scholarly journals Plasmodium falciparum dipeptidyl aminopeptidase 3 activity is important for efficient erythrocyte invasion by the malaria parasite

2017 ◽  
Author(s):  
Christine Lehmann ◽  
Michele Ser Ying Tan ◽  
Laura E. de Vries ◽  
Ilaria Russo ◽  
Mateo Isidrio Sanchez ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Cysteine Protease ◽  
Malaria Parasite ◽  
Biological Function ◽  
Wild Type ◽  
Knock Out ◽  
Erythrocyte Invasion ◽  
Parasite Replication ◽  
Dipeptidyl Aminopeptidase ◽  
Parasite Egress

ABSTRACTParasite egress from infected erythrocytes and invasion of new erythrocytes are essential for the exponential asexual replication of the malaria parasite, and both processes are regulated and mediated by proteases. The putative cysteine protease dipeptidyl aminopeptidase 3 (DPAP3) was previously suggested to be essential for parasite egress, but little is known about its biological function. Here, we demonstrate that DPAP3 has proteolytic activity, but contrary to previously studied DPAPs, removal of its prodomain is not required for activation. Interestingly, P. falciparum DPAP3 localizes to merozoite apical organelles from which it is secreted immediately before egress. Using a conditional knock out approach coupled to complementation studies with wild type or mutant DPAP3, we show that DPAP3 activity is critical for efficient RBC invasion and overall parasite replication, and demonstrate that it does not play a role in parasite egress. Overall, this study establishes DPAP3 as a key regulator of erythrocyte invasion.

scholarly journals Plasmodium falciparum dipeptidyl aminopeptidase 3 activity is important for efficient erythrocyte invasion by the malaria parasite

2018 ◽  
Vol 14 (5) ◽  
pp. e1007031 ◽  
Author(s):  
Christine Lehmann ◽  
Michele Ser Ying Tan ◽  
Laura E. de Vries ◽  
Ilaria Russo ◽  
Mateo I. Sanchez ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Parasite ◽  
Erythrocyte Invasion ◽  
Dipeptidyl Aminopeptidase

scholarly journals Molecular Analysis of Erythrocyte Invasion in Plasmodium falciparum Isolates from Senegal

2007 ◽  
Vol 75 (7) ◽  
pp. 3531-3538 ◽  
Author(s):  
Cameron V. Jennings ◽  
Ambroise D. Ahouidi ◽  
Martine Zilversmit ◽  
Amy K. Bei ◽  
Julian Rayner ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Gene Amplification ◽  
Malaria Parasite ◽  
Sequence Polymorphism ◽  
Invasion Pathways ◽  
Specific Sequence ◽  
Erythrocyte Invasion ◽  
Sequence Deletion ◽  
High Prevalence ◽  
Transmission Area

ABSTRACT The human malaria parasite, Plasmodium falciparum, utilizes multiple ligand-receptor interactions for the invasion of human erythrocytes. Members of the reticulocyte binding protein homolog (PfRh) family have been shown to be critical for directing parasites to alternative erythrocyte receptors that define invasion pathways. Recent studies have identified gene amplification, sequence polymorphism, and variant expression of PfRh paralogs as mechanisms underlying discrimination between pathways for invasion. In this study, we find considerable heterogeneity in the invasion profiles of clonal, uncultured P. falciparum parasite isolates from a low-transmission area in Senegal. Molecular analyses revealed minimal variation in protein expression levels of the PfRh ligands, PfRh1, PfRh2a, and PfRh2b, and an absence of gene amplification in these isolates. However, significant sequence polymorphism was found within repeat regions of PfRh1, PfRh2a, and PfRh2b. Furthermore, we identified a large sequence deletion (∼0.58 kb) in the C-terminal region of the PfRh2b gene at a high prevalence in this population. In contrast to findings of earlier studies, we found no associations between specific sequence variants and distinct invasion pathways. Overall these data highlight the importance of region-specific elaborations in PfRh sequence and expression polymorphisms, which has important implications in our understanding of how the malaria parasite responds to polymorphisms in erythrocyte receptors and/or evades the immune system.

scholarly journals Molecular Epidemiology of Plasmodium falciparum Chloroquine Resistance Transporter Genes among School Children in Kwara State, Southwestern Nigeria

2020 ◽  
pp. 1-12
Author(s):  
A. O. Oluwasogo ◽  
H. O. Ismail ◽  
D. A. Pelumi
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Parasite ◽  
Chloroquine Resistance ◽  
Fixation Method ◽  
Age Group ◽  
Wild Type ◽  
School Students ◽  
Southwestern Nigeria ◽  
Parasite Count ◽  
Chloroquine Resistance Transporter

