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PubMed2004

Persistent histidine-rich protein 2, parasite lactate dehydrogenase, and panmalarial antigen reactivity after clearance of Plasmodium falciparum monoinfection.

We tested 240 patients with Plasmodium falciparum monoinfection for persistent parasite antigenemia after successful standardized antimalarial therapy by using the ICT Malaria Pf/Pv and OptiMAL-IT assays that detect the malaria antigens Plasmodium falciparum histidine-rich protein 2 (HRP2) and parasite lactate dehydrogenase (pLDH), respectively, as well as a panmalarial antigen (PMA). The patients were screened for antigenemia on days 0, 3, 7, and 14 of follow-up. On day 0, all 240 patients showed positive reactivity with both assays. Of the 229 cases with negative parasitemia on day 3, persistent antigenemia was observed in 207 (90.4%) of the cases: 188 (82.1%) for HRP2 antigen and 75 (32.8%) for PMA. There was a gradual decrease in antigenemia on follow-up to day 14; however, the drop in reactivity to PMA was less than that for HRP2 antigen. In contrast to HRP2 antigenemia, there was a significant decrease in pLDH antigenemia to 38.4% and to 14.8% (PMA) on day 3 (P < 0.03). The pLDH antigenemia level dropped further to 14.8% on day 7. There was no significant association of persistent antigenemia with gametocytemia. One case with gametocytemia was negative for both the antigens. In conclusion, the OptiMAL-IT assay is more sensitive than the ICT Malaria Pf/Pv test for monitoring therapeutic responses after antimalarial therapy since the LDH activity ceases when the malarial parasite dies.

Adult↗

PubMed2025

Degradation of ribosomal RNA during Plasmodium falciparum gametocytogenesis.

The life cycle of Plasmodium falciparum is characterized by complex regulatory changes that allow adaptation of the parasites to different environmental conditions, which are especially pronounced during transmission between the mammalian host and the insect vector. Previous studies have shown that P. falciparum uses three types of ribosomal RNAs (rRNA A, S1, and S2 types) at different stages of its life cycle. We used Oxford Nanopore Technologies direct RNA sequencing to investigate the dynamics of rRNA usage throughout the parasite's intraerythrocytic development, as well as in salivary gland sporozoites. Our study revealed a preponderance of A-type rRNAs during the intraerythrocytic cycle and gametocytogenesis, while S-type rRNAs slowly increase in abundance in mosquito stages starting 3 days post-infection. Salivary gland sporozoites showed an even proportion of all rRNA types. By examining the length distributions of rRNA molecules, we detected an extensive and specific degradation of rRNAs during gametocytogenesis, starting in stage II gametocytes and continuing until the final stages of gametocyte development. We hypothesize that rRNA degradation may be linked to the global translational repression and metabolic quiescence described in stage V gametocytes, similar to mechanisms observed in bacterial and eukaryotic stress responses.IMPORTANCEOur study uses Oxford Nanopore direct RNA sequencing of tightly synchronized blood-stage Plasmodium falciparum parasites to investigate the expression of ribosomal RNAs during asexual and sexual development. P. falciparum utilizes distinct types of rRNA during its development. However, due to the challenges of differentiating these highly similar molecules, their regulation and the mechanism underlying the switch between rRNA types remain unclear. We observe significant rRNA degradation in mature gametocytes, leading us to propose that this potentially leads to a reduced number of functional ribosomes when parasites become quiescent and translation is repressed.

Plasmodium falciparum↗

PubMed1990

Complex transcription from the extrachromosomal DNA encoding mitochondrial functions of Plasmodium yoelii.

