral bioavailability. nanostructured lipid carriers (nlc) were developed to enhance the oral efficacy of this combination using the microemulsion template technique. they were characterized for drug content, entrapment efficiency, size distribution, in vitro release, antimalarial efficacy, and toxicity. the nlc showed sustained drug release. the recommended adult ...201627421912
invasion of hepatocytes by plasmodium sporozoites requires cgmp-dependent protein kinase and calcium dependent protein kinase 4.invasion of hepatocytes by sporozoites is essential for plasmodium to initiate infection of the mammalian host. the parasite's subsequent intracellular differentiation in the liver is the first developmental step of its mammalian cycle. despite their biological significance, surprisingly little is known of the signalling pathways required for sporozoite invasion. we report that sporozoite invasion of hepatocytes requires signalling through two second-messengers - cgmp mediated by the parasite's ...201627425827
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 ...201627427910
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 ...201627432939
chloroquine-containing organoruthenium complexes are fast-acting multistage antimalarial agents.we report the pharmacological activity of organoruthenium complexes containing chloroquine (cq) as a chelating ligand. the complexes displayed intraerythrocytic activity against cq-sensitive 3d7 and cq-resistant w2 strains of plasmodium falciparum, with potency and selectivity indexes similar to those of cq. complexes displayed activity against all intraerythrocytic stages, but moderate activity against plasmodium berghei liver stages. however, unlike cq, organoruthenium complexes impaired gamet ...201627439976
potential cerebral malaria therapy: intramuscular arteether and vitamin d co-administration.cerebral malaria (cm) shows lethality rate of 15-25% despite effective antimalarial chemotherapy. the effective adjunct treatment to counteract the cm pathogenesis is urgently required. in murine cm model, most interventions studied till date are administered before the onset of cm symptoms, which belittle its translational value to human. we studied intramuscular arteether-vitamin d (art-vd) combination treatment for cm outcome improvement after the onset of neurological symptoms. the intramusc ...201627440106
integrin αdβ2 (cd11d/cd18) mediates experimental malaria-associated acute respiratory distress syndrome (ma-ards).malaria-associated acute respiratory distress syndrome (ma-ards) is a potentially lethal complication of clinical malaria. acute lung injury in ma-ards shares features with ards triggered by other causes, including alveolar inflammation and increased alveolar-capillary permeability, leading to leak of protein-rich pulmonary oedema fluid. mechanisms and physiologic alterations in ma-ards can be examined in murine models of this syndrome. integrin αdβ2 is a member of the leukocyte, or β2 (cd18), s ...201627473068
cannabinoid receptor 2 modulates susceptibility to experimental cerebral malaria through a ccl17-dependent mechanism.cerebral malaria is a severe and often fatal complication of plasmodium falciparum infection. it is characterized by parasite sequestration, a breakdown of the blood-brain barrier, and a strong inflammation in the brain. we investigated the role of the cannabinoid receptor 2 (cb2), an important modulator of neuroinflammatory responses, in experimental cerebral malaria (ecm). strikingly, mice with a deletion of the cb2-encoding gene (cnr2(-/-)) inoculated with plasmodium berghei anka erythrocytes ...201627474745
tissue-resident cd169(+) macrophages form a crucial front line against plasmodium infection.tissue macrophages exhibit diverse functions, ranging from the maintenance of tissue homeostasis, including clearance of senescent erythrocytes and cell debris, to modulation of inflammation and immunity. their contribution to the control of blood-stage malaria remains unclear. here, we show that in the absence of tissue-resident cd169(+) macrophages, plasmodium berghei anka (pba) infection results in significantly increased parasite sequestration, leading to vascular occlusion and leakage and a ...201627477286
species-specific escape of plasmodium sporozoites from oocysts of avian, rodent, and human malarial parasites.malaria is transmitted when an infected mosquito delivers plasmodium sporozoites into a vertebrate host. there are many species of plasmodium and, in general, the infection is host-specific. for example, plasmodium gallinaceum is an avian parasite, while plasmodium berghei infects mice. these two parasites have been extensively used as experimental models of malaria transmission. plasmodium falciparum and plasmodium vivax are the most important agents of human malaria, a life-threatening disease ...201627480269
