scholarly journals CX3CL1 binding protein-2 (CBP2) of Plasmodium falciparum binds nucleic acids

2019 ◽  
Author(s):  
Ritu Saxena ◽  
Jasweer Kaur ◽  
Rachna Hora ◽  
Palwinder Singh ◽  
Vineeta Singh ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Nucleic Acids ◽  
Host Cell ◽  
Immune Modulation ◽  
Structural Changes ◽  
Parasite Development ◽  
Atp Binding ◽  
Reducing Conditions ◽  
Parasite Biology

AbstractSeveral exported Plasmodium falciparum(Pf) proteins contribute to malaria biology through their involvement in cytoadherence, immune evasion and host cell remodelling. Many of these exported proteins and other host molecules are present in iRBC (infected red blood cell) generated extracellular vesicles (EVs), which are responsible for host cell modification and parasite development. CX3CL1 binding proteins (CBPs) present on the surface of iRBC have been reported to contribute to cytoadhesion by binding with the chemokine ‘CX3CL1’ via their extracellular domains. Here, we have characterized the cytoplasmic domain of CBP2to understand its function in parasite biology using biochemical and biophysical methods. Recombinant cytoplasmic CBP2 (rcCBP2) binds nucleic acids showing interaction with DNA/RNA. rcCBP2 shows dimer formation under non-reducing conditions highlighting the role of disulphide bonds in oligomerization while ATP binding leads to structural changes in the protein. In vitro interaction studies depict its binding with a Maurer’s cleft resident protein ‘PfSBP1’, which is influenced by ATP binding of rcCBP2. Our results suggest CBP2 as a two-transmembrane (2TM) receptor responsible for targeting EVs and delivering cargo to host endothelial cells. We propose CBP2 as an important molecule having roles in cytoadherence and immune modulation through its extracellular and cytoplasmic domains respectively.

scholarly journals Reticulocyte Infection Leads to Altered Behaviour, Drug Sensitivity and Host Cell Remodelling by Plasmodium falciparum

2019 ◽  
Author(s):  
Renugah Naidu ◽  
Trang TT Chu ◽  
Jaishree Tripathi ◽  
Yang Hu ◽  
Gowtham Subramanian ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Red Blood Cells ◽  
Host Cell ◽  
Blood Cells ◽  
Host Cells ◽  
Differential Sensitivity ◽  
Parasite Development ◽  
Asexual Development ◽  
Disease Manifestation

AbstractPlasmodia are host-specific, both at the organism and cellular levels. During asexual development, Plasmodium spp. infect cells of erythroid lineage, with an overall propensity towards reticulocytes. This applies to even Plasmodium (P.) falciparum, the most common causative agent of human malaria, implications of which remain unexplored. Herein, for the first time, we characterize the developmental stages and features of P. falciparum cultured in vitro in young reticulocytes (CD71+) in comparison to standard normocyte (CD71-) cultures. We demonstrate that there are notable differences in the patterns of invasion, development and sensitivity to potent antimalarials (such as artemisinin and dihydroartemisinin) for parasites residing in CD71+ reticulocytes. Through a transcriptomic approach, we report that P. falciparum parasites are able to sense the host cell environment, and calibrate their metabolic and host cell remodelling pathways through differential gene expression. These results form an exciting avenue on which hitherto unexplored interactions between Plasmodium spp and different stages of host red blood cells could be investigated in the broader contexts of drug resistance, host tropism and zoonosis.Author SummaryParasites causing malaria infect red blood cells for development and proliferation during asexual development. This asexual erythrocytic stage determines higher parasite densities and eventual disease manifestation. Although the most virulent species of Plasmodium infecting humans known as Plasmodium falciparum is able to infect red blood cells of all ages, these parasites show a preference for younger blood cells. Of note, the biochemical and biophysical properties of young and adult red blood cells vary significantly. Herein, we undertook a comparative profiling of invasion process, parasite development and drug response of Plasmoddium falciparum in two host cells: young red blood cells (reticulocytes) and mature red blood cells (normocytes). We demonstrate that P. falciparum infects human reticulocytes with higher affinity and demonstrate differential sensitivity to drugs such as artemisinin while they reside within reticulocytes. Furthermore, we show that P. falciparum is able to detect differences in host environment and adapt to it by changing the expression of genes required for host cell remodelling.

scholarly journals Stage-dependent effect of deferoxamine on growth of Plasmodium falciparum in vitro

Blood ◽  
1990 ◽  
Vol 76 (6) ◽  
pp. 1250-1255 ◽  
Author(s):  
S Whitehead ◽  
TE Peto
Keyword(s):  
Plasmodium Falciparum ◽  
Growth Inhibition ◽  
Antimalarial Activity ◽  
Clinical Malaria ◽  
Inhibitory Effect ◽  
Parasite Development ◽  
And Control ◽  
Speed Of Onset