All tested members of genus Plasmodium contain tandemly arrayed, transcribed, extrachromosomal DNA with a unit length of 6.0 kb. This DNA contains two open reading frames with potential to encode cytochrome c oxidase subunit I (cox1) and cytochrome b (cob) as well as fragments of rRNA genes scattered on both strands. At least 10 discrete RNA molecules transcribed during erythrocytic stages of a rodent malarial parasite, Plasmodium yoelii, were recognized by the 6.0-kb DNA probes. The RNA molecules of 1.4 and 1.1 kb were identified as encoding cox1 and cob, respectively. Primer extension and RNA sequencing were used to locate and characterize 5' ends of these two RNAs, showing that an identical 12-nucleotide sequence, 5'-TATTTTT TGTTT-3', was present at these positions. This sequence may act as a promoter or as an RNA processing signal. A stem-loop structure signifying a possible transcription termination was present at the end of the cox1 open reading frame. At least six discrete RNA molecules of less than 250 nucleotides were recognized by different fractions of the 6.0-kb DNA. The largest of these, 200 nucleotides, was also characterized by primer extension and RNA sequencing. This molecule had a high homology to portions of the large-subunit rRNA domains IV and V. Other, small RNA molecules were recognized by regions of the 6.0-kb DNA that had homology to the highly conserved peptidyltransferase domain of large-subunit rRNA. These results show that the unusual compactly organized mitochondrionlike DNA of malarial parasites is transcribed in a complex pattern.

Amino Acid Sequence↗

PubMed2025

Acetyl-CoA synthetase mutations affect the susceptibility of Plasmodium falciparum to antimalarial drugs.

Plasmodium falciparum acetyl-CoA synthetase (PfAcAS) is an important source of acetyl-CoA. We detected mutations S868G and V950I in PfAcAS by whole-genome sequencing analysis in certain recrudescent parasites after treatment with artesunate and dihydroartemisinin-piperaquine. Using CRISPR/Cas9 technology, we engineered parasite lines to carry the PfAcAS S868G and V950I mutations in two genetic backgrounds and evaluated their susceptibilities to antimalarial drugs in vitro. The results demonstrated that PfAcAS S868G and V950I mutations alone or in combination affected the susceptibility of P. falciparum to several antimalarial drugs, including the artemisinin derivatives (dihydroartemisinin, artesunate, and artemether) and chloroquine, although absolute changes in susceptibilities were modest.IMPORTANCEMalaria, an infectious disease caused by Plasmodium parasites and transmitted by mosquitoes, continues to be one of the most pressing public health challenges worldwide. P. falciparum has demonstrated reduced sensitivity to artemisinin-based combination therapies (ACTs), thereby intensifying the difficulties associated with malaria management. Currently, only a limited number of molecular markers exist for identifying drug resistance in P. falciparum, and these markers do not fully elucidate the mechanisms behind this resistance. In this study, we performed whole-genome sequencing analysis on P. falciparum strains that reemerged following ACT treatment. We aim to identify molecules potentially associated with drug resistance, which may provide new molecular markers for monitoring drug resistance in P. falciparum.

Plasmodium falciparum↗

PubMed2004

Plasmodium sporozoite molecular cell biology.

Plasmodium sporozoites display complex phenotypes including gliding motility and invasion of and transmigration through cells in the mosquito vector and the vertebrate host. Sporozoite studies have been difficult to perform because of technical concerns. Nevertheless, they have already provided insights into several aspects of sporozoite biology, shared in part with other apicomplexan invasive stages. Structure/function analysis of the thrombospondin-related anonymous protein paved the way to the understanding of the molecular mechanisms of apicomplexan gliding motility and host cell invasion. Functional studies of circumsporozoite protein revealed its role in Plasmodium sporozoite morphogenesis in addition to its well-known function in host cell invasion. Transcriptional surveys, which facilitate the investigation of gene expression programs that control sporozoite phenotypes, have revealed a high degree of previously unappreciated complexity and novel proteins that mediate sporozoite host cell infection.

Animals↗

PubMed2003

Electrophysiological properties of the Plasmodium Falciparum-induced cation conductance of human erythrocytes.

