A5032304709- Malaria Research and Control
- Mosquito-borne diseases and control
- Complement system in diseases
- HIV Research and Treatment
- Computational Drug Discovery Methods
- Redox biology and oxidative stress
- Drug Transport and Resistance Mechanisms
- Vector-borne infectious diseases
- Venomous Animal Envenomation and Studies
- Invertebrate Immune Response Mechanisms
- Trypanosoma species research and implications
- Antimicrobial Peptides and Activities
- Heme Oxygenase-1 and Carbon Monoxide
- Aquaculture disease management and microbiota
- vaccines and immunoinformatics approaches
- HIV/AIDS drug development and treatment
- Insect Utilization and Effects
- Cellular transport and secretion
- Signaling Pathways in Disease
- Neonatal Health and Biochemistry
- Hemoglobinopathies and Related Disorders
- Enzyme function and inhibition
- Genomics, phytochemicals, and oxidative stress
London School of Hygiene & Tropical Medicine
2016-2024
University of London
2017-2023
Justus-Liebig-Universität Gießen
2013-2018
Heterochromatin-dependent gene silencing is central to the adaptation and survival of Plasmodium falciparum malaria parasites, allowing clonally variant expression during blood infection in humans. By assessing genome-wide heterochromatin protein 1 (HP1) occupancy, we present a comprehensive analysis landscapes across different species, strains, life cycle stages. Common targets epigenetic include fast-evolving multi-gene families encoding surface antigens small set conserved HP1-associated...
Tackling relapsing Plasmodium vivax and zoonotic knowlesi infections is critical to reducing malaria incidence mortality worldwide. Understanding the biology of these important related parasites was previously constrained by lack robust molecular genetic approaches. Here, we establish CRISPR-Cas9 genome editing in a culture-adapted P. strain define parameters for optimal homology-driven repair. We scalable protocol production repair templates PCR demonstrate flexibility system tagging...
There are no licensed vaccines against Plasmodium vivax. We conducted two phase 1/2a clinical trials to assess targeting P. vivax Duffy-binding protein region II (PvDBPII). Recombinant viral using chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) vectors as well a adjuvant formulation (PvDBPII/Matrix-M) were tested in both standard delayed dosing regimen. Volunteers underwent controlled human malaria infection (CHMI) after their last vaccination, alongside...
Significance Plasmodium knowlesi is a parasite that naturally infects cynomolgus monkeys but also major cause of severe zoonotic malaria in humans South East Asia. Comparing the genomes parasites restricted to growth culture with RBCs and those adapted human identified gene specifically required for invasion RBCs, process critical replication. This encodes normocyte-binding protein Xa, previously shown bind implicated invasion. Disruption this blocks not thus confirming key mediator...
We examine in detail the AP-2 adaptin complex from malaria parasite Plasmodium falciparum . In most studied organisms, is involved bringing material into cell outside, a process called endocytosis. Previous work shows that changes to μ subunit of can contribute drug resistance. Our experiments show essential for development blood but does not have any role clathrin-mediated This suggests specialized function has developed parasites, and this may be important understanding its impact on
In the malaria parasite Plasmodium falciparum, cellular redox potential influences signaling events, antioxidant defense, and mechanisms of drug action resistance. Until now, real-time determination in parasites has been limited because conventional approaches disrupt sub-cellular integrity. Using a glutathione biosensor comprising human glutaredoxin-1 linked to redox-sensitive green fluorescent protein (hGrx1-roGFP2), we systematically characterized basal values drug-induced changes...
Malaria is caused by Plasmodium parasites, which invade and replicate in erythrocytes. For falciparum, the major cause of severe malaria humans, a heterotrimeric complex comprised secreted parasite proteins, PfCyRPA, PfRIPR PfRH5 essential for erythrocyte invasion, mediated interaction between receptor basigin (BSG). However, whilst CyRPA RIPR are present most species, RH5 found only small Laverania subgenus. Existence analogous to PfRH5-PfCyRPA-PfRIPR targeting BSG, involvement however, has...
Abstract The symptoms of malaria occur during the blood stage infection, when parasite replicates within human red cells. parasite, Plasmodium vivax , selectively invades reticulocytes in a process which requires an interaction between ectodomain DARC receptor and Duffy-binding protein, PvDBP. Previous studies have revealed that small helical peptide from binds to region II PvDBP (PvDBP-RII). However, it is also known sulphation tyrosine residues on affects its binding these were not...
Abstract Invasion of red blood cells (RBCs) by Plasmodium merozoites is critical to their continued survival within the host. Two major protein families, Duffy binding-like proteins (DBPs/EBAs) and reticulocyte binding like (RBLs/RHs) have been studied extensively in P. falciparum are hypothesized overlapping, but roles just prior host cell entry. The zoonotic malaria parasite, knowlesi , has larger invasive contains a smaller, less redundant, DBP RBL repertoire than . One (DBPα) one RBL,...