Abstract Deferoxamine (DF) has antimalarial activity that can be demonstrated in vitro and in vivo. This study is designed to examine the speed of onset and stage dependency of growth inhibition by DF and to determine whether its antimalarial activity is cytostatic or cytocidal. Growth inhibition was assessed by suppression of hypoxanthine incorporation and differences in morphologic appearance between treated and control parasites. Using synchronized in vitro cultures of Plasmodium falciparum, growth inhibition by DF was detected within a single parasite cycle. Ring and nonpigmented trophozoite stages were sensitive to the inhibitory effect of DF but cytostatic antimalarial activity was suggested by evidence of parasite recovery in later cycles. However, profound growth inhibition, with no evidence of subsequent recovery, occurred when pigmented trophozoites and early schizonts were exposed to DF. At this stage in parasite development, the activity of DF was cytocidal and furthermore, the critical period of exposure may be as short as 6 hours. These observations suggest that iron chelators may have a role in the treatment of clinical malaria.

scholarly journals Ex VivoMaturation Assay for Testing Antimalarial Sensitivity of Rodent Malaria Parasites

2016 ◽  
Vol 60 (11) ◽  
pp. 6859-6866 ◽  
Author(s):  
Zi Wei Chang ◽  
Benoit Malleret ◽  
Bruce Russell ◽  
Laurent Rénia ◽  
Carla Claser
Keyword(s):  
Ex Vivo ◽  
Single Step ◽  
Parasite Development ◽  
Ring Stage ◽  
Malaria Parasites ◽  
Rodent Malaria ◽  
Content Type ◽  
Parasite Biology

ABSTRACTEx vivoassay systems provide a powerful approach to studying human malaria parasite biology and to testing antimalarials. For rodent malaria parasites, short-termin vitroculture andex vivoantimalarial susceptibility assays are relatively cumbersome, relying onin vivopassage for synchronization, since ring-stage parasites are an essential starting material. Here, we describe a new approach based on the enrichment of ring-stagePlasmodium berghei,P. yoelii, andP. vinckei vinckeiusing a single-step Percoll gradient. Importantly, we demonstrate that the enriched ring-stage parasites develop synchronously regardless of the parasite strain or species used. Using a flow cytometry assay with Hoechst and ethidium or MitoTracker dye, we show that parasite development is easily and rapidly monitored. Finally, we demonstrate that this approach can be used to screen antimalarial drugs.

scholarly journals Altered Plasmodium falciparum Sensitivity to the Antiretroviral Protease Inhibitor Lopinavir Associated with Polymorphisms in pfmdr1

2016 ◽  
Vol 61 (1) ◽  
Author(s):  
Ebere Sonoiki ◽  
Christian Nsanzabana ◽  
Jennifer Legac ◽  
Kirthana M. V. Sindhe ◽  
Joseph DeRisi ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Protease Inhibitor ◽  
Genome Sequencing ◽  
Copy Number ◽  
Hiv Protease ◽  
Parasite Development ◽  
Whole Genome ◽  
Aspartic Proteases ◽  
Content Type

ABSTRACT The HIV protease inhibitor lopinavir inhibits Plasmodium falciparum aspartic proteases (plasmepsins) and parasite development, and children receiving lopinavir-ritonavir experienced fewer episodes of malaria than those receiving other antiretroviral regimens. Resistance to lopinavir was selected in vitro over ∼9 months, with ∼4-fold decreased sensitivity. Whole-genome sequencing of resistant parasites showed a mutation and increased copy number in pfmdr1 and a mutation in a protein of unknown function, but no polymorphisms in plasmepsin genes.

scholarly journals Plasmodium falciparum Founder Populations in Western Cambodia Have Reduced Artemisinin SensitivityIn Vitro

2014 ◽  
Vol 58 (8) ◽  
pp. 4935-4937 ◽  
Author(s):  
Chanaki Amaratunga ◽  
Benoit Witkowski ◽  
Dalin Dek ◽  
Vorleak Try ◽  
Nimol Khim ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Parasite Clearance ◽  
Parasite Development ◽  
Ring Stage ◽  
Content Type ◽  
Short Course ◽  
Founder Populations ◽  
Admixed Population ◽  
Survival Assay

ABSTRACTReducedPlasmodium falciparumsensitivity to short-course artemisinin (ART) monotherapy manifests as a long parasite clearance half-life. We recently defined three parasite founder populations with long half-lives in Pursat, western Cambodia, where reduced ART sensitivity is prevalent. Using the ring-stage survival assay, we show that these founder populations have reduced ART sensitivityin vitroat the early ring stage of parasite development and that a genetically admixed population contains subsets of parasites with normal or reduced ART sensitivity.