Intraerythrocyte survival of the malaria pathogen Plasmodium Falciparum depends on the induction of the new-permeability-pathways (NPPs) in the host cell membrane. NPPs are characterized as anion- and organic osmolyte-permeable channels which also exhibit a low but significant permeability for inorganic cations. To disclose the electrophyiologial properties of this infection-induced cation permeability whole-cell currents were recorded in Plasmodium Falciparum-infected human erythrocytes (pRBC) using bath and pipette solutions with low Cl(-) concentrations. The data disclose a nonselective cation conductance (G(CAT)) which activated upon removal of extracellular Cl(-). Upon activation, G(CAT) was 0.3 +/- 0.05 nS (n=16) in control RBC and 2.0 +/- 0.3 nS (n = 32) in pRBC indicating an induction of G(CAT) during the infection. G(CAT) of pRBC exibited a relative permselectivity for monovalent cations of Cs(+)ñK(+)>Na(+)>Li(+) (P(Na)/P(K) ñ 0.5) with a significant permeability for Ca(2+). G(CAT) of pRBC was inhibited by NPPs blockers (furosemide and NPPB) and cation channel blockers (amiloride, EIPA, GdCl(3)) with the highest sensitivity to EIPA (IC(50)-0.5 microM). Most importantly, the blocker sensitivities differed between the infection-induced anion conductances and G(CAT) suggesting that G(CAT) and the anion conductances represent different channel proteins which in concert build up the NPPs.

Amiloride↗

PubMed2026

Population genomics of Plasmodium malariae from 4 African countries.

BACKGROUNDMalaria caused by Plasmodium malariae is geographically widespread and sometimes associated with prolonged infection, yet little is known about its genomic epidemiology.METHODSWe performed hybrid capture and whole-genome sequencing of 77 isolates collected from Cameroon (n = 7), the Democratic Republic of the Congo (n = 16), Nigeria (n = 4), and Tanzania (n = 50) between 2015 and 2021, analyzing parasite genetic population structure and demography.RESULTSThere is no evidence of geographic population structure. Nucleotide diversity was significantly lower than in colocalized P. falciparum isolates, while linkage disequilibrium was significantly higher. Genome-wide selection scans identified no erythrocyte invasion ligands or antimalarial resistance orthologs as top hits; however, targeted analyses of these loci revealed evidence of selective sweeps around 4 erythrocyte invasion ligands and 6 antimalarial resistance orthologs. Demographic inference modeling suggests that African P. malariae is recovering from a bottleneck.CONCLUSIONP. malariae is genomically atypical among human Plasmodium spp. and lacks strong population structure in Africa. The low diversity has potential impacts on understanding persistent versus new infection through genomic epidemiology.FUNDINGBill & Melinda Gates Foundation (grant 002202), USAID/PMI through Jhpiego and CDC, NIH (T32AI007151, T32AI070114, R01AI107949, R01AI129812, R21 AI148579, R01AI137395, R21AI152260, R01AI132547, and K24AI134990), and the DELTAS Africa initiative (DELGEME grant 107740/Z/15/Z).

Plasmodium malariae↗

PubMed2000

Frequency of pruritus in Plasmodium vivax malaria patients treated with chloroquine in Thailand.

Chloroquine-induced itch in black-skinned African malaria patients is common and frequently leads to poor compliance or treatment defaulting.To assess the frequency and severity of chloroquine-induced pruritus in an Asian population, we reviewed case records of 1189 Plasmodium vivax malaria patients treated with chloroquine (25 mg/kg over 3 days) at the Bangkok Hospital for Tropical Diseases from 1992 through 1997. The majority of patients were Thais or ethnic Burmese (light brown skin), referred from the western border of Thailand. Overall, there were 23 patients (1.9%) with complaints of pruritus during chloroquine therapy. Of these, 12 (52%) had palm and sole involvement, eight (35%) had generalized pruritus including the palms and soles, and three (13%) had palm itching only. One patient developed pruritus on the palms and soles on two consecutive admissions. The pruritus did not interfere with daily activity, was reduced in intensity by anti-histamine therapy, and did not affect the patient's willingness to complete the chloroquine regimen. Therapeutic responses in the 23 patients with chloroquine itch was similar to those without itch. Among the itch patients, there was no association with gender or level of parasitaemias. Our findings indicate that the frequency of chloroquine-induced pruritus in Asian patients treated with chloroquine for P. vivax malaria is low in comparison with black-skinned Africans.This may be related to pharmacogenetic factors, the infective Plasmodium species, drug metabolism or drug-parasite interactions, or a lower affinity of chloroquine for less pigmented skin.