production of plasmodium vivax enolase in escherichia coli and its protective properties.plasmodium vivax predominates in south-east asia and the american continent, causes significant morbidity and inflicts a huge socioeconomic burden. sequencing completion of the plasmodium vivax genome and transcriptome provides the chance to identify antigens. enolase is the eighth enzyme in the glycolytic pathway, which, apart from its glycolytic function, also possess antigenic properties and is present on the cell wall of many invasive organisms, such as candida albicans. in order to assess w ...201627487171
antimalarial potential of leaves of chenopodium ambrosioides l.in an effort to identify novel therapeutic alternatives for the treatment of malaria, the present study evaluated the antimalarial effect of the crude hydroalcoholic extract (hce) from the leaves of chenopodium ambrosioides l. for this purpose, the molecular affinity between the total proteins from erythrocytes infected with plasmodium falciparum and hce or chloroquine was evaluated by surface plasmon resonance (spr). subsequently, the plasmodicidal potential of hce was assessed in a p. falcipar ...201627492200
4, 5-dihydrooxazole-pyrazoline hybrids: synthesis and their evaluation as potential antimalarial agents.a new series of oxazoline-pyrazoline hybrids (4a-p) were synthesized by condensation reaction of substituted oxazoline based chalcones (3a-m) and substituted hydrazines in methanol. some of the compounds exhibited promising in vitro antimalarial activity for chloroquine sensitive cq(s) (3d7) strain and chloroquine resistant cq(r) (rkl9) strain. the most potent analogue 4i (ic50 0.322 μg/ml) exhibited significant in vivo antimalarial potential against plasmodium berghei mouse model. the stable co ...201627494165
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 ...201627502569
a suggested vital function for eif-5a and dhs genes during murine malaria blood-stage infection.the biological function of the post-translational modification hypusine in the eukaryotic initiation factor 5a (eif-5a) in eukaryotes is still not understood. hypusine is formed by two sequential enzymatic steps at a specific lysine residue in the precursor protein eif-5a. one important biological function of eif-5a which was recently identified is the translation of polyproline-rich mrna, suggesting its biological relevance in a variety of biological processes. hypusinated eif-5a controls the p ...201627516964
cytochrome c and c1 heme lyases are essential in plasmodium berghei.malaria parasites possess a de novo heme synthetic pathway. interestingly, this pathway is dispensable during the blood stages of development in mammalian hosts. the assembly of the two most important hemeproteins, cytochromes c and c1, is mediated by cytochrome heme lyase enzymes. plasmodium spp. possess two cytochrome heme lyases encoded by separate genes. given the redundancy of heme synthesis, we sought to determine if heme lyase function also exhibits redundancy. to answer this question, we ...201627520480
tacrolimus prevents murine cerebral malaria.tacrolimus and mycophenolate mofetil are immunosuppressants frequently used in human organ transplantation. tacrolimus is also reported to inhibit plasmodium falciparum growth in vitro. here, we report that tacrolimus prevented the death from cerebral malaria of plasmodium berghei anka-infected c57bl/6j mice, but not their death from malaria due to the high parasitaemia and severe anaemia. the mycophenolate mofetil-treated mice showed higher mortality from cerebral malaria and succumbed to malar ...201727546479
functional genomic analyses of enterobacter, anopheles and plasmodium reciprocal interactions that impact vector competence.malaria exerts a tremendous socioeconomic impact worldwide despite current control efforts, and novel disease transmission-blocking strategies are urgently needed. the enterobacter bacterium esp_z, which is naturally harboured in the mosquito midgut, can inhibit the development of plasmodium parasites prior to their invasion of the midgut epithelium through a mechanism that involves oxidative stress. here, a multifaceted approach is used to study the tripartite interactions between the mosquito, ...201627549662