Background: Plasmodium falciparum existence continues to develop resistance to conventional antimalaria drugs in malaria endemic areas. Plasmodia often prevent drugs from interacting with the target site, hence, developing resistance to antimalaria drugs. Mutations in the Plasmodium falciparum chloroquine resistance transporter (Pfcrt), are the major determinant of chloroquine resistance in human malaria parasite. Methodology: Malaria infection, Pfcrt and Pfmdr1 genes of isolates among school students within the age range of 11-22 years from four selected rural communities of Kwara state were studied. One hundred and eighty seven subjects (187) were selected for the study. Blood samples were collected by finger prick method for malaria screening. Nested PCR and restriction fragment length polymorphism (RFLP) were done to detect alleles of pfcrt at codon 76 and pfmdr1 at codon 86. DNA of isolates was appropriately extracted from the filter paper blots using the methanol fixation method. Logistic regression was performed on the binary observations obtained while linear regression was conducted on the fifty (50) subjects that tested positive to malaria. Results: Out of 187 subjects screened, 26.7% (50) were positive to P. falciparum. Highest malaria parasite count of 36.4% was recorded in 14-16 years age group while 20-22 years age group had the least malaria parasite count (15.4%). The result of the studied isolates indicated that out of 50 isolates analyzed for Pfcrt gene, wild type alleles accounted for 32% (16) while mutant alleles accounted for 68% (34). Alakuko Community accounted for the least number of T76 mutant alleles 10% (5) while Apado community recorded the highest number of T76 mutant gene 22% (11). For Pfmdr1 gene analysis at codon 86, isolates from Apado community showed the highest mutant type alleles (Y86) of 22% (11), while Igbonla community in Ifelodun local government had the least mutant alleles, 6% (3). Conclusion: The overall result revealed existence of mutant alleles in both the Pfcrt and Pfmdr1 genes which was higher than the wild type gene in both cases. The presence of chloroquine resistance genes among the studied population implies that alternative antimalaria drugs should be designed by pharmaceutical industry.

scholarly journals Calcium-Dependent Protein Kinase 5 Is Required for Release of Egress-Specific Organelles in Plasmodium falciparum

mBio ◽  
2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Sabrina Absalon ◽  
Karin Blomqvist ◽  
Rachel M. Rudlaff ◽  
Travis J. DeLano ◽  
Michael P. Pollastri ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Protein Kinase ◽  
Blood Cell ◽  
Red Blood Cell ◽  
Malaria Parasite ◽  
Dependent Protein Kinase ◽  
Calcium Dependent ◽  
Dependent Protein ◽  
Parasite Egress ◽  
Calcium Dependent Protein Kinase

ABSTRACT The human malaria parasite Plasmodium falciparum requires efficient egress out of an infected red blood cell for pathogenesis. This egress event is highly coordinated and is mediated by several signaling proteins, including the plant-like P. falciparum calcium-dependent protein kinase 5 (PfCDPK5). Knockdown of PfCDPK5 results in an egress block where parasites are trapped inside their host cells. The mechanism of this PfCDPK5-dependent block, however, remains unknown. Here, we show that PfCDPK5 colocalizes with a specialized set of parasite organelles known as micronemes and is required for their discharge, implicating failure of this step as the cause of the egress defect in PfCDPK5-deficient parasites. Furthermore, we show that PfCDPK5 cooperates with the P. falciparum cGMP-dependent kinase (PfPKG) to fully activate the protease cascade critical for parasite egress. The PfCDPK5-dependent arrest can be overcome by hyperactivation of PfPKG or by physical disruption of the arrested parasite, and we show that both treatments facilitate the release of the micronemes required for egress. Our results define the molecular mechanism of PfCDPK5 function and elucidate the complex signaling pathway of parasite egress. IMPORTANCE The signs and symptoms of clinical malaria result from the replication of parasites in human blood. Efficient egress of the malaria parasite Plasmodium falciparum out of an infected red blood cell is critical for pathogenesis. The P. falciparum calcium-dependent protein kinase 5 (PfCDPK5) is essential for parasite egress. Following PfCDPK5 knockdown, parasites remain trapped inside their host cell and do not egress, but the mechanism for this block remains unknown. We show that PfCDPK5 colocalizes with parasite organelles known as micronemes. We demonstrate that PfCDPK5 is critical for the discharge of these micronemes and that failure of this step is the molecular mechanism of the parasite egress arrest. We also show that hyperactivation of the cGMP-dependent kinase PKG can overcome this arrest. Our data suggest that small molecules that inhibit the egress signaling pathway could be effective antimalarial therapeutics.