Adolescent↗

PubMed2003

Generation of an erythrocyte vesicle transport system by Plasmodium falciparum malaria parasites.

The asexual maturation of Plasmodium falciparum is accompanied by the transport of parasite-encoded proteins to the erythrocyte plasma membrane. Activation of G proteins by treatment with aluminum fluoride produced an accumulation within the erythrocyte cytosol of vesicles coated with Plasmodium homologues of COPII and N-ethylmaleimide-sensitive factor, proteins involved in intracellular transport between the Golgi apparatus and the endoplasmic reticulum. These vesicles contain malarial proteins that appear on the erythrocyte plasma membrane, as well as actin and myosin. It is proposed that the parasite adapted a process well established for intracellular transport to mediate the extracellular movement of its proteins through the erythrocyte cytosol to the surface membrane.

Actins↗

PubMed2026

Plasmodium knowlesi can adapt to infect Duffy-negative erythrocytes.

Plasmodium knowlesi, a zoonotic malaria species, has become a significant public health concern in Southeast Asia. In regions such as Malaysia and southern Thailand, P knowlesi incidence has risen, even as other human malaria parasites are nearing elimination. Similar to its close relative Plasmodium vivax, P knowlesi relies on the Duffy antigen receptor for chemokine (DARC) as a key receptor for erythrocyte invasion. Only Duffy-positive individuals are thought to be susceptible to clinical infection. Here, we demonstrate that P knowlesi possesses greater invasion plasticity than previously recognized. This parasite can bypass the need for DARC, as shown by its in vitro adaptation to invade and replicate within Duffy-negative (Fy-) erythrocytes. This adaptation is stable and independent of DARC binding, enabling the adapted parasite line to be maintained in Fy- erythrocytes and to resist inhibition by α-DARC antibodies. Genomic analysis identified a genomic recombination event between the parasite's dbpα and dbpγ genes, resulting in a new chimeric gene dbpαγ. Using CRISPR-Cas9 targeted reversion, we could demonstrate that dbpαγ is essential for invasion of Fy- erythrocytes. These findings shed new light on the invasion plasticity of P knowlesi, with implications for the parasite's potential spread beyond Southeast Asia and for understanding the complex host-cell specificity and atypical invasion pathways seen in P vivax.

Plasmodium knowlesi↗

PubMed2001

A novel tetratricopeptide repeat (TPR) containing PP5 serine/threonine protein phosphatase in the malaria parasite, Plasmodium falciparum.

BACKGROUND: The malarial parasite, Plasmodium falciparum (Pf), is responsible for nearly 2 million deaths worldwide. However, the mechanisms of cellular signaling in the parasite remain largely unknown. Recent discovery of a few protein kinases and phosphatases point to a thriving reversible phosphorylation system in the parasite, although their function and regulation need to be determined. RESULTS: We provide biochemical and sequence evidence for a protein serine/threonine phosphatase type PP5 in Plasmodium falciparum, and named it PfPP5. The 594-amino acid polypeptide was encoded by a 1785 nucleotide long intronless gene in the parasite. The recombinant protein, expressed in bacteria, was indistinguishable from native PfPP5. Sequencing comparison indicated that the extra-long N-terminus of PfPP5 outside the catalytic core contained four tetratricopeptide repeats (TPRs), compared to three such repeats in other PP5 phosphatases. The PfPP5 N-terminus was required for stimulation of the phosphatase activity by polyunsaturated fatty acids. Co-immunoprecipitation demonstrated an interaction between native PfPP5 and Pf heat shock protein 90 (hsp90). PfPP5 was expressed in all the asexual erythrocytic stages of the parasite, and was moderately sensitive to okadaic acid. CONCLUSIONS: This is the first example of a TPR-domain protein in the Apicomplexa family of parasites. Since TPR domains play important roles in protein-protein interaction, especially relevant to the regulation of PP5 phosphatases, PfPP5 is destined to have a definitive role in parasitic growth and signaling pathways. This is exemplified by the interaction between PfPP5 and the cognate chaperone hsp90.