Early phagocytosis of glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes parasitized by Plasmodium falciparum were shown to protect G6PD-deficient populations from severe malaria. Here, we investigated the mechanism a novel antimalarial series, namely 3-[substituted-benzyl]-menadiones, understand whether these NADPH-consuming redox-cyclers, which induce oxidative stress, mimic natural protection G6PD deficiency.
Plasmodium falciparum is responsible for the most severe form of human malaria. P. vivax, in contrast, widespread malaria parasite with an enormous impact on health and economy, since infection characterized by high rates relapses. Due to mild course tertiana complicated vitro culturing conditions research parasites has focused so far. The redox metabolism a promising target novel antimalarial drugs, maintaining equilibrium fundamental importance parasite. contains cytosolic glutathione...
Plasmodium knowlesi, a zoonotic parasite causing severe-to-lethal malaria disease in humans, has only recently been adapted to continuous culture with human red blood cells (RBCs). In comparison the most virulent malaria, falciparum, there are, however, few cellular tools available study its biology, particular direct investigation of RBC invasion by blood-stage P. knowlesi merozoites. This leaves our current understanding biological differences across pathogenic spp. incomplete. Here, we...
Plasmodium knowlesi is a zoonotic malaria parasite in Southeast Asia that can cause severe and fatal humans.The main hosts are Macaques, but modern diagnostic tools reveal increasing numbers of human infections.After P. falciparum, the only other capable being maintained long term vitro culture with red blood cells (RBCs).Its closer ancestry to non-falciparum parasites, more balanced AT-content, larger merozoites higher transfection efficiencies, gives some key advantages over P.falciparum...
Several unrelated classes of antimalarial compounds developed against Plasmodium falciparum target a parasite-specific P-type ATP-dependent Na
Plasmodium malariae parasites are widely observed across the tropics and sub-tropics. This slow-growing species, known to maintain chronic asymptomatic infections, has been associated with reduced antimalarial susceptibility. We analyse 251 P. genomes from 28 countries, leveraging 131,601 high-quality SNPs, demonstrate segregation of African Asian isolates. Signals recent evolutionary selection were identified in genes encoding putative surface proteins (pmmsp1) erythrocyte invasion...
Studying redox metabolism in malaria parasites is of great interest for understanding parasite biology, parasite–host interactions, and mechanisms drug action. Genetically encoded fluorescent sensors have recently been described as powerful tools determining the glutathione-dependent potential living parasites. In present study, we genomically integrated expressed ratiometric hGrx1-roGFP2 (human glutaredoxin 1 fused to reduction–oxidation sensitive green protein) sfroGFP2 (superfolder...
Malaria remains a major cause of morbidity and mortality globally. Clinical symptoms the disease arise from growth multiplication Plasmodium parasites within blood host. Thus in vitro assays to determine how drug, antibody genetic perturbations affect rate are essential for development new therapeutics improving our understanding parasite biology. As both P. falciparum knowlesi can be maintained culture with human red cells, effect antimalarial drugs inhibitory antibodies that target...
The zoonotic malaria parasite Plasmodium knowlesi is an important public health concern in Southeast Asia. Invasion of host erythrocytes essential for growth, and thus, understanding the repertoire proteins that enable this process vital identifying vaccine candidates how some species are able to cause infection. Merozoite surface protein 1 (MSP1) found all perhaps most well-studied as a potential candidate. While MSP1 encoded by single gene P. falciparum, other human infective (P. vivax,...
Plasmodium knowlesi is primarily responsible for zoonotic malaria in several Southeast Asian countries. Precise identification of the parasite blood patients presently relies on an expensive and elaborate PCR procedure because microscopic examination other available field techniques lack adequate specificity. Therefore, use a simple inexpensive dual-colour fluorescence situ hybridization (FISH) assay, analogous to FISH assays recently described falciparum vivax, was investigated as potential...
There are no licensed vaccines against Plasmodium vivax , the most common cause of malaria outside Africa.We conducted two Phase I/IIa clinical trials to assess safety, immunogenicity and efficacy targeting region II P. Duffy-binding protein (PvDBPII). Recombinant viral (using ChAd63 MVA vectors) were administered at 0, 2 months or in a delayed dosing regimen (0, 17, 19 months), whilst protein/adjuvant formulation (PvDBPII/Matrix-M™) was monthly 1, months) 14 months). Delayed regimens due...
Summary The efficacy of current antimalarial drugs is threatened by reduced susceptibility Plasmodium falciparum to artemisinin. In the Mekong region this associated with mutations in kelch propeller-encoding domain pfkelch13 , but variants other parasite proteins are also thought modulate response drug. Evidence from human and rodent studies suggests that μ-subunit AP-2 adaptin trafficking complex one such protein interest. We generated transgenic parasites encoding I592T variant pfap2μ...