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1
HANADA, Kentaro, Toshihide MITAMURA, Masayoshi FUKASAWA, Pamela A. MAGISTRADO, Toshihiro HORII e Masahiro NISHIJIMA. "Neutral sphingomyelinase activity dependent on Mg2+ and anionic phospholipids in the intraerythrocytic malaria parasite Plasmodium falciparum". Biochemical Journal 346, n. 3 (7 marzo 2000): 671–77. http://dx.doi.org/10.1042/bj3460671.
Testo completoAbstract (sommario):
Sphingolipid metabolism and metabolites are important in various cellular events in eukaryotes. However, little is known about their function in plasmodial parasites. Here we demonstrate that neutral sphingomyelinase (SMase) involved in the sphingomyelin (SM) catabolism is retained by the intraerythrocytic parasite Plasmodium falciparum. When assayed in a neutral pH buffer supplemented with Mg2+ and phosphatidylserine, an activity for the release of the phosphocholine group from SM was detected in parasite-infected, but not in uninfected, erythrocyte ghosts. The SMase activity in the parasite-infected erythrocyte ghosts was enhanced markedly by anionic phospholipids including unsaturated but not saturated phosphatidylserine. Mn2+ could not substitute for Mg2+ to activate SMase in parasite-infected erythrocyte ghosts, whereas both Mn2+ and Mg2+ activated mammalian neutral SMase. The specific activity level of SMase was higher in isolated parasites than in infected erythrocyte ghosts; further fractionation of lysates of the isolated parasites showed that the activity was bound largely to the membrane fraction of the parasites. The plasmodial SMase seemed not to hydrolyse phosphatidylcholine or phosphatidylinositol. The plasmodial SMase, but not SM synthase, was sensitive to scyphostatin, an inhibitor of mammalian neutral SMase, indicating that the plasmodial activities for SM hydrolysis and SM synthesis are mediated by different catalysts. Our finding that the malaria parasites possess SMase activity might explain why the parasites seem to have an SM synthase activity but no activity to synthesize ceramide de novo.
2
Sá e Cunha, Cláudia, Britta Nyboer, Kirsten Heiss, Margarida Sanches-Vaz, Diana Fontinha, Ellen Wiedtke, Dirk Grimm et al. "Plasmodium berghei EXP-1 interacts with host Apolipoprotein H during Plasmodium liver-stage development". Proceedings of the National Academy of Sciences 114, n. 7 (30 gennaio 2017): E1138—E1147. http://dx.doi.org/10.1073/pnas.1606419114.
Testo completoAbstract (sommario):
The first, obligatory replication phase of malaria parasite infections is characterized by rapid expansion and differentiation of single parasites in liver cells, resulting in the formation and release of thousands of invasive merozoites into the bloodstream. Hepatic Plasmodium development occurs inside a specialized membranous compartment termed the parasitophorous vacuole (PV). Here, we show that, during the parasite’s hepatic replication, the C-terminal region of the parasitic PV membrane protein exported protein 1 (EXP-1) binds to host Apolipoprotein H (ApoH) and that this molecular interaction plays a pivotal role for successful Plasmodium liver-stage development. Expression of a truncated EXP-1 protein, missing the specific ApoH interaction site, or down-regulation of ApoH expression in either hepatic cells or mouse livers by RNA interference resulted in impaired intrahepatic development. Furthermore, infection of mice with sporozoites expressing a truncated version of EXP-1 resulted in both a significant reduction of liver burden and delayed blood-stage patency, leading to a disease outcome different from that generally induced by infection with wild-type parasites. This study identifies a host–parasite protein interaction during the hepatic stage of infection by Plasmodium parasites. The identification of such vital interactions may hold potential toward the development of novel malaria prevention strategies.
3
Kalanon, Ming, e Geoffrey I. McFadden. "Malaria, Plasmodium falciparum and its apicoplast". Biochemical Society Transactions 38, n. 3 (24 maggio 2010): 775–82. http://dx.doi.org/10.1042/bst0380775.
Testo completoAbstract (sommario):
Malaria, which is caused by species of the parasite genus Plasmodium, remains a major global health problem. A vestigial plastid homologous with the chloroplasts of plants and algae was discovered in malaria and related parasites from the phylum Apicomplexa and has radically changed our view of the evolutionary origins of these disease-causing protists. We now recognize that this large group of parasites had a photosynthetic ancestry and were converted into parasitism early in the evolution of animals. Apicomplexans have probably been parasitizing the animal kingdom for more than 500 million years. The relic plastid persists in most apicomplexans and is an essential component. Perturbation of apicoplast function or inheritance results in parasite death, making the organelle a promising target for chemotherapy. Plastids, including those of malaria parasites, are essentially reduced endosymbiotic bacteria living inside a eukaryotic host. This means that plastids have bacterial-type metabolic pathways and housekeeping processes, all of which are vulnerable to antibacterial compounds. Indeed, many antibacterials kill malaria parasites by blocking essential processes in the plastid. Furthermore, a range of herbicides that target plastid metabolism of undesired plants are also parasiticidal, making them potential new leads for antimalarial drugs. In the present review, we examine the evolutionary origins of the malaria parasite's plastid by endosymbiosis and outline the recent findings on how the organelle imports nuclear-encoded proteins through a set of translocation machineries in the membranes that bound the organelle.
4
Tewari, Rita, Solabomi A. Ogun, Ruwani S. Gunaratne, Andrea Crisanti e Anthony A. Holder. "Disruption of Plasmodium berghei merozoite surface protein 7 gene modulates parasite growth in vivo". Blood 105, n. 1 (1 gennaio 2005): 394–96. http://dx.doi.org/10.1182/blood-2004-06-2106.
Testo completoAbstract (sommario):
Abstract Merozoite invasion of red blood cells is crucial to the development of the parasite that causes malaria. Merozoite surface proteins (MSPs) mediate the first interaction between parasite and erythrocyte. In Plasmodium falciparum, they include a complex of products from at least 3 genes (msp1, msp6, and msp7), one of which, msp7, is part of a gene family containing 3 and 6 adjacent members in Plasmodium yoelii and Plasmodium falciparum, respectively. We have identified and disrupted msp7 in the Plasmodium berghei gene family. The protein is expressed in schizonts and colocalizes with MSP1. The synthesis and processing of MSP1 was unaffected in the parasite with the disrupted gene (MSP7ko). Disruption of msp7 was not lethal but affected blood-stage parasite growth. MSP7ko parasites initially grew more slowly than wild-type parasites. However, when reticulocytes were prevalent, the rate of increase in parasitemia was similar, suggesting that MSP7ko parasites prefer to invade and grow within reticulocytes. (Blood. 2005;105:394-396)
5
Morgan, D. M. L., U. Bachrach, Y. G. Assaraf, E. Harari e J. Golenser. "The effect of purified aminoaldehydes produced by polyamine oxidation on the development in vitro of Plasmodium falciparum in normal and glucose-6-phosphate-dehydrogenase-deficient erythrocytes". Biochemical Journal 236, n. 1 (15 maggio 1986): 97–101. http://dx.doi.org/10.1042/bj2360097.
Testo completoAbstract (sommario):
Purified aminoaldehydes produced by polyamine oxidation were toxic to the malarial parasite, Plasmodium falciparum, cultured in human erythrocytes. There was a profound effect on young ring forms, and, during maturation, parasites became more sensitive to the aldehydes. Oxidation of the aldehydes abolished the lethal effect. The plasmodia within glucose-6-phosphate-dehydrogenase (G6PD)-deficient erythrocytes were more sensitive to mono- and di-aldehydes than were parasites in normal erythrocytes. G6PD-deficient erythrocytes were also more sensitive to pretreatment with the dialdehyde produced by the oxidation of spermine. Pretreatment prevented further invasion by the parasites.
6
Gutiérrez-López, Rafael, Josué Martínez-de la Puente, Laura Gangoso, Ramón Soriguer e Jordi Figuerola. "Plasmodium transmission differs between mosquito species and parasite lineages". Parasitology 147, n. 4 (22 gennaio 2020): 441–47. http://dx.doi.org/10.1017/s0031182020000062.
Testo completoAbstract (sommario):
AbstractFactors such as the particular combination of parasite–mosquito species, their co-evolutionary history and the host's parasite load greatly affect parasite transmission. However, the importance of these factors in the epidemiology of mosquito-borne parasites, such as avian malaria parasites, is largely unknown. Here, we assessed the competence of two mosquito species [Culex pipiens and Aedes (Ochlerotatus) caspius], for the transmission of four avian Plasmodium lineages (Plasmodium relictum SGS1 and GRW11 and Plasmodium cathemerium-related lineages COLL1 and PADOM01) naturally infecting wild house sparrows. We assessed the effects of parasite identity and parasite load on Plasmodium transmission risk through its effects on the transmission rate and mosquito survival. We found that Cx. pipiens was able to transmit the four Plasmodium lineages, while Ae. caspius was unable to transmit any of them. However, Cx. pipiens mosquitoes fed on birds infected by P. relictum showed a lower survival and transmission rate than those fed on birds infected by parasites related to P. cathemerium. Non-significant associations were found with the host–parasite load. Our results confirm the existence of inter- and intra-specific differences in the ability of Plasmodium lineages to develop in mosquito species and their effects on the survival of mosquitoes that result in important differences in the transmission risk of the different avian malaria parasite lineages studied.