Amino Acid Sequence↗

PubMed2002

Characterisation and expression of a PP1 serine/threonine protein phosphatase (PfPP1) from the malaria parasite, Plasmodium falciparum: demonstration of its essential role using RNA interference.

BACKGROUND: Reversible protein phosphorylation is relatively unexplored in the intracellular protozoa of the Apicomplexa family that includes the genus Plasmodium, to which belong the causative agents of malaria. Members of the PP1 family represent the most highly conserved protein phosphatase sequences in phylogeny and play essential regulatory roles in various cellular pathways. Previous evidence suggested a PP1-like activity in Plasmodium falciparum, not yet identified at the molecular level. RESULTS: We have identified a PP1 catalytic subunit from P. falciparum and named it PfPP1. The predicted primary structure of the 304-amino acid long protein was highly similar to PP1 sequences of other species, and showed conservation of all the signature motifs. The purified recombinant protein exhibited potent phosphatase activity in vitro. Its sensitivity to specific phosphatase inhibitors was characteristic of the PP1 class. The authenticity of the PfPP1 cDNA was further confirmed by mutational analysis of strategic amino acid residues important in catalysis. The protein was expressed in all erythrocytic stages of the parasite. Abrogation of PP1 expression by synthetic short interfering RNA (siRNA) led to inhibition of parasite DNA synthesis. CONCLUSIONS: The high sequence similarity of PfPP1 with other PP1 members suggests conservation of function. Phenotypic gene knockdown studies using siRNA confirmed its essential role in the parasite. Detailed studies of PfPP1 and its regulation may unravel the role of reversible protein phosphorylation in the signalling pathways of the parasite, including glucose metabolism and parasitic cell division. The use of siRNA could be an important tool in the functional analysis of Apicomplexan genes.

Animals↗

PubMed2004

Inter-allelic recombination in the Plasmodium vivax merozoite surface protein 1 gene among Indian and Colombian isolates.

BACKGROUND: A major concern in malaria vaccine development is the polymorphism observed among different Plasmodium isolates in different geographical areas across the globe. The merozoite surface protein 1 (MSP-1) is a leading vaccine candidate antigen against asexual blood stages of malaria parasite. To date, little is known about the extent of sequence variation in the Plasmodium vivax MSP-1 gene (Pvmsp-1) among Indian isolates. Since P. vivax accounts for >50% of malaria cases in India and in Colombia, it is essential to know the Pvmsp-1 gene variability in these two countries to sustain it as a vaccine candidate. The extent of polymorphism in Pvmsp-1 gene among Indian and Colombian isolates is described. METHODS: The sequence variation in the region encompassing the inter-species conserved blocks (ICBs) five and six of Pvmsp-1 gene was examined. PCR was carried out to amplify the polymorphic region of Pvmsp-1 and the PCR products from twenty (nine Indian and 11 Colombian) isolates were sequenced and aligned with Belem and Salvador-1 sequences. RESULTS: Results revealed three distinct types of sequences among these isolates, namely, Salvador-like, Belem-like and a third type sequence which was generated due to interallelic recombination between Salvador-like sequences and Belem-like sequences. Existence of the third type in majority (44%) showed that allelic recombinations play an important role in PvMSP1 diversity in natural parasite population. Micro-heterogeneity was also seen in a few of these isolates due to nucleotide substitutions, insertions as well as deletions. CONCLUSIONS: Intergenic recombination in the Pvmsp-1 gene was found and suggest that this is the main cause for genetic diversity of the Pvmsp-1 gene.

Alleles↗

PubMed2004

Genetic diversity of Plasmodium vivax isolates from Azerbaijan.