scholarly journals The Plasmodium falciparum pseudoprotease SERA5 regulates the kinetics and efficiency of malaria parasite egress from host erythrocytes

2017 ◽  
Vol 13 (7) ◽  
pp. e1006453 ◽  
Author(s):  
Christine R. Collins ◽  
Fiona Hackett ◽  
Jonathan Atid ◽  
Michele Ser Ying Tan ◽  
Michael J. Blackman
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Parasite ◽  
Parasite Egress

scholarly journals Inhibition of protein N-myristoylation blocks Plasmodium falciparum intraerythrocytic development, egress and invasion

PLoS Biology ◽  
2021 ◽  
Vol 19 (10) ◽  
pp. e3001408
Author(s):  
Anja C. Schlott ◽  
Ellen Knuepfer ◽  
Judith L. Green ◽  
Philip Hobson ◽  
Aaron J. Borg ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Infected Erythrocyte ◽  
Complex Function ◽  
Pleiotropic Effect ◽  
Substantial Effect ◽  
Parasite Development ◽  
Human Malaria Parasite ◽  
Erythrocyte Invasion ◽  
Erythrocytic Cycle ◽  
Parasite Egress

We have combined chemical biology and genetic modification approaches to investigate the importance of protein myristoylation in the human malaria parasite, Plasmodium falciparum. Parasite treatment during schizogony in the last 10 to 15 hours of the erythrocytic cycle with IMP-1002, an inhibitor of N-myristoyl transferase (NMT), led to a significant blockade in parasite egress from the infected erythrocyte. Two rhoptry proteins were mislocalized in the cell, suggesting that rhoptry function is disrupted. We identified 16 NMT substrates for which myristoylation was significantly reduced by NMT inhibitor (NMTi) treatment, and, of these, 6 proteins were substantially reduced in abundance. In a viability screen, we showed that for 4 of these proteins replacement of the N-terminal glycine with alanine to prevent myristoylation had a substantial effect on parasite fitness. In detailed studies of one NMT substrate, glideosome-associated protein 45 (GAP45), loss of myristoylation had no impact on protein location or glideosome assembly, in contrast to the disruption caused by GAP45 gene deletion, but GAP45 myristoylation was essential for erythrocyte invasion. Therefore, there are at least 3 mechanisms by which inhibition of NMT can disrupt parasite development and growth: early in parasite development, leading to the inhibition of schizogony and formation of “pseudoschizonts,” which has been described previously; at the end of schizogony, with disruption of rhoptry formation, merozoite development and egress from the infected erythrocyte; and at invasion, when impairment of motor complex function prevents invasion of new erythrocytes. These results underline the importance of P. falciparum NMT as a drug target because of the pleiotropic effect of its inhibition.

scholarly journals Analysis of Antibodies Directed against Merozoite Surface Protein 1 of the Human Malaria Parasite Plasmodium falciparum

2006 ◽  
Vol 74 (2) ◽  
pp. 1313-1322 ◽  
Author(s):  
Ute Woehlbier ◽  
Christian Epp ◽  
Christian W. Kauth ◽  
Rolf Lutz ◽  
Carole A. Long ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Merozoite Surface Protein 1 ◽  
Erythrocyte Invasion ◽  
Parasite Plasmodium ◽  
Parasite Plasmodium Falciparum ◽  
Parasite Multiplication ◽  
Parasite Replication

ABSTRACT The 190-kDa merozoite surface protein 1 (MSP-1) of Plasmodium falciparum, an essential component in the parasite's life cycle, is a primary candidate for a malaria vaccine. Rabbit antibodies elicited by the heterologously produced MSP-1 processing products p83, p30, p38, and p42, derived from strain 3D7, were analyzed for the potential to inhibit in vitro erythrocyte invasion by the parasite and parasite growth. Our data show that (i) epitopes recognized by antibodies, which inhibit parasite replication, are distributed throughout the entire MSP-1 molecule; (ii) when combined, antibodies specific for different regions of MSP-1 inhibit in a strictly additive manner; (iii) anti-MSP-1 antibodies interfere with erythrocyte invasion as well as with the intraerythrocytic growth of the parasite; and (iv) antibodies raised against MSP-1 of strain 3D7 strongly cross-inhibit replication of the heterologous strain FCB-1. Accordingly, anti-MSP-1 antibodies appear to be capable of interfering with parasite multiplication at more than one level. Since the overall immunogenicity profile of MSP-1 in rabbits closely resembles that found in sera of Aotus monkeys immunized with parasite-derived MSP-1 and of humans semi-immune to malaria from whom highly inhibiting antigen-specific antibodies were recovered, we consider the findings reported here to be relevant for the development of MSP-1-based vaccines against malaria.

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