7
Mirzaei, Farzaneh, Abolghasem Siyadatpanah, Roghayeh Norouzi, Soheila Pournasir, Veeranoot Nissapatorn e Maria de Lourdes Pereira. "Blood Parasites in Domestic Birds in Central Iran". Veterinary Sciences 7, n. 3 (4 settembre 2020): 126. http://dx.doi.org/10.3390/vetsci7030126.
Testo completoAbstract (sommario):
Parasites may affect the dynamics of bird populations. Plasmodium, Leucocytozoon and Haemoproteus are well-known avian haematozoa that can trigger decreased productivity and high mortality in domesticated birds. In this study, we evaluated the prevalence of avian blood parasites (Plasmodium, Leucocytozoon and Haemoproteus) against 335 birds of 8 species in the Yazd province in central Iran. To detect blood parasites, Giemsa-stained blood smears were prepared. Of the birds, 11.64% (39/335) were infected with at least one parasite genus, particularly Haemoproteus (32.6%; 23/335). The total prevalence values for Plasmodium, Haemoproteus and Leucocytozoon were 1.7, 6.8 and 2.9%, respectively. Plasmodium had lower prevalence rates of 1.7% (6/335). Among birds, pigeons, hens and ducks have the highest prevalence of Haemoproteus, Leucocytozoon and Plasmodium parasites at 1.7%, 6.8% and 2.9%, respectively. Results from this research extend our knowledge on the incidence of avian blood parasites in domesticated birds living in central Iran. The overall low incidence of avian blood parasites in birds was found in the Yazd province, Iran.
8
Tebben, Kieran, Salif Yirampo, Drissa Coulibaly, Abdoulaye K. Koné, Matthew B. Laurens, Emily M. Stucke, Ahmadou Dembélé et al. "Malian children infected with Plasmodium ovale and Plasmodium falciparum display very similar gene expression profiles". PLOS Neglected Tropical Diseases 17, n. 1 (25 gennaio 2023): e0010802. http://dx.doi.org/10.1371/journal.pntd.0010802.
Testo completoAbstract (sommario):
Plasmodium parasites caused 241 million cases of malaria and over 600,000 deaths in 2020. Both P. falciparum and P. ovale are endemic to Mali and cause clinical malaria, with P. falciparum infections typically being more severe. Here, we sequenced RNA from nine pediatric blood samples collected during infections with either P. falciparum or P. ovale, and characterized the host and parasite gene expression profiles. We found that human gene expression varies more between individuals than according to the parasite species causing the infection, while parasite gene expression profiles cluster by species. Additionally, we characterized DNA polymorphisms of the parasites directly from the RNA-seq reads and found comparable levels of genetic diversity in both species, despite dramatic differences in prevalence. Our results provide unique insights into host-pathogen interactions during malaria infections and their variations according to the infecting Plasmodium species, which will be critical to develop better elimination strategies against all human Plasmodium parasites.
9
Matz, Joachim M., Alyssa Ingmundson, Jean Costa Nunes, Werner Stenzel, Kai Matuschewski e Taco W. A. Kooij. "In Vivo Function of PTEX88 in Malaria Parasite Sequestration and Virulence". Eukaryotic Cell 14, n. 6 (27 marzo 2015): 528–34. http://dx.doi.org/10.1128/ec.00276-14.
Testo completoAbstract (sommario):
ABSTRACT Malaria pathology is linked to remodeling of red blood cells by eukaryotic Plasmodium parasites. Central to host cell refurbishment is the trafficking of parasite-encoded virulence factors through the Plasmodium translocon of exported proteins (PTEX). Much of our understanding of its function is based on experimental work with cultured Plasmodium falciparum , yet direct consequences of PTEX impairment during an infection remain poorly defined. Using the murine malaria model parasite Plasmodium berghei , it is shown here that efficient sequestration to the pulmonary, adipose, and brain tissue vasculature is dependent on the PTEX components thioredoxin 2 (TRX2) and PTEX88. While TRX2 -deficient parasites remain virulent, PTEX88 -deficient parasites no longer sequester in the brain, correlating with abolishment of cerebral complications in infected mice. However, an apparent trade-off for virulence attenuation was spleen enlargement, which correlates with a strongly reduced schizont-to-ring-stage transition. Strikingly, general protein export is unaffected in PTEX88 -deficient mutants that mature normally in vitro . Thus, PTEX88 is pivotal for tissue sequestration in vivo , parasite virulence, and preventing exacerbation of spleen pathology, but these functions do not correlate with general protein export to the host erythrocyte. The presented data suggest that the protein export machinery of Plasmodium parasites and their underlying mechanistic features are considerably more complex than previously anticipated and indicate challenges for targeted intervention strategies.
10
Kassim, Yasmin M., Feng Yang, Hang Yu, Richard J. Maude e Stefan Jaeger. "Diagnosing Malaria Patients with Plasmodium falciparum and vivax Using Deep Learning for Thick Smear Images". Diagnostics 11, n. 11 (27 ottobre 2021): 1994. http://dx.doi.org/10.3390/diagnostics11111994.
Testo completoAbstract (sommario):
We propose a new framework, PlasmodiumVF-Net, to analyze thick smear microscopy images for a malaria diagnosis on both image and patient-level. Our framework detects whether a patient is infected, and in case of a malarial infection, reports whether the patient is infected by Plasmodium falciparum or Plasmodium vivax. PlasmodiumVF-Net first detects candidates for Plasmodium parasites using a Mask Regional-Convolutional Neural Network (Mask R-CNN), filters out false positives using a ResNet50 classifier, and then follows a new approach to recognize parasite species based on a score obtained from the number of detected patches and their aggregated probabilities for all of the patient images. Reporting a patient-level decision is highly challenging, and therefore reported less often in the literature, due to the small size of detected parasites, the similarity to staining artifacts, the similarity of species in different development stages, and illumination or color variations on patient-level. We use a manually annotated dataset consisting of 350 patients, with about 6000 images, which we make publicly available together with this manuscript. Our framework achieves an overall accuracy above 90% on image and patient-level.
11
Wünsch, Stefan, Cecilia P. Sanchez, Michael Gekle, Lars Große-Wortmann, Jochen Wiesner e Michael Lanzer. "Differential Stimulation of the Na+/H+ Exchanger Determines Chloroquine Uptake in Plasmodium falciparum". Journal of Cell Biology 140, n. 2 (26 gennaio 1998): 335–45. http://dx.doi.org/10.1083/jcb.140.2.335.
Testo completoAbstract (sommario):
Here we describe the identification and characterization of a physiological marker that is associated with the chloroquine-resistant (CQR) phenotype in the human malarial parasite Plasmodium falciparum. Single cell in vivo pH measurements revealed that CQR parasites consistently have an elevated cytoplasmic pH compared to that of chloroquine-sensitive (CQS) parasites because of a constitutively activated Na+/H+ exchanger (NHE). Together, biochemical and physiological data suggest that chloroquine activates the plasmodial NHE of CQS parasites, resulting in a transitory phase of rapid sodium/hydrogen ion exchange during which chloroquine is taken up by this protein. The constitutively stimulated NHE of CQR parasites are capable of little or no further activation by chloroquine. We propose that the inability of chloroquine to stimulate its own uptake through the constitutively activated NHE of resistant parasites constitutes a minimal and necessary event in the generation of the chloroquine-resistant phenotype.
12
Fontinha, Diana, Isabel Moules e Miguel Prudêncio. "Repurposing Drugs to Fight Hepatic Malaria Parasites". Molecules 25, n. 15 (28 luglio 2020): 3409. http://dx.doi.org/10.3390/molecules25153409.
Testo completoAbstract (sommario):
Malaria remains one of the most prevalent infectious diseases worldwide, primarily affecting some of the most vulnerable populations around the globe. Despite achievements in the treatment of this devastating disease, there is still an urgent need for the discovery of new drugs that tackle infection by Plasmodium parasites. However, de novo drug development is a costly and time-consuming process. An alternative strategy is to evaluate the anti-plasmodial activity of compounds that are already approved for other purposes, an approach known as drug repurposing. Here, we will review efforts to assess the anti-plasmodial activity of existing drugs, with an emphasis on the obligatory and clinically silent liver stage of infection. We will also review the current knowledge on the classes of compounds that might be therapeutically relevant against Plasmodium in the context of other communicable diseases that are prevalent in regions where malaria is endemic. Repositioning existing compounds may constitute a faster solution to the current gap of prophylactic and therapeutic drugs that act on Plasmodium parasites, overall contributing to the global effort of malaria eradication.
13
Galinski, Mary R. "Functional genomics of simian malaria parasites and host–parasite interactions". Briefings in Functional Genomics 18, n. 5 (26 giugno 2019): 270–80. http://dx.doi.org/10.1093/bfgp/elz013.
Testo completoAbstract (sommario):
AbstractTwo simian malaria parasite species, Plasmodium knowlesi and Plasmodium cynomolgi, cause zoonotic infections in Southeast Asia, and they have therefore gained recognition among scientists and public health officials. Notwithstanding, these species and others including Plasmodium coatneyi have served for decades as sources of knowledge on the biology, genetics and evolution of Plasmodium, and the diverse ramifications and outcomes of malaria in their monkey hosts. Experimental analysis of these species can help to fill gaps in knowledge beyond what may be possible studying the human malaria parasites or rodent parasite species. The genome sequences for these simian malaria parasite species were reported during the last decade, and functional genomics research has since been pursued. Here research on the functional genomics analysis involving these species is summarized and their importance is stressed, particularly for understanding host–parasite interactions, and potentially testing novel interventions. Importantly, while Plasmodium falciparum and Plasmodium vivax can be studied in small New World monkeys, the simian malaria parasites can be studied more effectively in the larger Old World monkey macaque hosts, which are more closely related to humans. In addition to ex vivo analyses, experimental scenarios can include passage through Anopheline mosquito hosts and longitudinal infections in monkeys to study acute and chronic infections, as well as relapses, all in the context of the in vivo host environment. Such experiments provide opportunities for understanding functional genomic elements that govern host–parasite interactions, immunity and pathogenesis in-depth, addressing hypotheses not possible from in vitro cultures or cross-sectional clinical studies with humans.