scholarly journals RNA Secondary Structurome Revealed Distinct Thermoregulation in Plasmodium falciparum

2022 ◽  
Vol 9 ◽  
Author(s):  
Yanwei Qi ◽  
Yuhong Zhang ◽  
Quankai Mu ◽  
Guixing Zheng ◽  
Mengxin Zhang ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Secondary Structure ◽  
Rna Structure ◽  
Rna Secondary Structure ◽  
Structural Changes ◽  
Environmental Changes ◽  
Parasite Development ◽  
Temperature Dependent ◽  
Trophozoite Stage ◽  
Temperature Changes

The development of Plasmodium parasites, a causative agent of malaria, requests two hosts and the completion of 11 different parasite stages during development. Therefore, an efficient and fast response of parasites to various complex environmental changes, such as ambient temperature, pH, ions, and nutrients, is essential for parasite development and survival. Among many of these environmental changes, temperature is a decisive factor for parasite development and pathogenesis, including the thermoregulation of rRNA expression, gametogenesis, and parasite sequestration in cerebral malaria. However, the exact mechanism of how Plasmodium parasites rapidly respond and adapt to temperature change remains elusive. As a fundamental and pervasive regulator of gene expression, RNA structure can be a specific mechanism for fine tuning various biological processes. For example, dynamic and temperature-dependent changes in RNA secondary structures can control the expression of different gene programs, as shown by RNA thermometers. In this study, we applied the in vitro and in vivo transcriptomic-wide secondary structurome approach icSHAPE to measure parasite RNA structure changes with temperature alteration at single-nucleotide resolution for ring and trophozoite stage parasites. Among 3,000 probed structures at different temperatures, our data showed structural changes in the global transcriptome, such as S-type rRNA, HRPII gene, and the erythrocyte membrane protein family. When the temperature drops from 37°C to 26°C, most of the genes in the trophozoite stage cause significantly more changes to the RNA structure than the genes in the ring stage. A multi-omics analysis of transcriptome data from RNA-seq and RNA structure data from icSHAPE reveals that the specific RNA secondary structure plays a significant role in the regulation of transcript expression for parasites in response to temperature changes. In addition, we identified several RNA thermometers (RNATs) that responded quickly to temperature changes. The possible thermo-responsive RNAs in Plasmodium falciparum were further mapped. To this end, we identified dynamic and temperature-dependent RNA structural changes in the P. falciparum transcriptome and performed a comprehensive characterization of RNA secondary structures over the course of temperature stress in blood stage development. These findings not only contribute to a better understanding of the function of the RNA secondary structure but may also provide novel targets for efficient vaccines or drugs.

scholarly journals Plasmodium falciparum sexual parasites develop in human erythroblasts and affect erythropoiesis

Blood ◽  
2020 ◽  
Vol 136 (12) ◽  
pp. 1381-1393 ◽  
Author(s):  
Gaëlle Neveu ◽  
Cyrielle Richard ◽  
Florian Dupuy ◽  
Prativa Behera ◽  
Fiona Volpe ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Plasmodium Falciparum ◽  
Host Cell ◽  
Erythroid Differentiation ◽  
Parasite Transmission ◽  
New Host ◽  
Sexual Stages ◽  
Hematopoietic Niche

Abstract Plasmodium falciparum gametocytes, the sexual stage responsible for malaria parasite transmission from humans to mosquitoes, are key targets for malaria elimination. Immature gametocytes develop in the human bone marrow parenchyma, where they accumulate around erythroblastic islands. Notably though, the interactions between gametocytes and this hematopoietic niche have not been investigated. Here, we identify late erythroblasts as a new host cell for P falciparum sexual stages and show that gametocytes can fully develop inside these nucleated cells in vitro and in vivo, leading to infectious mature gametocytes within reticulocytes. Strikingly, we found that infection of erythroblasts by gametocytes and parasite-derived extracellular vesicles delay erythroid differentiation, thereby allowing gametocyte maturation to coincide with the release of their host cell from the bone marrow. Taken together, our findings highlight new mechanisms that are pivotal for the maintenance of immature gametocytes in the bone marrow and provide further insights on how Plasmodium parasites interfere with erythropoiesis and contribute to anemia in malaria patients.

scholarly journals Icacina senegalensis (Icacinaceae), traditionally used for the treatment of malaria, inhibits in vitro Plasmodium falciparum growth without host cell toxicity

2011 ◽  
Vol 10 (1) ◽  
pp. 85 ◽  
Author(s):  
Serigne O Sarr ◽  
Sylvie Perrotey ◽  
Ibrahima Fall ◽  
Saïd Ennahar ◽  
Minjie Zhao ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Host Cell ◽  
Cell Toxicity
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