BACKGROUND: Plasmodium vivax, although causing a less serious disease than Plasmodium falciparum, is the most widespread of the four human malarial species. Further to the recent recrudescence of P. vivax cases in the Newly Independent States (NIS) of central Asia, a survey on the genetic diversity and dissemination in Azerbaijan was undertaken. Azerbaijan is at the crossroads of Asia and, as such, could see a rise in the number of cases, although an effective malaria control programme has been established in the country. METHODS: Thirty-six P. vivax isolates from Central Azerbaijan were characterized by analysing the genetic polymorphism of the circumsporozoite protein (CSP) and the merozoite surface protein 1 (MSP-1) genes, using PCR amplifications and amplicons sequencing. RESULTS: Analysis of CSP sequences showed that all the processed isolates belong to the VK 210 type, with variations in the alternation of alanine residue (A) or aspartic acid residue (D) in the repeat motif GDRA(A/D)GQPA along the sequence. As far as MSP-1 genotyping is concerned, it was found that the majority of isolates analysed belong to Belem and Sal I types. Five recombinant isolates were also identified. Combined analysis with the two genetic markers allowed the identification of 19 plasmodial sub-types. CONCLUSION: The results obtained in the present study indicate that there are several P. vivax clones circulating in Azerbaijan and, consequently, a careful malaria surveillance could be of paramount importance to identify, at early stage, the occurrence of possible P. vivax malaria outbreaks.

Adolescent↗

PubMed2004

Low sensitivity of nested PCR using Plasmodium DNA extracted from stained thick blood smears: an epidemiological retrospective study among subjects with low parasitaemia in an endemic area of the Brazilian Amazon region.

BACKGROUND: The success of PCR technique depends on many factors, such as high quality DNA pellets obtained from blood samples, good reagents and adequate conditions of amplification. Taking these limitations into account, a retrospective epidemiological study for malaria diagnosis was conducted in a mesoendemic area in the Brazilian Amazon. METHODS: A nested PCR protocol with DNA extracted from two blood storage devices obtained from Giemsa-stained thick blood smears and filter-papers was used for malaria diagnosis. The extracted DNA was used as a template to amplify approximately 100 bp species-specific sequences of the small subunit of the ribosomal RNA (18S SSU rRNA) of Plasmodium sp. The prevalence of single and mixed infections was examined in a cross-sectional survey carried out among 369 miners living in the district of Apiacás, Mato Grosso State. The parasitemia levels detected by microscopic examination were compared to the PCR results. RESULTS: DNA samples isolated from blood on filter-paper allowed the detection and identification of Plasmodium in 165 (44.7%) of the 369 individuals evaluated, while only 62 (16.8%) had positive results using DNA obtained from thick smears, a similar rate observed by microscopic examination. The sensitivities of PCR using DNA from blood smears and filter-papers were 65% and 73.0%, respectively. Low parasite infections (below 20 parasites/ micro L blood) were not detected when thick blood smears were used as a DNA source. CONCLUSIONS: Although the blood preserved as thick blood smears provides an alternative and useful tool for malaria molecular diagnosis, its relatively poor performance at low level parasitemias impairs the correct determination of malaria prevalence in epidemiological studies. However, the results obtained in the present study confirm that the use of filter-paper to collect blood is useful for field studies.

Animals↗

PubMed2005

Practical PCR genotyping protocols for Plasmodium vivax using Pvcs and Pvmsp1.

BACKGROUND: Plasmodium vivax is the second most prevalent malaria parasite affecting more than 75 million people each year, mostly in South America and Asia. In addition to major morbidity this parasite is associated with relapses and a reduction in birthweight. The emergence and spread of drug resistance in Plasmodium falciparum is a major factor in the resurgence of this parasite. P. vivax resistance to drugs has more recently emerged and monitoring the situation would be helped, as for P. falciparum, by molecular methods that can be used to characterize parasites in field studies and drug efficacy trials. METHODS: Practical PCR genotyping protocols based on polymorphic loci present in two P. vivax genetic markers, Pvcs and Pvmsp1, were developed. The methodology was evaluated using 100 P. vivax isolates collected in Thailand. RESULTS AND DISCUSSION: Analysis revealed that P. vivax populations in Thailand are highly diverse genetically, with mixed genotype infections found in 26 % of the samples (average multiplicity of infection = 1.29). A large number of distinguishable alleles were found for the two markers, 23 for Pvcs and 36 for Pvmsp1. These were generally randomly distributed amongst the isolates. A total of 68 distinct genotypes could be enumerated in the 74 isolates with a multiplicity of infection of 1. CONCLUSION: These results indicate that the genotyping protocols presented can be useful in the assessment of in vivo drug efficacy clinical trials conducted in endemic areas and for epidemiological studies of P. vivax infections.