14
Smith, Lauren M., Francis C. Motta, Garima Chopra, J. Kathleen Moch, Robert R. Nerem, Bree Cummins, Kimberly E. Roche et al. "An intrinsic oscillator drives the blood stage cycle of the malaria parasite Plasmodium falciparum". Science 368, n. 6492 (14 maggio 2020): 754–59. http://dx.doi.org/10.1126/science.aba4357.
Testo completoAbstract (sommario):
The blood stage of the infection of the malaria parasite Plasmodium falciparum exhibits a 48-hour developmental cycle that culminates in the synchronous release of parasites from red blood cells, which triggers 48-hour fever cycles in the host. This cycle could be driven extrinsically by host circadian processes or by a parasite-intrinsic oscillator. To distinguish between these hypotheses, we examine the P. falciparum cycle in an in vitro culture system and show that the parasite has molecular signatures associated with circadian and cell cycle oscillators. Each of the four strains examined has a different period, which indicates strain-intrinsic period control. Finally, we demonstrate that parasites have low cell-to-cell variance in cycle period, on par with a circadian oscillator. We conclude that an intrinsic oscillator maintains Plasmodium’s rhythmic life cycle.
15
ISHTIAQ, FARAH, JON S. BEADELL, BEN H.WARREN e ROBERT C. FLEISCHER. "Diversity and distribution of avian haematozoan parasites in the western Indian Ocean region: a molecular survey". Parasitology 139, n. 2 (11 novembre 2011): 221–31. http://dx.doi.org/10.1017/s0031182011001831.
Testo completoAbstract (sommario):
SUMMARYThe genetic diversity of haematozoan parasites in island avifauna has only recently begun to be explored, despite the potential insight that these data can provide into the history of association between hosts and parasites and the possible threat posed to island endemics. We used mitochondrial DNA sequencing to characterize the diversity of 2 genera of vector-mediated parasites (Plasmodium and Haemoproteus) in avian blood samples from the western Indian Ocean region and explored their relationship with parasites from continental Africa. We detected infections in 68 out of 150 (45 3%) individuals and cytochrome b sequences identified 9 genetically distinct lineages of Plasmodium spp. and 7 lineages of Haemoproteus spp. We found considerable heterogeneity in parasite lineage composition across islands, although limited sampling may, in part, be responsible for perceived differences. Two lineages of Plasmodium spp. and 2 lineages of Haemoproteus spp. were shared by hosts in the Indian Ocean and also on mainland Africa, suggesting that these lineages may have arrived relatively recently. Polyphyly of island parasites indicated that these parasites were unlikely to constitute an endemic radiation and instead probably represent multiple colonization events. This study represents the first molecular survey of vector-mediated parasites in the western Indian Ocean, and has uncovered a diversity of parasites. Full understanding of parasite community composition and possible threats to endemic avian hosts will require comprehensive surveys across the avifauna of this region.
16
Simão-Gurge, Raquel M., Neha Thakre, Jessica Strickland, Jun Isoe, Lillian R. Delacruz, Brandi K. Torrevillas, Anna M. Rodriguez, Michael A. Riehle e Shirley Luckhart. "Activation of Anopheles stephensi Pantothenate Kinase and Coenzyme A Biosynthesis Reduces Infection with Diverse Plasmodium Species in the Mosquito Host". Biomolecules 11, n. 6 (29 maggio 2021): 807. http://dx.doi.org/10.3390/biom11060807.
Testo completoAbstract (sommario):
Malaria parasites require pantothenate from both human and mosquito hosts to synthesize coenzyme A (CoA). Specifically, mosquito-stage parasites cannot synthesize pantothenate de novo or take up preformed CoA from the mosquito host, making it essential for the parasite to obtain pantothenate from mosquito stores. This makes pantothenate utilization an attractive target for controlling sexual stage malaria parasites in the mosquito. CoA is synthesized from pantothenate in a multi-step pathway initiated by the enzyme pantothenate kinase (PanK). In this work, we manipulated A. stephensi PanK activity and assessed the impact of mosquito PanK activity on the development of two malaria parasite species with distinct genetics and life cycles: the human parasite Plasmodium falciparum and the mouse parasite Plasmodium yoelii yoelii 17XNL. We identified two putative A. stephensi PanK isoforms encoded by a single gene and expressed in the mosquito midgut. Using both RNAi and small molecules with reported activity against human PanK, we confirmed that A. stephensi PanK manipulation was associated with corresponding changes in midgut CoA levels. Based on these findings, we used two small molecule modulators of human PanK activity (PZ-2891, compound 7) at reported and ten-fold EC50 doses to examine the effects of manipulating A. stephensi PanK on malaria parasite infection success. Our data showed that oral provisioning of 1.3 nM and 13 nM PZ-2891 increased midgut CoA levels and significantly decreased infection success for both Plasmodium species. In contrast, oral provisioning of 62 nM and 620 nM compound 7 decreased CoA levels and significantly increased infection success for both Plasmodium species. This work establishes the A. stephensi CoA biosynthesis pathway as a potential target for broadly blocking malaria parasite development in anopheline hosts. We envision this strategy, with small molecule PanK modulators delivered to mosquitoes via attractive bait stations, working in concert with deployment of parasite-directed novel pantothenamide drugs to block parasite infection in the human host. In mosquitoes, depletion of pantothenate through manipulation to increase CoA biosynthesis is expected to negatively impact Plasmodium survival by starving the parasite of this essential nutrient. This has the potential to kill both wild type parasites and pantothenamide-resistant parasites that could develop under pantothenamide drug pressure if these compounds are used as future therapeutics for human malaria.
17
Slavic, Ksenija, Michael J. Delves, Miguel Prudêncio, Arthur M. Talman, Ursula Straschil, Elvira T. Derbyshire, Zhengyao Xu et al. "Use of a Selective Inhibitor To Define the Chemotherapeutic Potential of the Plasmodial Hexose Transporter in Different Stages of the Parasite's Life Cycle". Antimicrobial Agents and Chemotherapy 55, n. 6 (14 marzo 2011): 2824–30. http://dx.doi.org/10.1128/aac.01739-10.
Testo completoAbstract (sommario):
ABSTRACTDuring blood infection, malarial parasites used-glucose as their main energy source. ThePlasmodium falciparumhexose transporter (PfHT), which mediates the uptake ofd-glucose into parasites, is essential for survival of asexual blood-stage parasites. Recently, genetic studies in the rodent malaria model,Plasmodium berghei, found that the orthologous hexose transporter (PbHT) is expressed throughout the parasite's development within the mosquito vector, in addition to being essential during intraerythrocytic development. Here, using ad-glucose-derived specific inhibitor of plasmodial hexose transporters, compound 3361, we have investigated the importance ofd-glucose uptake during liver and transmission stages ofP. berghei. Initially, we confirmed the expression of PbHT during liver stage development, using a green fluorescent protein (GFP) tagging strategy. Compound 3361 inhibited liver-stage parasite development, with a 50% inhibitory concentration (IC50) of 11 μM. This process was insensitive to the externald-glucose concentration. In addition, compound 3361 inhibited ookinete development and microgametogenesis, with IC50s in the region of 250 μM (the latter in ad-glucose-sensitive manner). Consistent with our findings for the effect of compound 3361 on vector parasite stages, 1 mM compound 3361 demonstrated transmission blocking activity. These data indicate that novel chemotherapeutic interventions that target PfHT may be active against liver and, to a lesser extent, transmission stages, in addition to blood stages.
18
Bindschedler, Annina, Jacqueline Schmuckli-Maurer, Rahel Wacker, Nicolas Kramer, Ruth Rehmann, Reto Caldelari e Volker T. Heussler. "Plasmodium berghei-Mediated NRF2 Activation in Infected Hepatocytes Enhances Parasite Survival". Cellular Microbiology 2022 (12 marzo 2022): 1–17. http://dx.doi.org/10.1155/2022/7647976.
Testo completoAbstract (sommario):
The protozoan parasite Plasmodium, causative agent of malaria, initially invades and develops in hepatocytes where it resides in a parasitophorous vacuole (PV). A single invaded parasite develops into thousands of daughter parasites. Survival of the host cell is crucial for successful completion of liver stage development. Nuclear factor erythroid-derived 2-related factor 2 (NRF2) is a transcription factor known to induce transcription of cytoprotective genes when activated. Here we show that NRF2 is activated in Plasmodium berghei-infected hepatocytes. We observed that this NRF2 activation depends on PV membrane resident p62 recruiting KEAP1, the negative regulator of NRF2. Disrupting the NRF2 gene results in reduced parasite survival, indicating that NRF2 signaling is an important event for parasite development in hepatocytes. Together, our observations uncovered a novel mechanism of how Plasmodium parasites ensure host cell survival during liver stage development.
19
Lisk, Godfrey, e Sanjay A. Desai. "The Plasmodial Surface Anion Channel Is Functionally Conserved in Divergent Malaria Parasites". Eukaryotic Cell 4, n. 12 (dicembre 2005): 2153–59. http://dx.doi.org/10.1128/ec.4.12.2153-2159.2005.