glucagon-like peptide-1 analogue, liraglutide, in experimental cerebral malaria: implications for the role of oxidative stress in cerebral malaria.cerebral malaria from plasmodium falciparum infection is major cause of death in the tropics. the pathogenesis of the disease is complex and the contribution of reactive oxygen and nitrogen species (ros/rns) in the brain is incompletely understood. insulinotropic glucagon-like peptide-1 (glp-1) mimetics have potent neuroprotective effects in animal models of neuropathology associated with ros/rns dysfunction. this study investigates the effect of the glp-1 analogue, liraglutide against the clini ...201627554094
blockage of galectin-receptor interactions by α-lactose exacerbates plasmodium berghei-induced pulmonary immunopathology.malaria-associated acute lung injury (ali) is a frequent complication of severe malaria that is often caused by "excessive" immune responses. to better understand the mechanism of ali in malaria infection, here we investigated the roles of galectin (gal)-1, 3, 8, 9 and the receptors of gal-9 (tim-3, cd44, cd137, and pdi) in malaria-induced ali. we injected alpha (α)-lactose into mice-infected with plasmodium berghei anka (pbanka) to block galectins and found significantly elevated total proteins ...201627554340
antiprotozoal screening of the cuban native plant scutellaria havanensis.scutellaria havanensis jacq. (lamiaceae) is a native medicinal herb with a history of use in cuba.201627564587
high resolution microscopy reveals an unusual architecture of the plasmodium berghei endoplasmic reticulum.to fuel the tremendously fast replication of plasmodium liver stage parasites, the endoplasmic reticulum (er) must play a critical role as a major site of protein and lipid biosynthesis. in this study, we analysed the parasite's er morphology and function. previous studies exploring the parasite er have mainly focused on the blood stage. visualizing the plasmodium berghei er during liver stage development, we found that the er forms an interconnected network throughout the parasite with perinucl ...201627566438
establishment of a murine model of cerebral malaria in kunming mice infected with plasmodium berghei anka.malaria remains one of the most devastating diseases. cerebral malaria (cm) is a severe complication of plasmodium falciparum infection resulting in high mortality and morbidity worldwide. analysis of precise mechanisms of cm in humans is difficult for ethical reasons and animal models of cm have been employed to study malaria pathogenesis. here, we describe a new experimental cerebral malaria (ecm) model with plasmodium berghei anka infection in kunming (km) mice. km mice developed ecm after bl ...201627574013
spect/ct analysis of splenic function in genistein-treated malaria-infected mice.spleen traps malaria-infected red blood cells, thereby leading to splenomegaly. splenomegaly induces impairment in splenic function, i.e., rupture. therefore, splenomegaly inhibition is required to protect the spleen. in our previous study, genistein was found to have an influence on malaria-induced splenomegaly. however, the effect of genistein in malaria-induced splenomegaly, especially on the function of spleen, has not been fully investigated. in this study, hematoxylin and eosin (h&e) stain ...201627585499
nanostructured lipid carriers of artemether-lumefantrine combination for intravenous therapy of cerebral malaria.patients with cerebral malaria (cm) are unable to take oral medication due to impaired consciousness and vomiting thus necessitating parenteral therapy. quinine, artemether, and artesunate which are currently used for parenteral malaria therapy have their own drawbacks. the world health organization (who) has now banned monotherapy and recommends artemisinin-based combination therapy for malaria treatment. however, presently there is no intravenous formulation available for combination therapy o ...201627596113
ex vivo maturation assay for testing antimalarial sensitivity of rodent malaria parasites.ex vivo assay systems provide a powerful approach to studying human malaria parasite biology and to testing antimalarials. for rodent malaria parasites, short-term in vitro culture and ex vivo antimalarial susceptibility assays are relatively cumbersome, relying on in vivo passage for synchronization, since ring-stage parasites are an essential starting material. here, we describe a new approach based on the enrichment of ring-stage plasmodium berghei, p. yoelii, and p. vinckei vinckei using a s ...201627600050