Alleles↗

PubMed2005

Plasmodium yoelii 17XL infection up-regulates RANTES, CCR1, CCR3 and CCR5 expression, and induces ultrastructural changes in the cerebellum.

BACKGROUND: Malaria afflicts 300-500 million people causing over 1 million deaths globally per year. The immunopathogenesis of malaria is mediated partly by co mplex cellular and immunomodulator interactions involving co-regulators such as cytokines and adhesion molecules. However, the role of chemokines and their receptors in malaria immunopathology remains unclear. RANTES (Regulated on Activation Normal T-Cell Expressed and Secreted) is a chemokine involved in the generation of inflammatory infiltrates. Recent studies indicate that the degradation of cell-cell junctions, blood-brain barrier dysfunction, recruitment of leukocytes and Plasmodium-infected erythrocytes into and occlusion of microvessels relevant to malaria pathogenesis are associated with RANTES expression. Additionally, activated lymphocytes, platelets and endothelial cells release large quantities of RANTES, thus suggesting a unique role for RANTES in the generation and maintenance of the malaria-induced inflammatory response. The hypothesis of this study is that RANTES and its corresponding receptors (CCR1, CCR3 and CCR5) modulate malaria immunopathogenesis. A murine malaria model was utilized to evaluate the role of this chemokine and its receptors in malaria. METHODS: The alterations in immunomodulator gene expression in brains of Plasmodium yoelii 17XL-infected mice was analysed using cDNA microarray screening, followed by a temporal comparison of mRNA and protein expression of RANTES and its corresponding receptors by qRT-PCR and Western blot analysis, respectively. Plasma RANTES levels was determined by ELISA and ultrastructural studies of brain sections from infected and uninfected mice was conducted. RESULTS: RANTES (p < 0.002), CCR1 (p < 0.036), CCR3 (p < 0.033), and CCR5 (p < 0.026) mRNA were significantly upregulated at peak parasitaemia and remained high thereafter in the experimental mouse model. RANTES protein in the brain of infected mice was upregulated (p < 0.034) compared with controls. RANTES plasma levels were significantly upregulated; two to three fold in infected mice compared with controls (p < 0.026). Some distal microvascular endothelium in infected cerebellum appeared degraded, but remained intact in controls. CONCLUSION: The upregulation of RANTES, CCR1, CCR3, and CCR5 mRNA, and RANTES protein mediate inflammation and cellular degradation in the cerebellum during P. yoelii 17XL malaria.

Animals↗

PubMed2006

Molecular surveillance of mutations in the cytochrome b gene of Plasmodium falciparum in Gabon and Ethiopia.

BACKGROUND: Atovaquone is part of the antimalarial drug combination atovaquone-proguanil (Malarone) and inhibits the cytochrome bc1 complex of the electron transport chain in Plasmodium spp. Molecular modelling showed that amino acid mutations are clustered around a putative atovaquone-binding site resulting in a reduced binding affinity of atovaquone for plasmodial cytochrome b, thus resulting in drug resistance. METHODS: The prevalence of cytochrome b point mutations possibly conferring atovaquone resistance in Plasmodium falciparum isolates in atovaquone treatment-naïve patient cohorts from Lambaréné, Gabon and from South Western Ethiopia was assessed. RESULTS: Four/40 (10%) mutant types (four different single polymorphisms, one leading to an amino acid change from M to I in a single case) in Gabonese isolates, but all 141/141 isolates were wild type in Ethiopia were found. CONCLUSION: In the absence of drug pressure, spontaneous and possibly resistance-conferring mutations are rare.

Animals↗