Testo completoAbstract (sommario):
ABSTRACT The plasmodial surface anion channel (PSAC), a novel ion channel induced on human erythrocytes infected with Plasmodium falciparum, mediates increased permeability to nutrients and presumably supports intracellular parasite growth. Isotope flux studies indicate that other malaria parasites also increase the permeability of their host erythrocytes, but the precise mechanisms are unknown. Channels similar to PSAC or alternative mechanisms, such as the upregulation of endogenous host transporters, might fulfill parasite nutrient demands. Here we evaluated these possibilities with rhesus monkey erythrocytes infected with Plasmodium knowlesi, a parasite phylogenetically distant from P. falciparum. Tracer flux and osmotic fragility studies revealed dramatically increased permeabilities paralleling changes seen after P. falciparum infection. Patch-clamp of P. knowlesi-infected rhesus erythrocytes revealed an anion channel with striking similarities to PSAC: its conductance, voltage-dependent gating, pharmacology, selectivity, and copy number per infected cell were nearly identical. Our findings implicate a family of unusual anion channels highly conserved on erythrocytes infected with various malaria parasites. Together with PSAC's exposed location on the host cell surface and its central role in transport changes after infection, this conservation supports development of antimalarial drugs against the PSAC family.
20
Antinori, Spinello, Laura Galimberti, Laura Milazzo e Mario Corbellino. "BIOLOGY OF HUMAN MALARIA PLASMODIA INCLUDING PLASMODIUM KNOWLESI". Mediterranean Journal of Hematology and Infectious Diseases 4, n. 1 (9 marzo 2012): e2012013. http://dx.doi.org/10.4084/mjhid.2012.013.
Testo completoAbstract (sommario):
Malaria is a vector-borne infection caused by unicellular parasite of the genus Plasmodium. Plasmodia are obligate intracellular parasites that in humans after a clinically silent replication phase in the liver are able to infect and replicate within the erythrocytes. Four species (P.falciparum, P.malariae, P.ovale and P.vivax) are traditionally recognized as responsible of natural infection in human beings but the recent upsurge of P.knowlesi malaria in South-East Asia has led clinicians to consider it as the fifth human malaria parasite. Recent studies in wild-living apes in Africa have revealed that P.falciparum, the most deadly form of human malaria, is not only human-host restricted as previously believed and its phylogenetic lineage is much more complex with new species identified in gorilla, bonobo and chimpanzee. Although less impressive, new data on biology of P.malariae, P.ovale and P.vivax are also emerging and will be briefly discussed in this review.
21
Li, Meizhi Irene, Diyar Mailepessov, Indra Vythilingam, Vernon Lee, Patrick Lam, Lee Ching Ng e Cheong Huat Tan. "Prevalence of simian malaria parasites in macaques of Singapore". PLOS Neglected Tropical Diseases 15, n. 1 (25 gennaio 2021): e0009110. http://dx.doi.org/10.1371/journal.pntd.0009110.
Testo completoAbstract (sommario):
Plasmodium knowlesi is a simian malaria parasite currently recognized as the fifth causative agent of human malaria. Recently, naturally acquired P. cynomolgi infection in humans was also detected in Southeast Asia. The main reservoir of both parasites is the long-tailed and pig-tailed macaques, which are indigenous in this region. Due to increased urbanization and changes in land use, there has been greater proximity and interaction between the long-tailed macaques and the general population in Singapore. As such, this study aims to determine the prevalence of simian malaria parasites in local macaques to assess the risk of zoonosis to the general human population. Screening for the presence of malaria parasites was conducted on blood samples from 660 peridomestic macaques collected between Jan 2008 and Mar 2017, and 379 wild macaques collected between Mar 2009 and Mar 2017, using a Pan-Plasmodium-genus specific PCR. Positive samples were then screened using a simian Plasmodium species-specific nested PCR assay to identify the species of parasites (P. knowlesi, P. coatneyi, P. fieldi, P. cynomolgi, and P. inui) present. All the peridomestic macaques sampled were tested negative for malaria, while 80.5% of the 379 wild macaques were infected. All five simian Plasmodium species were detected; P. cynomolgi being the most prevalent (71.5%), followed by P. knowlesi (47.5%), P. inui (42.0%), P. fieldi (32.5%), and P. coatneyi (28.5%). Co-infection with multiple species of Plasmodium parasites was also observed. The study revealed that Singapore’s wild long-tailed macaques are natural hosts of the five simian malaria parasite species, while no malaria was detected in all peridomestic macaques tested. Therefore, the risk of simian malaria transmission to the general human population is concluded to be low. However, this can be better demonstrated with the incrimination of the vectors of simian malaria parasites in Singapore.
22
Jarra, William, e Georges Snounou. "Only Viable Parasites Are Detected by PCR following Clearance of Rodent Malarial Infections by Drug Treatment or Immune Responses". Infection and Immunity 66, n. 8 (1 agosto 1998): 3783–87. http://dx.doi.org/10.1128/iai.66.8.3783-3787.1998.
Testo completoAbstract (sommario):
ABSTRACT Detection and analysis of pathogens by PCR plays an important role in infectious disease research. The value of these studies would be diminished if nuclear material from dead parasites were found to remain in circulation for extended periods and thus result in positive amplification. This possibility was tested in experimental rodent malaria infections. Blood samples were obtained from infected mice during and following drug or immune clearance of Plasmodium chabaudi chabaudi parasitemias. Detection of parasite DNA by a sensitive Plasmodium-specific PCR amplification assay was associated with the presence of viable parasites, as detected by subinoculation. No parasite DNA could be detected by PCR 48 h after the injection of killed parasites into mice. Nuclear material from parasites removed by drug or immune responses is rapidly cleared from the circulation and does not contribute significantly to amplification. Thus, results from PCR analysis of malaria-infected blood accurately reflect the presence of live parasites.
23
Arisandi, Desto, Sofvirah R. Sohy e Fitri Nadifah. "Identification of Malaria Parasites in Chasan Boesoirie General Hospital Ternate East Nusa Tenggara". Journal of Health 3, n. 1 (31 gennaio 2016): 39. http://dx.doi.org/10.30590/vol3-no1-p39-44.
Testo completoAbstract (sommario):
Background: Malaria is still a global health problem especially in tropical countries, such as Indonesia. Based on survey 35% of the Indonesia population were live in endemic areas of malaria, such as Provinces of Maluku, North Maluku, Papua, West Papua, North Sumatra, and East Nusa Tenggara. Malaria is caused by a mosquito bite of female Anopheles sp. containing Plasmodium parasite. Generally it bites humans at night or dawn. Such malaria parasites are Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, and Plasmodium ovale. Malaria is a disease of both highest in Ternate and mostly occur in general hospitals of Chasan Boesoirie General Hospital. This research aims to identify the type of malaria parasites in the Chasan Boesoirie General Hospital Ternate.
Method: This is a descriptive research conducted in Chasan Boesoirie General Hospital in Ternate, East Nusa Tenggara in March 2015. Research data obtained include: age, sex, education, and employment. Identification of malaria is carried out based on an examination of the existence of Plasmodium in preparation of thin and thick blood apus. Descriptive analysis using STATA programs for Windows version 12.0 (Stata Corp LP., College Station, TX, USA) are presented in the form of tables and narratives.
Result: This research subjects were 69 people suspected with malaria infection. Suspected malaria to be infected by Plasmodium is more are young age group 94%, 88% were males, 100% have a poor education or un-educated, as well as the of 100% were fishermen. As much as 54 people (78%) were infected by Plasmodium parasites consisting of Plasmodium falcifarum 48 people (89%) and Plasmodium vivax 6 people (11%).
Conclusion: The incidence of malaria infections in Chasan Boesoirie General Hospital amounted to 78% and the type of infected parasites were Plasmodium falcifarum and Plasmodium vivax.
24
Sultan, Ali A., Vandana Thathy, Victor Nussenzweig e Robert Ménard. "Green Fluorescent Protein as a Marker in Plasmodium berghei Transformation". Infection and Immunity 67, n. 5 (1 maggio 1999): 2602–6. http://dx.doi.org/10.1128/iai.67.5.2602-2606.1999.
Testo completoAbstract (sommario):
ABSTRACT We present a new marker that confers both resistance to pyrimethamine and green fluorescent protein-based fluorescence on the malarial parasite Plasmodium berghei. A single copy of the cassette integrated into the genome is sufficient to direct fluorescence in parasites throughout the life cycle, in both its mosquito and vertebrate hosts. Erythrocyte stages of the parasite that express the marker can be sorted from control parasites by flow cytometry. Pyrimethamine pressure is not necessary for maintaining the cassette in transformed parasites during their sporogonic cycle in mosquitoes, including when it is borne by a plasmid. This tool should thus prove useful in molecular studies of P. berghei, both for generating parasite variants and monitoring their behavior.
25
Muniz-Junqueira, Maria Imaculada, e Carlos Eduardo Tosta. "Stages of in vitro phagocytosis of Plasmodium falciparum-infected erythrocytes by human monocytes". Revista da Sociedade Brasileira de Medicina Tropical 42, n. 2 (aprile 2009): 103–6. http://dx.doi.org/10.1590/s0037-86822009000200001.