distinct prominent roles for enzymes of plasmodium berghei heme biosynthesis in sporozoite and liver stage maturation.malarial parasites have evolved complex regulation of heme supply and disposal to adjust to heme-rich and -deprived host environments. in addition to its own pathway for heme biosynthesis, plasmodium likely harbors mechanisms for heme scavenging from host erythrocytes. elaborate compartmentalization of de novo heme synthesis into three subcellular locations, including the vestigial plastid organelle, indicates critical roles in life cycle progression. in this study, we systematically profile the ...201627600503
asiatic acid influences parasitaemia reduction and ameliorates malaria anaemia in p. berghei infected sprague-dawley male rats.current malaria treatment is either "anti-parasitic", "anti-infectivity" or both without addressing the pathophysiological derangement (anti-disease aspect) associated with the disease. asiatic acid is a natural phytochemical with oxidant, antioxidant and anti-inflammatory properties whose effect on malarial and accompanying pathophysiology are yet to be investigated. asiatic acid influence in p. berghei-infected sprague dawley rats on %parasitaemia and malarial anaemia were investigated.201627618936
t-cell immunoglobulin- and mucin-domain-containing molecule 3 signaling blockade improves cell-mediated immunity against malaria.cell-mediated immune responses play important roles in immune protection against plasmodium infection. however, impaired immunity, such as lymphocyte exhaustion, is a common phenomenon in malaria. t-cell immunoglobulin- and mucin-domain-containing molecule 3 (tim-3) is an important regulatory molecule in cell-mediated immunity and has been implicated in malaria. in this study, it was found that tim-3 expression on key populations of lymphocytes was significantly increased in both plasmodium falc ...201627638944
endothelin-1 treatment induces an experimental cerebral malaria-like syndrome in c57bl/6 mice infected with plasmodium berghei nk65.plasmodium berghei anka infection of c57bl/6 mice is a widely used model of experimental cerebral malaria (ecm). by contrast, the nonneurotropic p. berghei nk65 (pbn) causes severe malarial disease in c57bl/6 mice but does not cause ecm. previous studies suggest that endothelin-1 (et-1) contributes to the pathogenesis of ecm. in this study, we characterize the role of et-1 on ecm vascular dysfunction. mice infected with 10(6) pbn-parasitized red blood cells were treated with either et-1 or salin ...201627640146
tetrahydrobiopterin supplementation improves phenylalanine metabolism in a murine model of severe malaria.tetrahydrobiopterin (bh4) is an essential cofactor for both phenylalanine hydroxylase and nitric oxide synthase. patients with severe malaria have low urinary bh4, elevated plasma phenylalanine, and impaired endothelium-dependent vasodilation, suggesting that bh4 depletion may limit phenylalanine metabolism and nitric oxide synthesis. we infected c57bl/6 mice with plasmodium berghei anka to characterize bh4 availability and to investigate the effects of bh4 supplementation. p. berghei anka infec ...201627641435
transmission blocking effects of neem (azadirachta indica) seed kernel limonoids on plasmodium berghei early sporogonic development.azadirachta indica, known as neem tree and traditionally called "nature's drug store" makes part of several african pharmacopeias and is widely used for the preparation of homemade remedies and commercial preparations against various illnesses, including malaria. employing a bio-guided fractionation approach, molecules obtained from a. indica ripe and green fruit kernels were tested for activity against early sporogonic stages of plasmodium berghei, the parasite stages that develop in the mosqui ...201627642038
udp-galactose and acetyl-coa transporters as plasmodium multidrug resistance genes.a molecular understanding of drug resistance mechanisms enables surveillance of the effectiveness of new antimicrobial therapies during development and deployment in the field. we used conventional drug resistance selection as well as a regime of limiting dilution at early stages of drug treatment to probe two antimalarial imidazolopiperazines, kaf156 and gnf179. the latter approach permits the isolation of low-fitness mutants that might otherwise be out-competed during selection. whole-genome s ...201627642791
natural products from zanthoxylum heitzii with potent activity against the malaria parasite.zanthoxylum heitzii (rutaceae) (olon) is used in traditional medicine in central and west africa to treat malaria. to identify novel compounds with anti-parasitic activity and validate medicinal usage, extracts and compounds isolated from this tree were tested against the erythrocytic stages of the human malaria parasite plasmodium falciparum and for inhibition of transmission in rodent malaria parasite plasmodium berghei.201627649682