Testo completoAbstract (sommario):
Monocytes/macrophages play a critical role in the defense mechanisms against malaria parasites, and are the main cells responsible for the elimination of malaria parasites from the blood circulation. We carried out a microscope-aided evaluation of the stages of in vitro phagocytosis of Plasmodium falciparum-infected erythrocytes, by human monocytes. These cells were obtained from healthy adult individuals by means of centrifugation through a cushion of Percoll density medium and were incubated with erythrocytes infected with Plasmodium falciparum that had previously been incubated with a pool of anti-plasmodial immune serum. We described the stages of phagocytosis, starting from adherence of infected erythrocytes to the phagocyte membrane and ending with their destruction within the phagolisosomes of the monocytes. We observed that the different erythrocytic forms of the parasite were ingested by monocytes, and that the process of phagocytosis may be completed in around 30 minutes. Furthermore, we showed that phagocytosis may occur continuously, such that different phases of the process were observed in the same phagocyte.
26
Ramey, A. M., J. A. Reed, J. A. Schmutz, T. F. Fondell, B. W. Meixell, J. W. Hupp, D. H. Ward, J. Terenzi e C. R. Ely. "Prevalence, transmission, and genetic diversity of blood parasites infecting tundra-nesting geese in Alaska". Canadian Journal of Zoology 92, n. 8 (agosto 2014): 699–706. http://dx.doi.org/10.1139/cjz-2014-0041.
Testo completoAbstract (sommario):
A total of 842 blood samples collected from five species of tundra-nesting geese in Alaska was screened for haemosporidian parasites using molecular techniques. Parasites of the genera Leucocytozoon Danilewsky, 1890, Haemoproteus Kruse, 1890, and Plasmodium Marchiafava and Celli, 1885 were detected in 169 (20%), 3 (<1%), and 0 (0%) samples, respectively. Occupancy modeling was used to estimate prevalence of Leucocytozoon parasites and assess variation relative to species, age, sex, geographic area, year, and decade. Species, age, and decade were identified as important in explaining differences in prevalence of Leucocytozoon parasites. Leucocytozoon parasites were detected in goslings sampled along the Arctic Coastal Plain using both historic and contemporary samples, which provided support for transmission in the North American Arctic. In contrast, lack of detection of Haemoproteus and Plasmodium parasites in goslings (n = 238) provided evidence to suggest that the transmission of parasites of these genera may not occur among waterfowl using tundra habitats in Alaska, or alternatively, may only occur at low levels. Five haemosporidian genetic lineages shared among different species of geese sampled from two geographic areas were indicative of interspecies parasite transmission and supported broad parasite or vector distributions. However, identical Leucocytozoon and Haemoproteus lineages on public databases were limited to waterfowl hosts suggesting constraints in the range of parasite hosts.
27
Inyimai, Simon Peter, Mosses Ocan, Benjamin Wabwire e Peter Olupot-Olupot. "Asymptomatic Plasmodium Parasites among Adults in Eastern Uganda: A Case of Donor Blood Screening at Mbale Regional Blood Bank". Journal of Tropical Medicine 2018 (9 luglio 2018): 1–6. http://dx.doi.org/10.1155/2018/6359079.
Testo completoAbstract (sommario):
Background. There is a paucity of data on asymptomatic carriage of Plasmodium parasite among adult population in Eastern Uganda, an area of perennial high transmission of malaria. In this study, we estimated the prevalence of Plasmodium parasites in donor blood units at Mbale Regional Blood Bank (Mbale RBB), a satellite centre of the Uganda Blood Transfusion Service (UBTS). Method. This was a cross-sectional descriptive study in which 380 screened donor blood units were examined for the presence of Plasmodium parasites. A systematic random sampling technique using the interval of 7 was used in selecting the screened blood units for testing. Two experienced malaria slide microscopists (MC1 and MC2) independently examined each thick and thin blood slide under high power magnification of X400 and then X1000 as stated on the study standard operation procedure (SOP). Each slide was examined for 100 oil immersion fields before the examiner declared them negative for Plasmodium parasites. The results by each microscopist’s examination were tallied separately, and finally, the two tallies were compared. The third independent microscopist (MC3) was blinded to the results from MC1 and MC2, but whose role was to perform quality control on the slides randomly sampled and read 38 (10%) of all the slides and was available to examine any slides with inconsistent findings by MC1 or MC2. Results. All the microscopists were unanimous in all the slide readings. Five of the thick smears (1.3%) confirmed the presence of Plasmodium parasites among donor blood units. Of these, 4/5 were from male donors. Plasmodium falciparum was identified in 4 positive samples, while Plasmodium malariae was identified in one of the donor units. Conclusion. The 1.3% prevalence of Plasmodium malaria parasites in screened donor blood units represents risk of malaria blood transfusion transmitted infection and a pool of community transmittable malaria infections, respectively.
28
Frame, I. J., Emilio F. Merino, Vern L. Schramm, María B. Cassera e Myles H. Akabas. "Malaria parasite type 4 equilibrative nucleoside transporters (ENT4) are purine transporters with distinct substrate specificity". Biochemical Journal 446, n. 2 (14 agosto 2012): 179–90. http://dx.doi.org/10.1042/bj20112220.
Testo completoAbstract (sommario):
Malaria, caused by Plasmodia parasites, affects hundreds of millions of people. As purine auxotrophs, Plasmodia use transporters to import host purines for subsequent metabolism by the purine salvage pathway. Thus purine transporters are attractive drug targets. All sequenced Plasmodia genomes encode four ENTs (equilibrative nucleoside transporters). During the pathogenic intraerythrocytic stages, ENT1 is a major route of purine nucleoside/nucleobase transport. Another plasma membrane purine transporter exists because Plasmodium falciparum ENT1-knockout parasites survive at supraphysiological purine concentrations. The other three ENTs have not been characterized functionally. Codon-optimized Pf- (P. falciparum) and Pv- (Plasmodium vivax) ENT4 were expressed in Xenopus laevis oocytes and substrate transport was determined with radiolabelled substrates. ENT4 transported adenine and 2′-deoxyadenosine at the highest rate, with millimolar-range apparent affinity. ENT4-expressing oocytes did not accumulate hypoxanthine, a key purine salvage pathway substrate, or AMP. Micromolar concentrations of the plant hormone cytokinin compounds inhibited both PfENT4 and PvENT4. In contrast with PfENT1, ENT4 interacted with the immucillin compounds in the millimolar range and was inhibited by 10 μM dipyridamole. Thus ENT4 is a purine transporter with unique substrate and inhibitor specificity. Its role in parasite physiology remains uncertain, but is likely to be significant because of the strong conservation of ENT4 homologues in Plasmodia genomes.
29
De Nys, Hélène M., Sébastien Calvignac-Spencer, Ursula Thiesen, Christophe Boesch, Roman M. Wittig, Roger Mundry e Fabian H. Leendertz. "Age-related effects on malaria parasite infection in wild chimpanzees". Biology Letters 9, n. 4 (23 agosto 2013): 20121160. http://dx.doi.org/10.1098/rsbl.2012.1160.
Testo completoAbstract (sommario):
Wild great apes are widely infected with a number of malaria parasites ( Plasmodium spp.). Yet, nothing is known about the biology of these infections in the wild. Using faecal samples collected from wild chimpanzees, we investigated the effect of age on Plasmodium spp. detection rates. The data show a strong association between age and malaria parasite positivity, with significantly lower detection rates in adults. This suggests that, as in humans, individuals reaching adulthood have mounted an effective protective immunity against malaria parasites.
30
Huang, Xi, Zelin Chen, Guocheng Yang, Canwei Xia, Qiujin Luo, Xiang Gao e Lu Dong. "Assemblages of Plasmodium and Related Parasites in Birds with Different Migration Statuses". International Journal of Molecular Sciences 23, n. 18 (7 settembre 2022): 10277. http://dx.doi.org/10.3390/ijms231810277.
Testo completoAbstract (sommario):
Migratory birds spend several months in their breeding grounds in sympatry with local resident birds and relatively shorter periods of time at stopover sites. During migration, parasites may be transmitted between migratory and resident birds. However, to what extent they share these parasites remains unclear. In this study, we compared the assemblages of haemosporidian parasites in migratory, resident, and passing birds, as well as the correlations between parasite assemblages and host phylogeny. Compared with passing birds, migratory birds were more likely to share parasites with resident birds. Shared lineages showed significantly higher prevalence rates than other lineages, indicating that common parasites are more likely to spill over from the current host to other birds. For shared lineages, the prevalence was significantly higher in resident birds than in migratory birds, suggesting that migratory birds pick up parasites at their breeding ground. Among the shared lineages, almost two-thirds presented no phylogenetic signal in their prevalence, indicating that parasite transmission among host species is weakly or not correlated with host phylogeny. Moreover, similarities between parasite assemblages are not correlated with either migration status or the phylogeny of hosts. Our results show that the prevalence, rather than host phylogeny, plays a central role in parasite transmission between migratory and resident birds in breeding grounds.
31
Roques, Magali, Annina Bindschedler, Raphael Beyeler e Volker T. Heussler. "Same, same but different: Exploring Plasmodium cell division during liver stage development". PLOS Pathogens 19, n. 3 (30 marzo 2023): e1011210. http://dx.doi.org/10.1371/journal.ppat.1011210.
Testo completoAbstract (sommario):
Plasmodium parasites have a complex life cycle alternating between a mosquito and a vertebrate host. Following the bite of an Anopheles female mosquito, Plasmodium sporozoites are transmitted from the skin to the liver; their first place of replication within the host. Successfully invaded sporozoites undergo a massive replication and growth involving asynchronous DNA replication and division that results in the generation of tens of thousands or even hundreds of thousands of merozoites depending on the Plasmodium species. The generation of a high number of daughter parasites requires biogenesis and segregation of organelles to finally reach a relatively synchronous cytokinesis event. At the end of liver stage (LS) development, merozoites are packed into merosomes and released into the bloodstream. They are then liberated and infect red blood cells to again produce merozoites by schizogony for the erythrocytic stage of the life cycle. Although parasite LS and asexual blood stage (ABS) differ in many respects, important similarities exist between the two. This review focuses on the cell division of Plasmodium parasite LS in comparison with other life cycle stages especially the parasite blood stage.
32
de Angeli Dutra, Daniela, Nayara Belo e Erika M. Braga. "Prevalence and richness of malaria and malaria-like parasites in wild birds from different biomes in South America". PeerJ 10 (19 maggio 2022): e13485. http://dx.doi.org/10.7717/peerj.13485.
Testo completoAbstract (sommario):
South America has different biomes with a high richness of wild bird species and Diptera vectors, representing an ideal place to study the influence of habitat on vector-borne parasites. In order to better understand how different types of habitats do or do not influence the prevalence of haemosporidians, we performed a new analysis of two published datasets comprising wild birds from the Brazilian Savanna (Cerrado) as well as wild birds from the Venezuelan Arid Zone. We investigated the prevalence and genetic diversity of haemosporidian parasites belonging to two genera: Plasmodium and Haemoproteus. We evaluated data from 676 wild birds from the Cerrado and observed an overall prevalence of 49%, whereas, in the Venezuelan Arid Zone, we analyzed data from 527 birds and found a similar overall prevalence of 43%. We recovered 44 lineages, finding Plasmodium parasites more prevalent in the Cerrado (15 Plasmodium and 12 Haemoproteus lineages) and Haemoproteus in the Venezuelan Arid Zone (seven Plasmodium and 10 Haemoproteus lineages). No difference was observed on parasite richness between the two biomes. We observed seven out of 44 haemosporidian lineages that are shared between these two distinct South American biomes. This pattern of parasite composition and prevalence may be a consequence of multiple factors, such as host diversity and particular environmental conditions, especially precipitation that modulate the vector’s dynamics. The relationship of blood parasites with the community of hosts in large and distinct ecosystems can provide more information about what factors are responsible for the variation in the prevalence and diversity of these parasites in an environment.
33
Devi, Sanasam Bijara, e Sanjeev Kumar. "In-Silico Structural Modeling and Prediction of Conformational B-Cell Epitopes of Potential Vaccine Candidate Pre-Binding Protein". ECS Transactions 107, n. 1 (24 aprile 2022): 15809–16. http://dx.doi.org/10.1149/10701.15809ecst.
Testo completoAbstract (sommario):
Malaria is a life threatening infectious disease causes by Plasmodium species, wherein Plasmodium falciparum being the most lethal causes severe malaria. Plasmodium parasites have a complex life cycle and employed several immunity evading mechanism that enable the parasite to multiply and survive avoiding the host immunity. The rise in drug-resistant Plasmodium parasites and the unavailability of an effective vaccine lead to major challenges in controlling the parasite. Therefore, it is of utmost important to identify novel potential targets that can be directed for therapeutic intervention. In the present study, conservancy, localization, and the antigenicity of PREBP was determined by using different bioinformatics tools. The 3D structure of PREBP was modeled and conformational B-cell epitopes of the protein were predicted using Ellipro. The resulted epitopes might be of great importance as a vaccine sub-unit in the development of an effective malaria vaccine and the generated 3D structure of the protein can be further used for other structural analysis.
34
Bruce, M. C., P. Alano, S. Duthie e R. Carter. "Commitment of the malaria parasite Plasmodium falciparum to sexual and asexual development". Parasitology 100, n. 2 (aprile 1990): 191–200. http://dx.doi.org/10.1017/s0031182000061199.
Testo completoAbstract (sommario):
SUMMARYBlood-stage malaria parasites in the vertebrate host can develop either into the asexual, multiplying forms, called schizonts, or into gametocytes, the sexual stages of the parasite. In the present work we studied the differentiation into asexual parasites or gametocytes of the progeny of single, isolated schizonts of the clone 3D7A of Plasinodium falciparum, using monoclonal antibodies specific for the sexual or asexual stages of the parasite. We observed that schizonts obtained from a continuous culture undergoing serial cycles of growth and dilution with fresh red blood cells produced either only gametocytes or only asexual parasites, showing a high degree of commitment to one or the other developmental pathway.The relative proportion of schizonts which produced gametocytes was very low at low parasite densities in culture, while at high parasite densities a much greater proportion of schizonts produced gametocytes. Nevertheless, at both low and high parasite densities individual schizonts were almost always fully committed to producing only gametocytes or only asexual parasites.
35
Van Tyne, Daria, Alessandro D. Uboldi, Julie Healer, Alan F. Cowman e Dyann F. Wirth. "Modulation of PF10_0355 (MSPDBL2) Alters Plasmodium falciparum Response to Antimalarial Drugs". Antimicrobial Agents and Chemotherapy 57, n. 7 (15 aprile 2013): 2937–41. http://dx.doi.org/10.1128/aac.02574-12.
Testo completoAbstract (sommario):
ABSTRACTMalaria's ability to rapidly adapt to new drugs has allowed it to remain one of the most devastating infectious diseases of humans. Understanding and tracking the genetic basis of these adaptations are critical to the success of treatment and intervention strategies. The novel antimalarial resistance locusPF10_0355(Pfmspdbl2) was previously associated with the parasite response to halofantrine, and functional validation confirmed that overexpression of this gene lowered parasite sensitivity to both halofantrine and the structurally related antimalarials mefloquine and lumefantrine, predominantly through copy number variation. Here we further characterize the role ofPfmspdbl2in mediating the antimalarial drug response ofPlasmodium falciparum. Knockout ofPfmspdbl2increased parasite sensitivity to halofantrine, mefloquine, and lumefantrine but not to unrelated antimalarials, further suggesting that this gene mediates the parasite response to a specific class of antimalarial drugs. A single nucleotide polymorphism encoding a C591S mutation withinPfmspdbl2had the strongest association with halofantrine sensitivity and showed a high derived allele frequency among Senegalese parasites. Transgenic parasites expressing the ancestralPfmspdbl2allele were more sensitive to halofantrine and structurally related antimalarials than were parasites expressing the derived allele, revealing an allele-specific effect on drug sensitivity in the absence of copy number effects. Finally, growth competition experiments showed that under drug pressure, parasites expressing the derived allele ofPfmspdbl2outcompeted parasites expressing the ancestral allele within a few generations. Together, these experiments demonstrate that modulation ofPfmspdbl2affects malaria parasite responses to antimalarial drugs.
36
Clements, Rebecca L., Vincent Streva, Peter Dumoulin, Weigang Huang, Edward Owens, Dipak K. Raj, Barbara Burleigh et al. "A Novel Antiparasitic Compound Kills Ring-Stage Plasmodium falciparum and Retains Activity Against Artemisinin-Resistant Parasites". Journal of Infectious Diseases 221, n. 6 (16 ottobre 2019): 956–62. http://dx.doi.org/10.1093/infdis/jiz534.
Testo completoAbstract (sommario):
Abstract Spreading antimalarial resistance threatens effective treatment of malaria, an infectious disease caused by Plasmodium parasites. We identified a compound, BCH070, that inhibits asexual growth of multiple antimalarial-resistant strains of Plasmodium falciparum (half maximal inhibitory concentration [IC50] = 1–2 µM), suggesting that BCH070 acts via a novel mechanism of action. BCH070 preferentially kills early ring-form trophozoites, and, importantly, equally inhibits ring-stage survival of wild-type and artemisinin-resistant parasites harboring the PfKelch13:C580Y mutation. Metabolomic analysis demonstrates that BCH070 likely targets multiple pathways in the parasite. BCH070 is a promising lead compound for development of new antimalarial combination therapy that retains activity against artemisinin-resistant parasites.
37
Wel, Anna M. van der, Ana M. Tomás, Clemens H. M. Kocken, Pawan Malhotra, Chris J. Janse, Andrew P. Waters e Alan W. Thomas. "Transfection of the Primate Malaria Parasite Plasmodium knowlesi Using Entirely Heterologous Constructs". Journal of Experimental Medicine 185, n. 8 (21 aprile 1997): 1499–504. http://dx.doi.org/10.1084/jem.185.8.1499.
Testo completoAbstract (sommario):
The recently developed transfection systems for Plasmodium berghei and Plasmodium falciparum offer important new tools enabling further insight into the biology of malaria parasites. These systems rely upon artificial parasite–host combinations which do not allow investigation into the complex interactions between parasites and their natural hosts. Here we report on stable transfection of Plasmodium knowlesi (a primate malaria parasite that clusters phylogenetically with P. vivax) for which both natural and artificial experimental hosts are available. Transfection of this parasite offers the opportunity to further analyze the biology of antigens not only in a natural host but also in hosts that are closely related to humans. To facilitate future development of integration-dependent transfection in P. knowlesi, completely heterologous plasmids that would reduce homologous recombination at unwanted sites in the genome were constructed. These plasmids contained the pyrimethamine-resistant form of dihydrofolate reductase-thymidylate synthase (dhfr-ts) from Toxoplasma gondii or P. berghei, under control of either (a) P. berghei or (b) P. falciparum promoters. Plasmids were electroporated into mature P. knowlesi schizonts and these cells were injected into rhesus monkeys (Macaca mulatta). After pyrimethamine treatment of these monkeys, resistant parasites were obtained that contained the plasmids. Promoter regions of both P. berghei and P. falciparum controlling dhfr-ts expression were effective in conferring pyrimethamine resistance in P. knowlesi, indicating that common signals control gene expression in phylogenetically distant Plasmodium species.