erythroferrone contributes to hepcidin repression in a mouse model of malarial anemia.malaria, a major global health challenge worldwide, is accompanied by a severe anemia secondary to hemolysis and increased erythrophagocytosis. iron is an essential functional component of erythrocyte hemoglobin and its availability is controlled by the liver-derived hormone hepcidin. we examined the regulation of hepcidin during malarial infection in mice using the rodent parasite plasmodium berghei k173. mice infected with plasmodium berghei k173 develop a severe anemia and die after 18 to 22 ...201727658439
the evolutionary divergence of stat transcription factor in different anopheles species.anopheles mosquito transmits plasmodium, the malaria causing parasite. different species of anopheles mosquito dominate in a particular geographical location and are capable of transmitting specific strains of plasmodium. it is important to understand the biology of different anophelines to control the parasite transmission. stat is an evolutionary conserved transcription factor that regulates the parasite development in african malaria vector anopheles gambiae. unlike drosophila and aedes aegyp ...201727664587
conjugation of n-acylhydrazone and 1,2,4-oxadiazole leads to the identification of active antimalarial agents.malaria, caused by several plasmodium species, is the major life-threatening parasitic infection worldwide. due to the parasite resistance to quinoline based drugs, the search for antimalarial agents is necessary. here, we report the structural design, synthesis and antiparasitic evaluation of two novel series of 1,2,4-oxadiazoles in conjugation to n-acylhydrazones, both groups recognized as privileged structures, as well as the studies on the antimalarial activity of 16 previous described analo ...201627667552
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 ...201627693349
uptake of parasite-derived vesicles by astrocytes and microglial phagocytosis of infected erythrocytes may drive neuroinflammation in cerebral malaria.astrocytes and microglia are activated during cerebral malaria (cm) and contribute to the production and release of several mediators during neuroinflammatory processes. whether these changes are the consequence of a direct crosstalk between glial cells and the malarial parasite and how these cells participate in the pathogenesis of cm is not yet clear. we therefore examined the interaction of astrocytes and microglia with plasmodium berghei anka-infected red blood cells using primary cell cultu ...201727696532
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 ...201627701420
usp15 regulates type i interferon response and is required for pathogenesis of neuroinflammation.genes and pathways in which inactivation dampens tissue inflammation present new opportunities for understanding the pathogenesis of common human inflammatory diseases, including inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis. we identified a mutation in the gene encoding the deubiquitination enzyme usp15 (usp15(l749r)) that protected mice against both experimental cerebral malaria (ecm) induced by plasmodium berghei and experimental autoimmune encephalomyelitis (eae). c ...201727721430
transient expression of plasmodium berghei msp8 and hap2 in the marine protozoan parasite perkinsus marinus.perkinsus marinus is a protozoan parasite of molluscs that can be propagated in vitro in a defined culture medium, in the absence of host cells. we previously reported that p. marinus trophozoites can be transfected with high efficiency by electroporation using a plasmid based on moe, a highly expressed gene, and proposed its potential use as a "pseudoparasite." this is a novel gene expression platform for parasites of medical relevance for which the choice of the surrogate organism is based on ...201727723436
infection with plasmodium berghei ookinetes alters protein expression in the brain of anopheles albimanus mosquitoes.the behaviour of anopheles spp. mosquitoes, vectors for plasmodium parasites, plays a crucial role in the propagation of malaria to humans. consequently, it is important to understand how the behaviour of these mosquitoes is influenced by the interaction between the brain and immunological status. the nervous system is intimately linked to the immune and endocrine systems. there is evidence that the malaria parasite alters the function of these systems upon infecting the mosquito. although there ...201627724938
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