38
Honorio, Rute Isabel, Barbara Karina Menezes Dias, Jude Marek Przyborski e Celia Regina Garcia. "Melatonin as a microenvironmental cue for parasite development inside the host". Melatonin Research 5, n. 1 (8 aprile 2022): 84–100. http://dx.doi.org/10.32794/mr112500122.
Testo completoAbstract (sommario):
Throughout the evolutionary process, parasites have
acquired characteristics that function as survival mechanisms. It has been
reported that melatonin, a molecule present in virtually all living organisms,
has several roles in parasite biology such as preventing tissue damage,
regulating gene expression and inflammatory processes, and acting as a free
radical scavenger. Additionally,
melatonin produced by the hosts accelerates the intra-erythrocytic cycle of the
human malaria parasite Plasmodium falciparum and the rodent malaria
parasite P. chabaudi, respectively. These findings have recently led to
an increased research enthusiasm to find how melatonin influences the
biological cycle of parasites. Therefore, this review aims to gather and
analyze the potential relationships of host produced melatonin with the
parasites Plasmodium sp., Trypanosoma cruzi, Leishmania
spp., Toxoplasma gondii, Schistosoma mansoni, Opisthorchis viverrini, and Entamoeba
histolytica, respectively.
39
Howick, Virginia M., Andrew J. C. Russell, Tallulah Andrews, Haynes Heaton, Adam J. Reid, Kedar Natarajan, Hellen Butungi et al. "The Malaria Cell Atlas: Single parasite transcriptomes across the complete Plasmodium life cycle". Science 365, n. 6455 (22 agosto 2019): eaaw2619. http://dx.doi.org/10.1126/science.aaw2619.
Testo completoAbstract (sommario):
Malaria parasites adopt a remarkable variety of morphological life stages as they transition through multiple mammalian host and mosquito vector environments. We profiled the single-cell transcriptomes of thousands of individual parasites, deriving the first high-resolution transcriptional atlas of the entire Plasmodium berghei life cycle. We then used our atlas to precisely define developmental stages of single cells from three different human malaria parasite species, including parasites isolated directly from infected individuals. The Malaria Cell Atlas provides both a comprehensive view of gene usage in a eukaryotic parasite and an open-access reference dataset for the study of malaria parasites.
40
Waller, Ross F., Stuart A. Ralph, Michael B. Reed, Vanessa Su, James D. Douglas, David E. Minnikin, Alan F. Cowman, Gurdyal S. Besra e Geoffrey I. McFadden. "A Type II Pathway for Fatty Acid Biosynthesis Presents Drug Targets in Plasmodium falciparum". Antimicrobial Agents and Chemotherapy 47, n. 1 (gennaio 2003): 297–301. http://dx.doi.org/10.1128/aac.47.1.297-301.2003.
Testo completoAbstract (sommario):
ABSTRACT It has long been held that the malaria parasite, Plasmodium sp., is incapable of de novo fatty acid synthesis. This view has recently been overturned with the emergence of data for the presence of a fatty acid biosynthetic pathway in the relict plastid of P. falciparum (known as the apicoplast). This pathway represents the type II pathway common to plant chloroplasts and bacteria but distinct from the type I pathway of animals including humans. Specific inhibitors of the type II pathway, thiolactomycin and triclosan, have been reported to target this Plasmodium pathway. Here we report further inhibitors of the plastid-based pathway that inhibit Plasmodium parasites. These include several analogues of thiolactomycin, two with sixfold-greater efficacy than thiolactomycin. We also report that parasites respond very rapidly to such inhibitors and that the greatest sensitivity is seen in ring-stage parasites. This study substantiates the importance of fatty acid synthesis for blood-stage parasite survival and shows that this pathway provides scope for the development of novel antimalarial drugs.
41
TEMPLETON, THOMAS J., ELLEN MARTINSEN, MORAKOT KAEWTHAMASORN e OSAMU KANEKO. "The rediscovery of malaria parasites of ungulates". Parasitology 143, n. 12 (22 luglio 2016): 1501–8. http://dx.doi.org/10.1017/s0031182016001141.
Testo completoAbstract (sommario):
SUMMARYOver a hundred years since their first description in 1913, the sparsely described malaria parasites (genus Plasmodium) of ungulates have been rediscovered using molecular typing techniques. In the span of weeks, three studies have appeared describing the genetic characterization and phylogenetic analyses of malaria parasites from African antelope (Cephalophus spp.) and goat (Capra aegagrus hircus), Asian water buffalo (Bubalus bubalis), and North American white-tailed deer (Odocoileus virginianus). Here we unify the contributions from those studies with the literature on pre-molecular characterizations of ungulate malaria parasites, which are largely based on surveys of Giemsa-reagent stained blood smears. We present a phylogenetic tree generated from all available ungulate malaria parasite sequence data, and show that parasites from African duiker antelope and goat, Asian water buffalo and New World white-tailed deer group together in a clade, which branches early in Plasmodium evolution. Anopheline mosquitoes appear to be the dominant, if not sole vectors for parasite transmission. We pose questions for future phylogenetic studies, and discuss topics that we hope will spur further molecular and cellular studies of ungulate malaria parasites.
42
Davis, Andrew K., Andrew C. Benz, Leslie E. Ruyle, Whitney M. Kistler, Barbara C. Shock e Michael J. Yabsley. "Searching Before It Is Too Late: A Survey of Blood Parasites in Ctenosaura melanosterna, a Critically Endangered Reptile of Honduras". ISRN Parasitology 2013 (28 novembre 2013): 1–6. http://dx.doi.org/10.5402/2013/495304.
Testo completoAbstract (sommario):
For species at risk of extinction, any parasites they have would be expected to face a similar fate. In such cases, time is running out for efforts to identify and study their parasitic fauna before they are gone. We surveyed the hemoparasite fauna of 50 black-chested, spiny-tailed iguanas (Ctenosaura melanosterna), a critically-endangered species, on an island off the coast of Honduras. Blood samples from captured animals were tested for hemoparasites by thin blood smear and molecular analyses. Based on microscopy, two parasites were identified, a Plasmodium sp. in 14% of iguanas and a Hepatozoon sp. in 32%. For both parasites, parasitemia levels were <0.1%. Prevalence and parasitemias of Hepatozoon declined with increasing host size, a pattern differing from most prior studies of saurian reptiles. From a subset of iguanas with microscopy-confirmed Plasmodium infections, sequence analysis of 454 bp of the cytochrome b gene indicated that the Plasmodium species was distinct from known Plasmodium and was most closely related to P. chiricahuae (96.5% similarity) followed by P. mexicanum (95.8% similarity). Efforts to amplify the Hepatozoon parasite using PCR were not successful. Additional surveys and studies of this host-parasite system would be valuable, both to science and to the management of this endangered animal.
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McRobert, Louisa, Peter Preiser, Sarah Sharp, William Jarra, Mallika Kaviratne, Martin C. Taylor, Laurent Renia e Colin J. Sutherland. "Distinct Trafficking and Localization of STEVOR Proteins in Three Stages of the Plasmodium falciparum Life Cycle". Infection and Immunity 72, n. 11 (novembre 2004): 6597–602. http://dx.doi.org/10.1128/iai.72.11.6597-6602.2004.
Testo completoAbstract (sommario):
ABSTRACT The genome of Plasmodium falciparum harbors three extensive multigene families, var, rif, and stevor (for subtelomeric variable open reading frame), located mainly in the subtelomeric regions of the parasite's 14 chromosomes. STEVOR variants are known to be expressed in asexual parasites, but no function has as yet been ascribed to this protein family. We have examined the expression of STEVOR proteins in intraerythrocytic sexual stages, gametocytes, and extracellular sporozoites isolated from infected Anopheles mosquitoes. In gametocytes, stevor transcripts appear transiently early in development but STEVOR proteins persist for several days and are transported out of the parasite, travel through the host cell cytoplasm, and localize to the erythrocyte plasma membrane. In contrast to asexual parasites, gametocytes move STEVOR to the periphery via a trafficking pathway independent of Maurer's clefts. In sporozoites, STEVOR appear dispersed throughout the cytoplasm in vesicle-like structures. The pattern of STEVOR localization we have observed in gametocytes and sporozoites differs significantly from that in asexual parasite stages. STEVOR variants are therefore likely to perform different functions in each stage of the parasites life cycle in which they occur.
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Margos, Gabriele, Sandra Navarette, Geoff Butcher, Alex Davies, Christine Willers, Robert E. Sinden e Peter J. Lachmann. "Interaction between Host Complement and Mosquito-Midgut-Stage Plasmodium berghei". Infection and Immunity 69, n. 8 (1 agosto 2001): 5064–71. http://dx.doi.org/10.1128/iai.69.8.5064-5071.2001.
Testo completoAbstract (sommario):
ABSTRACT After ingestion by mosquitoes, gametocytes of malaria parasites become activated and form extracellular gametes that are no longer protected by the red blood cell membrane against immune effectors of host blood. We have studied the action of complement onPlasmodium developmental stages in the mosquito blood meal using the rodent malaria parasite Plasmodium berghei and rat complement as a model. We have shown that in the mosquito midgut, rat complement components necessary to initiate the alternative pathway (factor B, factor D, and C3) as well as C5 are present for several hours following ingestion of P. berghei-infected rat blood. In culture, 30 to 50% of mosquito midgut stages of P. berghei survived complement exposure during the first 3 h of development. Subsequently, parasites became increasingly sensitive to complement lysis. To investigate the mechanisms involved in their protection, we tested for C3 deposition on parasite surfaces and whether host CD59 (a potent inhibitor of the complement membrane attack complex present on red blood cells) was taken up by gametes while emerging from the host cell. Between 0.5 and 22 h, 90% of Pbs21-positive parasites were positive for C3. While rat red and white blood cells stained positive for CD59, Pbs21-positive parasites were negative for CD59. In addition, exposure of parasites to rat complement in the presence of anti-rat CD59 antibodies did not increase lysis. These data suggest that parasite or host molecules other than CD59 are responsible for the protection of malaria parasites against complement-mediated lysis. Ongoing research aims to identify these molecules.
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Schalkwijk, Joost, Erik L. Allman, Patrick A. M. Jansen, Laura E. de Vries, Julie M. J. Verhoef, Suzanne Jackowski, Peter N. M. Botman et al. "Antimalarial pantothenamide metabolites target acetyl–coenzyme A biosynthesis in Plasmodium falciparum". Science Translational Medicine 11, n. 510 (18 settembre 2019): eaas9917. http://dx.doi.org/10.1126/scitranslmed.aas9917.
Testo completoAbstract (sommario):
Malaria eradication is critically dependent on new therapeutics that target resistant Plasmodium parasites and block transmission of the disease. Here, we report that pantothenamide bioisosteres were active against blood-stage Plasmodium falciparum parasites and also blocked transmission of sexual stages to the mosquito vector. These compounds were resistant to degradation by serum pantetheinases, showed favorable pharmacokinetic properties, and cleared parasites in a humanized mouse model of P. falciparum infection. Metabolomics revealed that coenzyme A biosynthetic enzymes converted pantothenamides into coenzyme A analogs that interfered with parasite acetyl–coenzyme A anabolism. Resistant parasites generated in vitro showed mutations in acetyl–coenzyme A synthetase and acyl–coenzyme A synthetase 11. Introduction and reversion of these mutations in P. falciparum using CRISPR-Cas9 gene editing confirmed the roles of these enzymes in the sensitivity of the malaria parasites to pantothenamides. These pantothenamide compounds with a new mode of action may have potential as drugs against malaria parasites.
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Pegoraro, Mirko, e Gareth D. Weedall. "Malaria in the ‘Omics Era’". Genes 12, n. 6 (30 maggio 2021): 843. http://dx.doi.org/10.3390/genes12060843.
Testo completoAbstract (sommario):
Genomics has revolutionised the study of the biology of parasitic diseases. The first Eukaryotic parasite to have its genome sequenced was the malaria parasite Plasmodium falciparum. Since then, Plasmodium genomics has continued to lead the way in the study of the genome biology of parasites, both in breadth—the number of Plasmodium species’ genomes sequenced—and in depth—massive-scale genome re-sequencing of several key species. Here, we review some of the insights into the biology, evolution and population genetics of Plasmodium gained from genome sequencing, and look at potential new avenues in the future genome-scale study of its biology.
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Duraisingh, Manoj T., e Kristen M. Skillman. "Epigenetic Variation and Regulation in Malaria Parasites". Annual Review of Microbiology 72, n. 1 (8 settembre 2018): 355–75. http://dx.doi.org/10.1146/annurev-micro-090817-062722.
Testo completoAbstract (sommario):
Eukaryotic pathogens must survive in different hosts, respond to changing environments, and exploit specialized niches to propagate. Plasmodium parasites cause human malaria during bloodstream infections, where they must persist long enough to be transmitted. Parasites have evolved diverse strategies of variant gene expression that control critical biological processes of blood-stage infections, including antigenic variation, erythrocyte invasion, innate immune evasion, and nutrient acquisition, as well as life-cycle transitions. Epigenetic mechanisms within the parasite are being elucidated, with discovery of epigenomic marks associated with gene silencing and activation, and the identification of epigenetic regulators and chromatin proteins that are required for the switching and maintenance of gene expression. Here, we review the key epigenetic processes that facilitate transition through the parasite life cycle and epigenetic regulatory mechanisms utilized by Plasmodium parasites to survive changing environments and consider epigenetic switching in the context of the outcome of human infections.
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Quansah, Elvis, Faustina Pappoe, Jilong Shen, Miao Liu, Shijie Yang, Li Yu e Chao Zhang. "ApiAP2 Gene-Network Regulates Gametocytogenesis in Plasmodium Parasites". Cellular Microbiology 2022 (19 luglio 2022): 1–16. http://dx.doi.org/10.1155/2022/5796578.
Testo completoAbstract (sommario):
Malaria is a mosquito-borne infectious disease, caused by unicellular Apicomplexan protozoa of the genus Plasmodium. The sexual stage of Plasmodium is one of the most fascinating aspects of the Plasmodium life cycle, yet relatively less explored until now. The production of sexually fit gametocytes through gametocytogenesis is essential to the transmission of the Plasmodium parasite into an anopheline mosquito vector. Understanding how gametocytogenesis is regulated promotes the identification of novel drug targets and also the development of transmission-blocking vaccines that would help reduce the disease burden in endemic areas. Transcriptional regulation in Plasmodium parasites is primarily controlled by a family of twenty-seven Apicomplexan Apetela 2 (ApiAP2) genes which act in a cascade to enable the parasite to progress through its asexual replication as well as gametocytogenesis. Here, we review the latest progress made on members of the ApiAP2 family characterized as key players of the transcriptional machinery of gametocytes. Further, we will highlight the transcriptional regulation network of ApiAP2 genes at each stage of gametocytogenesis.
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Sarquis-Adamson, Yanina, e Elizabeth A. MacDougall-Shackleton. "Song sparrows Melospiza melodia have a home-field advantage in defending against sympatric malarial parasites". Royal Society Open Science 3, n. 8 (agosto 2016): 160216. http://dx.doi.org/10.1098/rsos.160216.
Testo completoAbstract (sommario):
Hosts and parasites interact on both evolutionary and ecological timescales. The outcome of these interactions, specifically whether hosts are more resistant to their local parasites (sympatric) than to parasites from another location (allopatric), is likely to affect the spread of infectious disease and the fitness consequences of host dispersal. We conducted a cross-infection experiment to determine whether song sparrows ( Melospiza melodia ) have an advantage in dealing with sympatric parasites. We captured birds from two breeding sites 437 km apart, and inoculated them with avian malaria ( Plasmodium spp.) cultured either from their capture site or from the other site. Infection risk was lower for birds exposed to sympatric than to allopatric Plasmodium lineages, suggesting that song sparrows may have a home-field advantage in defending against local parasite strains. This pattern was more pronounced at one capture site than at the other, consistent with mosaic models of host–parasite interactions. Home-field advantage may arise from evolutionary processes, whereby host populations become adapted to their local parasites, and/or from ecological interactions, whereby host individuals develop resistance to the local parasites through previous immune exposure. Our findings suggest that greater susceptibility to novel parasites may represent a fitness consequence of natal dispersal.
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Ndung'u, Loise, Benard Langat, Esther Magiri, Joseph Ng'ang'a, Beatrice Irungu, Alexis Nzila e Daniel Kiboi. "Amodiaquine resistance in Plasmodium berghei is associated with PbCRT His95Pro mutation, loss of chloroquine, artemisinin and primaquine sensitivity, and high transcript levels of key transporters". Wellcome Open Research 2 (20 giugno 2017): 44. http://dx.doi.org/10.12688/wellcomeopenres.11768.1.
Testo completoAbstract (sommario):
Background: The human malaria parasite Plasmodium falciparum has evolved complex drug evasion mechanisms to all available antimalarials. To date, the combination of amodiaquine-artesunate is among the drug of choice for treatment of uncomplicated malaria. In this combination, a short acting, artesunate is partnered with long acting, amodiaquine for which resistance may emerge rapidly especially in high transmission settings. Here, we used a rodent malaria parasite Plasmodium berghei ANKA as a surrogate of P. falciparum to investigate the mechanisms of amodiaquine resistance. Methods: We used serial technique to select amodiaquine resistance by submitting the parasites to continuous amodiaquine pressure. We then employed the 4-Day Suppressive Test to monitor emergence of resistance and determine the cross-resistance profiles. Finally, we genotyped the resistant parasite by PCR amplification, sequencing and relative quantitation of mRNA transcript of targeted genes. Results: Submission of P. berghei ANKA to amodiaquine pressure yielded resistant parasite within thirty-six passages. The effective dosage that reduced 90% of parasitaemia (ED90) of sensitive line and resistant line were 4.29mg/kg and 19.13mg/kg, respectively. After freezing at -80ºC for one month, the resistant parasite remained stable with an ED90 of 18.22mg/kg. Amodiaquine resistant parasites are also resistant to chloroquine (6fold), artemether (10fold), primaquine (5fold), piperaquine (2fold) and lumefantrine (3fold). Sequence analysis of Plasmodium berghei chloroquine resistant transporter revealed His95Pro mutation. No variation was identified in Plasmodium berghei multidrug resistance gene-1 (Pbmdr1), Plasmodium berghei deubiquitinating enzyme-1 or Plasmodium berghei Kelch13 domain nucleotide sequences. Amodiaquine resistance is also accompanied by high mRNA transcripts of key transporters; Pbmdr1, V-type/H+ pumping pyrophosphatase-2 and sodium hydrogen ion exchanger-1 and Ca2+/H+ antiporter. Conclusions: Selection of amodiaquine resistance yielded stable “multidrug-resistant’’ parasites and thus may be used to study common resistance mechanisms associated with other antimalarial drugs. Genome wide studies may elucidate other functionally important genes controlling AQ resistance in P. berghei.